Review ArticleAdult Neuroplasticity More Than 40 Years of Research

Eberhard Fuchs12 and Gabriele Fluumlgge1

1 German Primate Center Leibniz Institute for Primate Research Kellnerweg 4 37077 Gottingen Germany2Department of Neurology Medical School University of Gottingen 37075 Gottingen Germany

Correspondence should be addressed to Gabriele Flugge gfluegggwdgde

Received 15 January 2014 Accepted 9 April 2014 Published 4 May 2014

Academic Editor Paul Lucassen

Copyright copy 2014 E Fuchs and G Flugge This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Within the last four decades our view of themature vertebrate brain has changed significantly Today it is generally accepted that theadult brain is far from being fixed A number of factors such as stress adrenal and gonadal hormones neurotransmitters growthfactors certain drugs environmental stimulation learning and aging change neuronal structures and functions The processesthat these factors may induce are morphological alterations in brain areas changes in neuron morphology network alterationsincluding changes in neuronal connectivity the generation of new neurons (neurogenesis) and neurobiochemical changes Herewe review several aspects of neuroplasticity and discuss the functional implications of the neuroplastic capacities of the adult anddifferentiated brain with reference to the history of their discovery

1 Introduction

The term ldquoneuronal plasticityrdquo was already used by the ldquofatherof neurosciencerdquo Santiago Ramon y Cajal (1852-1934) whodescribed nonpathological changes in the structure of adultbrains The term stimulated a controversial discussion assome neuropathologists favored the ldquoold dogmardquo that thereis a fixed number of neurons in the adult brain that cannotbe replaced when the cells die (for review see [1]) In awider sense plasticity of the brain can be regarded as ldquotheability to make adaptive changes related to the structure andfunction of the nervous systemrdquo [2] Accordingly ldquoneuronalplasticityrdquo can stand not only for morphological changes inbrain areas for alterations in neuronal networks includingchanges in neuronal connectivity as well as the generation ofnew neurons (neurogenesis) but also for neurobiochemicalchanges We provide here a short overview of differentforms of neuroplasticity with reference to the history of theirdiscovery

2 Changes in Neuron Morphology

In the late 1960s the term ldquoneuroplasticityrdquo was introducedfor morphological changes in neurons of adult brains Using

electron microcopy Raisman [3] demonstrated an ldquoanatom-ical reorganizationrdquo of the neuropil in the septal nuclei ofadult rats after a selective lesion to distinct axons whichterminate on the neurons in those nuclei Since then manychanges in the morphology of neurons in response to variousinternal and external stimuli have been described A strongexternal stimulus that evokes numerous neuroplastic changesis stress Repeated or chronic stress changes the morphol-ogy of neurons in various brain areas Probably the mostthoroughly investigated neuromorphological change is thestress-induced regression of the geometrical length of apicaldendrites of pyramidal neurons thatwas first demonstrated inthe hippocampus [4] The hippocampus is part of the limbic-HPA (hypothalamic-pituitary-adrenal) system and regulatesthe stress response Retraction of dendrites of CA3 pyramidalneurons has been repeatedly documented after chronic stressas well as after chronic glucocorticoid administration [5ndash7]Dendritic retraction does of course reduce the surface of theneurons which diminishes the number of synapses Also neu-rons in the medial prefrontal cortex retract their dendrites inresponse to stress but the effects depend on the hemisphere[8 9] Studies on the prefrontal cortex showed that neuronsin this brain region are particularly plastic in that they changetheir dendritic morphology with the diurnal rhythm [10]

Hindawi Publishing CorporationNeural PlasticityVolume 2014 Article ID 541870 10 pageshttpdxdoiorg1011552014541870

2 Neural Plasticity

Such neuroplastic reactions are not a one-way road In theamygdala the dendritic arborization of the pyramidal andstellate neurons in the basolateral complex was enhanced bya similar chronic stress paradigm that reduces branching ofdendrites in hippocampal CA3 pyramidal neurons [11] Thebrainrsquos pronounced neuroplastic capacities are also reflectedby the fact that the synapses are replaced as soon as thestress is terminated [12] Furthermore drugs that stimulateneuroplasticity can prevent the stress-induced retraction ofdendrites in the hippocampal formation [13] A form offunctional neuroplasticity is long-term potentiation (LTP)that is the long-lasting enhancement in signal transmissionbetween two neurons after synchronous stimulation [14]

3 Neuron Death

The research on neuroplasticity in adult brains was stronglystimulated by observations that brain neurons may die forexample because of trauma or degenerative illnesses suchas Parkinsonrsquos or Alzheimerrsquos disease [15] In the late 1990sthere were reports that even the stress that an individualexperiences can kill neurons in the brain This messagewas based on studies in wild vervet monkeys that hadbeen housed in a primate center in Kenya where they diedsuddenly The animals had experienced severe stress becauseof social isolation from their group [16]The finding that theirbrains revealed dead pyramidal neurons in the hippocampusattracted great public attention as the message was reducedto ldquostress kills neuronsrdquo However it later turned out that inthis study on wild life animals the post mortem treatmentof the brain tissue had been not optimal The time betweendeath of the animals and fixation of the brains for theneuropathological analysis was obviously too long so thatmorphology of the neurons was affected to an extent that hadnothing to do with the previous stress exposure of the livinganimals Since stress raises plasma glucocorticoids (GC)monkeys were chronically treated with GC in a subsequentstudy and also the brains of these animals revealed changesin neuron morphology that were interpreted as dead ordying neurons [17] However these findings could not beconfirmed by others Instead it was recognized that themorphological analysis of pyramidal neurons is technicallydelicate It became apparent that after a subjectrsquos deathneuronsmay dramatically change their morphology and turninto ldquodark neuronsrdquo when the brain tissue has not beenfixed adequately for the histological analysis [18] When thechronic stress experiments were repeated under conditionsthat acknowledged those technical issues it turned out thatstress does not kill neurons which is definitely a goodmessage for stressed individuals [19] Further studies showedthat apoptosis (programmed cell death) in the hippocampalformation is a relatively rare event and that chronic stressmayeven reduce cell death in certain hippocampal subfields whileincreasing apoptosis in others [20] Since chronic social stressin animals is regarded as preclinical model for depressionthe finding of a lack of neuron death in stressed animalsalso shed new light on a hypothesis saying that in humansmajor depression kills neurons in the brain Indeed it was

later found that hippocampal neuron numbers in depressedsubjects do not significantly differ from the numbers inhealthy individuals [21] Also the hypothesis that chronicGC exposure leads to neuron death had to be revised Asummary of a range of studies on these issues concludedthat it is unlikely that endogenous GC can cause structuraldamage to the hippocampal formation [22] Nevertheless itis an established fact that ldquoadverse influencesrdquo such as stressdepression and chronic GC treatments may cause shrinkageof the hippocampal formation [23] However the underlyingprocesses are obviously not neuron loss but other changesin the tissue such as reductions in neuronal dendrites andfurther presumptive alterations in the neuropil that have notbeen identified in detail yet ([6 24] for review see [25])

4 Neurogenesis in Adult Vertebrates

The most appealing phenomenon of neuroplasticity appearsto be adult neurogenesis that is the generation of newneurons in adult brains Neurogenesis takes of course placein the developing central nervous system but in view ofthe fact that certain illnesses such as Parkinsonrsquos disease andmultiple sclerosis occur in adulthood the interesting questionis whether also adult brains are able to replace lost neurons

In contrast to most cells of the body such as those in thegut the skin or the blood which are constantly renewed thebrainmdashand in particular the mammalian brainmdashhas alwaysbeen regarded as a nonrenewable organ Most neurons of theadult central nervous system appear as terminally differen-tiated Although the adult brain can sometimes functionallycompensate for damage by generating new connectionsamong surviving neurons it does not have a large capacityto repair itself because most brain regions are devoid of stemcells that are necessary for neuronal regeneration This lackof neuroplasticity was first described by Santiago Ramony Cajal who stated that ldquoIn adult centers the nerve pathsare something fixed ended immutable Everything may dienothing may be regenerated It is for science of the future tochange if possible this harsh decreerdquo [26]

The ldquono new neuronsrdquo dogma was already challengedalmost five decades ago Using autoradiographywith the triti-ated DNA nucleoside 3H-thymidine Altman [27 28] gainedfirst evidence for the production of glia cells and possibly alsoof neurons in the brains of young adult rats and adult catsIn subsequent studies 10-day-old rats received 3H-thymidineand the tritium radioactivity was visualized 2 months laterin cells of the subgranular zone in the dentate gyrus [29]Unfortunately autoradiography with 3H-thymidine is a verydelicate method and it is not easy to pick up the lownumber of neurons that is generated daily in for example thedentate gyrus of adult mammals Accordingly 3H-thymidineautoradiographs produced at that time could not generallyconvince the scientific community that adult neurogenesisreally exists Thus only a limited number of experimentsfollowed the initial studies mentioned above However theneuronal character of newly generated cells in the rodentdentate gyrus was confirmed and further substantiated bydemonstrating that these newborn cells receive synaptic input

Neural Plasticity 3

and extend axons into the mossy fiber pathway that projectsto the CA3 subfield [30ndash32] Another landmark was in theearly 1980s when substantial neurogenesis was demonstratedin a vocal control nucleus of the adult canary brain [33]and a functional link between behavior song learning andthe production of new neurons was established [34] Thefinding that in songbirds (canaries zebra finches) maleshave larger song control nuclei in their brains as comparedto females indicated that the number of neurons in thoseadult birds may change with the season [35] Indeed theneuron number in song control nuclei increases in springtime when male zebra finches begin to sing and newbornneuronswere also found in theHVC (hyperstriatum ventralepars caudalis) of adult canaries [36] Studies on the HVC inbirds showed that steroid hormones play important roles inthese processes of neuroplasticity in particular the gonadalhormone testosterone [35 37]

In line with these findings Cajalrsquos statement on the fixednumber of neurons in adult brainswas further challenged as itbecame clear that even inmammals parts of the adult centralnervous system are able to replace neurons In the olfactoryepithelium of themammalian nose sensory neurons are con-tinuously generated throughout the lifespan as first shown inadult squirrel monkeys [38] This electron microscopic studyclearly showed large numbers of newborn sensory neuronsthat are produced every day in the olfactory epithelium ofthe adult animals Later it was found that also neurons in theolfactory bulb (OB) of adult mammals can be replaced Thenew OB neurons derive from the subventricular zone at thelateral ventricle where neuroblasts are generated that migratethrough the rostral migratory stream to the OB (Figure 1)The neuroblasts differentiate to functional neurons in thatcase granule cells which form synapses with mitral cells ([3940] for review see [41]) However OB neurogenesis is easierto detect than hippocampal neurogenesis and it took severalyears until there was reliable evidence that hippocampalneurogenesis does exist in adult mammals

In particular neurogenesis could long not be demon-strated in the brains of adult nonhuman primates suchas rhesus monkeys thereby leading to the assumption thatneuronal replication is not tolerated in primates In an initialstudy Rakic [42] investigated neurogenesis in adult rhesusmonkeys using 3H-thymidine examining major structuresand subdivisions of the brain including the visual motor andthe associationneocortex hippocampus andOBRakic foundldquonot a single heavily labeled cell with the morphologicalcharacteristics of a neuron in any brain in any adult animalrdquoand concluded that ldquoall neurons of the rhesus monkey brainare generated during prenatal and early postnatal liferdquo [4243] Furthermore Rakic argued that ldquoa stable population ofneurons may be a biological necessity in an organism whosesurvival relies on learned behavior acquired over a longperiod of timerdquo These statements had a profound influenceon the development of the research field in that they formedthe basis for researchers of the time to show little interest todetect neurogenesis in the adult mammalian brain

A revolution in the field of neurogenesis research tookplace when the thymidine analog 5-bromo-21015840-deoxyuridine

(BrdU) and corresponding antibodies were introduced forlabeling newborn neurons by immunohistochemistry [44]Using this newmdashand in comparison to autoradiographymdashsimple and fast technique it became clear that adult hip-pocampal neurogenesis in mammals is not restricted torodents but has been conserved throughout mammalianevolution The formation of new granule neurons was forexample demonstrated in the dentate gyrus of adult rats andtree shrews [45 46] the later species is regarded as phylo-genetically located between insectivores and primates [47]Evidence of neurogenesis in the adult primate brain derivedfrom studies in marmoset monkeys [48] a small nonhumanprimate from South America and in macaques which aretypical representatives of the nonhumanOld-World primates[49 50] Finally the existence of neurogenesis in the adulthuman brain was shown in cancer patients who were injectedwith BrdU to monitor tumor cell proliferation Some of thesepatients died from their illness and small samples of theirhippocampi were evaluated for the presence of BrdU-labeledneurons Since BrdU had been systemically administered alldividing cells were supposed to be labeled Indeed newbornneurons were detected in the dentate gyrus granule celllayer of all individuals [51] These data unequivocally showedthat adult neurogenesis is a common phenomenon acrossmammalian species It thus became generally accepted thatadult neurogenesis not only does occur in the olfactorybulb and the gyrus dentatus of the hippocampal formationof mammals but can also be detected in ldquohigherrdquo brainregions such as the neocortex [52 53] However there arestill open questions regarding the extent of neurogenesis inhomologous brain regions of different mammalian species(see below)

To detect neurogenesis in brains of adult humans thegroup of J Frisen took advantage of the increased concentra-tion of 14C in the atmosphere after nuclear bomb tests [54]After a nuclear explosion this radioisotope is increasinglyincorporated into dividing cells of living organisms includinghumans Through the determination of 14C the authorsfound that about 700 new neurons are generated daily inthe hippocampal formation of adult humans Interestinglythe 14C analysis of human brains revealed adult neurogenesisin the striatum adjacent to a site at the lateral ventriclewhere neuronal precursor cells are generated and thereare indications that the neuroblasts in the human striatumdifferentiate to interneurons [55] Surprisingly no newbornneurons could be detected with the 14C technique in theadult humanOBThesemost recent findings clearly show thatspecies and brain-region specific processes of neurogenesisawait further elucidation

Adult neurogenesis does occur not only in mammalsand birds but also in amphibians reptiles and bony fishes(for references see [56]) Despite this omnipresence of adultneurogenesis within vertebrates comparative studies haverevealed significant differences between classes So far itappears that in most mammals the generation of newneurons in adult brains takes place in two regions thesubventricular zone and the dentate gyrus and the number

4 Neural Plasticity

(2) Neurogenesis in the dentategyrus (DG)

Hip

OB

ea b c d

(1) Generation of stem

subventricularzone (SVZ)

cells in the

Stimulation by olfactory

learning

Positive modulatorsEnvironmental stimuliLearningExercise (running)EstrogensAntidepressantsmiddot middot middot

Negative modulatorsAcute and chronic stressNMDA receptor activationAgingGlucocorticoidsmiddot middot middot

DGSVZ

RMS

II

Figure 1 A schematic view on adult neurogenesis Neuronal progenitor cells are generated in the subventricular zone (SVZ) and in the dentategyrus (DG) of the hippocampal formation (Hip) (1) In the SVZ neuroepithelial progenitor cells are generated that migrate through the RMS(rostral migratory stream) to the olfactory bulb (OB)They differentiate to mature neurons and are integrated as functional elements into theneuronal olfactory circuitry (2) In the DG quiescent neural progenitors (a) become amplifying neural progenitors (b) that differentiate firstto neuroblasts (c) then to immature neurons (d) and finally to functionally mature granule neurons (e)

of newly generated neurons is small compared to the totalnumber of brain cells (Figure 1) However there are alsoreports from studies in mice that new neurons can begenerated in the adult substantia nigra although with ldquoa slowphysiological turnover of neuronsrdquo [57] In contrast in fisha huge number of neurons are continuously produced inmany areas of the adult brain [56] Also important tomentionthat in comparison with fishes reptiles and birds the rate ofneurogenesis in adult mammals decreases with age [58]

5 Regulators of Adult Neurogenesis

The existence of neurogenesis in adult brains gives hope thateven damaged brain regions can be functionally repairedIndeed injury to the adult brain such as ischemic insults stim-ulates the proliferation of subventricular zone cells and thusthe formation of neuronal precursor cells These neuroblastsmigrate along blood vessels to the damaged region (for reviewsee [41]) However only a small percentage can survivein part because inflammatory processes that occur in theischemic brain region inhibit neurogenesis and the successfulintegration of new cells into a functional neuronal network[59] Anti-inflammatory drugs can restore neurogenesis asshown in rodentmodels of peripheral inflammation and afterirradiation [60]

Knowledge about the regulation of adult neurogenesis isdefinitely a prerequisite for future therapeutic interventionsthat may take advantage of the generation of new neurons inadult brains Kempermann [61] emphasized that there is anldquoimmense spectrum of neurogenic regulatorsrdquo which reflectldquothe sensitivity of adult neurogenesis to many different typesof stimulirdquo Respective regulatory elements that are so farknown include single molecules as well as environmentalconditions that lead to changes in a large number of fac-tors which themselves influence neurogenesis Among themolecular factors that were first identified as regulators of

adult neurogenesis are sex steroids such as estrogen whichcan at least transiently stimulate neurogenesis in the dentategyrus [62] Steroid hormones have pleiotropic effects on theexpression of many genes among which are also genes whichthemselves encode regulators of neurogenesis Accordinglyin female mammals effects of steroid hormones on adultneurogenesis depend on the estrous cycle and other stagesrelated to reproductive biology [63] It is not surprising thatgrowth factors such as BDNF (brain-derived neurotrophicfactor) and VEGF (peripheral vascular endothelial growthfactor) regulate adult neurogenesis [64ndash66] Also the neuro-transmitter glutamate and astroglia have an impact on adultneurogenesis probably by generating a distinct microen-vironment that may favor the generationdifferentiation ofneuroblasts [67ndash69]The large number of factors that regulateadult neurogenesis has been reviewed before [70]

Effects of stress on neurogenesis in the dentate gyrus(the so-called hippocampal neurogenesis) have been studiedby several groups Chronic social stress in tree shrewsand other adverse stress experiences in marmoset monkeysreduced hippocampal neurogenesis [23 46 48] The effectsof social and other forms of stress depend on the stressorrsquosintensity and its duration and they may be reversible [71]Prenatal stress in rhesus monkeys has persistent effects asa reduction in neurogenesis was observed in the adolescentindividuals [72] In newborn marmoset monkeys whichwere intrauterinely exposed to the synthetic glucocorticoiddexamethasone the proliferation of putative precursor cellsbut not the differentiation into mature cells was impaired[73] Interestingly this decreased proliferation rate observedin newborn monkeys was no longer detectable in their 2-year-old siblings suggesting no long-lasting effect of prenatalhyperexposure to dexamethasone on neuronal proliferationand differentiation in the dentate gyrus of marmoset mon-keys [74]

Several authors attributed the effects of stress on neuro-genesis to the actions of glucocorticoids which are elevated in

Neural Plasticity 5

(a) (b)

(c) (d)

Figure 2 Electron micrographs of pyramidal neuron nuclei in the hippocampus of control and stressed male tree shrews (a) controlCA1 (b) stress CA1 (c) control CA3 (d) stress CA3 Note the homogeneous nucleoplasma (NP) in the controls and the large numberof heterochromatin clusters (arrow) in nuclei of CA3 pyramidal neurons in stressed animals NL nucleolus Calibration bar 2 120583m

the blood of stressed individuals Corticosteroids do indeedregulate neurogenesis and the glucocorticoid receptor antag-onist mifepristone prevented the stress-induced reduction inhippocampal neurogenesis [75] Also the mineralocorticoidreceptor appears to play a particular role as indicated by thefact that a genetic disruption of the receptor impaired adulthippocampal neurogenesis in mice [76] However elementsof the glucocorticoid system are not the only regulatoryfactors of adult neurogenesis in stress Instead as pointedout above other components of the stress cascade such asenhanced excitatory neurotransmission (increased glutamaterelease) play also a role In several preclinical models ofdepression using stress to induce depressive-like symptomsin animals certain antidepressants restored the neurogenesisthat had been impaired by the stress (see eg [23 77])Thereare indications that antidepressants activate the glucocorti-coid receptor which may increase hippocampal neurogenesis[78] However it remains an enigma whether endogenous or

synthetic substances exist that can boost adult neurogenesisvia this receptor system

The formation of new neurons is regulated by substancesderived from blood vessels and is targeted by an enormousnumber of factors [61 79] Coinciding with this view arereports demonstrating that adult neurogenesis is enhanced byphysical activity such as running [80] by learning [81] or byenvironmental enrichment [82ndash84]

6 Functional Role of Adult Neurogenesis

Soon after the discovery of adult neurogenesis it was hypoth-esized that hippocampal neurogenesis (ie the neurogenesisin the subgranular zone of the dentate gyrus a region ofthe hippocampal formation) plays a crucial role in learningand memory [81] However experimental results on therole of different forms of memory in adult rodents (egspatial learning versus associative memory) were in part

6 Neural Plasticity

20

15

10

5

Control Stress Cortisol

CA1 CA3

Relat

ive n

umbe

rnu

cleus

20

15

10

5

Relat

ive n

umbe

rnu

cleuslowast lowast lowast

lowast lowast lowast

Control Stress Cortisol

Figure 3 Relative number of heterochromatin clusters in electron micrographs from nuclei of pyramidal cells in CA1 and CA3 Data aremean plusmn SEM (119875 le 00001)

contradictory In a comprehensive review Koehl and Abrous[85] came to the conclusion that adult neurogenesis inrodents is involved ldquowhen the task requires the establishmentof relationships amongmultiple environmental cues for theflexible use of acquired informationrdquo Whether this is truefor all mammals remains to be determined as a low rate oreven absence of neurogenesis was found in the hippocampalformation of adult bats [86] and in whales [87] species withan excellent spatial working memory In the OB adult-bornnew neurons are integrated into the neuronal circuits that areresponsible for olfaction and olfactory memory respectively(for review see [88])

The fact that in animal models of depression certainantidepressants restored normal neurogenesis that had beenimpaired by stress led to the hypothesis that the benefi-cial effects of antidepressants depend on the restoration ofnormal neurogenesis [77] The volume of the hippocampalformation is reduced in patients with major depression andantidepressants can normalize hippocampal volume [89]However the hippocampal shrinkage is probably not due to adecrease in neurogenesis but rather tomore complex changesin the neural network which involve dendritic axonal andpossibly also glial alterations [24] Kempermann et al [90]proposed that ldquofailing adult hippocampal neurogenesis maynot explain major depression addiction or schizophreniabut contributes to the hippocampal aspects of the diseasesrdquoA comparison of the neural stem-cell proliferation in postmortem brain samples from patients with major depres-sion bipolar affective disorder schizophrenia and controlsubjects revealed no evidence of reduced neurogenesis inthe dentate gyrus of depressed individuals Furthermoreantidepressant treatment did not increase neural stem-cellproliferation Unexpectedly significantly reduced numbersof newly formed cells were found only in schizophrenicpatients [91] Concerning impaired neurogenesis as presump-tive cause of depression a group of experts summarized that

ldquoa lasting reduction in neurogenesisrdquo (is) ldquounlikely toproduce the full mood disorderrdquo [92] However more recentreports based on post mortem studies showed decreasednumbers of neuronal progenitor cells in the dentate gyrusof depressed patients and a selective enhancing effect ofantidepressant treatment in the anterior and middle den-tate gyrus of depressed individuals [93ndash95] To overcomethe manifold limitations of post mortem studies a futureapproach to address the question of adult neurogenesis inhumans more precisely (possibly in longitudinal studies)could be the visualization of this process in live subjectsusing advanced in vivo imaging techniques Moreover thisapproach could help answer the open questions on the role ofneurogenesis in cognitive functions and its functional impactand contribution to the etiology of depression

7 Chromatin Changes

When searching for dead neurons in the hippocampal for-mation of male tree shrews standard histology showed thatchronic social stress does not lead to neuronal death butchanges the appearance of the nuclei in the hippocampal neu-rons [96] Closer investigations revealed that chronic stressincreases the formation of heterochromatin in the nuclei ofthe hippocampal neurons [97] In this study the nuclearultrastructure of hippocampal pyramidal neurons in maletree shrews that had been exposed to daily social stress duringfour weeks according to a standard stress paradigm wasanalyzed Electron microscopic analysis revealed that in thestressed animals the nucleoplasma of CA3 pyramidal neuronsdisplayed numerous heterochromatin clusters (Figure 2)Heterochromatin is a form of condensed chromatin whoseoccurrence indicates that transcription of genes is reducedin those cells Quantification of the clusters revealing areaslarger than 1 120583m2 in the hippocampal region CA3 showed

Neural Plasticity 7

that there was more heterochromatin in stressed animalscompared to controls In contrast in area CA1 the stress hadno effect on the density of heterochromatin clusters (Figure 3[97]) Although in those days it was totally unknown whichgenes in the hippocampal nuclei were ldquosilencedrdquo by thechronic stress these morphological data indicated alreadywhat was later called ldquoepigeneticsrdquo the phenomenon thatenvironmental factors change the structure of chromatininfluence transcription and induce changes in the genome[98] Since glucocorticoid hormones are often regarded asimportant factors that convey many effects of chronic stressit was tested whether a chronic cortisol treatment wouldhave the same effects on the chromatin as the chronic socialstress Interestingly chronic cortisol changed the number ofheterochromatin clusters only in hippocampal region CA1but not in CA3 the region that is targeted by stress (Figure 3)These results indicate a site and treatment specific reactionto stress and glucocorticoid treatment in the hippocampalformation The obvious differences between chronic stressand chronic glucocorticoid treatment must be kept in mindbecause they possibly reflect different cellular pathways acti-vated by the two treatments

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] F W Stahnisch and R Nitsch ldquoSantiago Ramon y Cajalrsquosconcept of neuronal plasticity the ambiguity lives onrdquo Trendsin Neurosciences vol 25 no 11 pp 589ndash591 2002

[2] K Zilles ldquoNeuronal plasticity as an adaptive property of thecentral nervous systemrdquo Annals of Anatomy vol 174 no 5 pp383ndash391 1992

[3] G Raisman ldquoNeuronal plasticity in the septal nuclei of the adultratrdquo Brain Research vol 14 no 1 pp 25ndash48 1969

[4] Y Watanabe E Gould and B S McEwen ldquoStress inducesatrophy of apical dendrites of hippocampal CA3 pyramidalneuronsrdquo Brain Research vol 588 no 2 pp 341ndash345 1992

[5] C S Woolley E Gould and B S McEwen ldquoExposure toexcess glucocorticoids alters dendritic morphology of adulthippocampal pyramidal neuronsrdquo Brain Research vol 531 no1-2 pp 225ndash231 1990

[6] A M Magarinos B S McEwen G Flugge and E FuchsldquoChronic psychosocial stress causes apical dendritic atrophyof hippocampal CA3 pyramidal neurons in subordinate treeshrewsrdquo Journal of Neuroscience vol 16 no 10 pp 3534ndash35401996

[7] M H Kole T Costoli J M Koolhaas and E Fuchs ldquoBidi-rectional shift in the cornu ammonis 3 pyramidal dendriticorganization following brief stressrdquo Neuroscience vol 125 no2 pp 337ndash347 2004

[8] S C Cook and C L Wellman ldquoChronic stress alters dendriticmorphology in rat medial prefrontal cortexrdquo Journal of Neuro-biology vol 60 no 2 pp 236ndash248 2004

[9] C Perez-Cruz J I H Muller-Keuker U Heilbronner E Fuchsand G Flugge ldquoMorphology of pyramidal neurons in the ratprefrontal cortex lateralized dendritic remodeling by chronic

stressrdquo Neural Plasticity vol 2007 Article ID 46276 14 pages2007

[10] C Perez-Cruz M Simon G Flugge E Fuchs and B CzehldquoDiurnal rhythm and stress regulate dendritic architecture andspine density of pyramidal neurons in the rat infralimbiccortexrdquo Behavioural Brain Research vol 205 no 2 pp 406ndash4132009

[11] A Vyas R Mitra B S Shankaranarayana Rao and S Chat-tarji ldquoChronic stress induces contrasting patterns of dendriticremodeling in hippocampal and amygdaloid neuronsrdquo Journalof Neuroscience vol 22 no 15 pp 6810ndash6818 2002

[12] C Sandi H A Davies M I Cordero J J Rodriguez V IPopov andM G Stewart ldquoRapid reversal of stress induced lossof synapses in CA3 of rat hippocampus following water mazetrainingrdquo European Journal of Neuroscience vol 17 no 11 pp2447ndash2456 2003

[13] Y Watanabe E Gould D C Daniels H Cameron and B SMcEwen ldquoTianeptine attenuates stress-induced morphologicalchanges in the hippocampusrdquo European Journal of Pharmacol-ogy vol 222 no 1 pp 157ndash162 1992

[14] T V P Bliss and T Lomo ldquoLong lasting potentiation ofsynaptic transmission in the dentate area of the anaesthetizedrabbit following stimulation of the perforant pathrdquo Journal ofPhysiology vol 232 no 2 pp 331ndash356 1973

[15] H G Kuhn T D Palmer and E Fuchs ldquoAdult neurogenesisa compensatory mechanism for neuronal damagerdquo EuropeanArchives of Psychiatry and Clinical Neuroscience vol 251 no 4pp 152ndash158 2001

[16] H Uno R Tarara J G ElseM A Suleman and RM SapolskyldquoHippocampal damage associated with prolonged and fatalstress in primatesrdquo Journal of Neuroscience vol 9 no 5 pp1705ndash1711 1989

[17] R M Sapolsky H Uno C S Rebert and C E Finch ldquoHip-pocampal damage associated with prolonged glucocorticoidexposure in primatesrdquo Journal of Neuroscience vol 10 no 9 pp2897ndash2902 1990

[18] J Cammermeyer ldquoArgentophil neuronal perikarya and neu-rofibrils induced by postmortem trauma and hypertonic per-fusatesrdquo Acta Anatomica vol 105 no 1 pp 9ndash24 1979

[19] G K Vollmann-Honsdorf G Flugge and E Fuchs ldquoChronicpsychosocial stress does not affect the number of pyramidalneurons in tree shrew hippocampusrdquo Neuroscience Letters vol233 no 2-3 pp 121ndash124 1997

[20] P J Lucassen G K Vollmann-HonsdorfMGleisberg B CzehE R De Kloet and E Fuchs ldquoChronic psychosocial stressdifferentially affects apoptosis in hippocampal subregions andcortex of the adult tree shrewrdquoEuropean Journal ofNeurosciencevol 14 no 1 pp 161ndash166 2001

[21] M BMuller P J Lucassen A YassouridisW J G HoogendijkF Holsboer and D F Swaab ldquoNeither major depression norglucocorticoid treatment affects the cellular integrity of thehuman hippocampusrdquo European Journal of Neuroscience vol14 no 10 pp 1603ndash1612 2001

[22] N Sousa M M Paula-Barbosa and O F X Almeida ldquoLigandand subfield specificity of corticoid-induced neuronal loss inthe rat hippocampal formationrdquoNeuroscience vol 89 no 4 pp1079ndash1087 1999

[23] B Czeh T Michaelis T Watanabe et al ldquoStress-inducedchanges in cerebral metabolites hippocampal volume and cellproliferation are prevented by antidepressant treatment withtianeptinerdquo Proceedings of the National Academy of Sciences of

8 Neural Plasticity

the United States of America vol 98 no 22 pp 12796ndash128012001

[24] B Czeh and P J Lucassen ldquoWhat causes the hippocampalvolume decrease in depression Are neurogenesis glial changesand apoptosis implicatedrdquo European Archives of Psychiatry andClinical Neuroscience vol 257 no 5 pp 250ndash260 2007

[25] P J Lucassen J Pruessner N Sousa et al ldquoNeuropathology ofstressrdquo Acta Neuropathologica vol 127 pp 109ndash135 2014

[26] R S Cajal Degeneration and Regeneration of the NervousSystem vol 2 Hafner New York NY USA 1959

[27] J Altman ldquoAre new neurons formed in the brains of adultmammalsrdquo Science vol 135 no 3509 pp 1127ndash1128 1962

[28] J Altman ldquoAutoradiographic investigation of cell proliferationin the brains of rats and catsrdquo The Anatomical record vol 145pp 573ndash591 1963

[29] J Altman and G D Das ldquoAutoradiographic and histologicalevidence of postnatal hippocampal neurogenesis in ratsrdquo Jour-nal of Comparative Neurology vol 124 no 3 pp 319ndash335 1965

[30] M S Kaplan and J W Hinds ldquoNeurogenesis in the adult ratelectronmicroscopic analysis of light radioautographsrdquo Sciencevol 197 no 4308 pp 1092ndash1094 1977

[31] M S Kaplan ldquoNeurogenesis in the 3-month-old rat visualcortexrdquo Journal of Comparative Neurology vol 195 no 2 pp323ndash338 1981

[32] B B Stanfield and J E Trice ldquoEvidence that granule cellsgenerated in the dentate gyrus of adult rats extend axonalprojectionsrdquo Experimental Brain Research vol 72 no 2 pp399ndash406 1988

[33] S A Goldman and F Nottebohm ldquoNeuronal productionmigration and differentiation in a vocal control nucleus of theadult female canary brainrdquo Proceedings of the National Academyof Sciences of the United States of America vol 80 no 8 pp2390ndash2394 1983

[34] A Alvarez-Buylla M Theelen and F Nottebohm ldquoBirth ofprojection neurons in the higher vocal center of the canaryforebrain before during and after song learningrdquoProceedings ofthe National Academy of Sciences of the United States of Americavol 85 no 22 pp 8722ndash8726 1988

[35] F Nottebohm and A P Arnold ldquoSexual dimorphism in vocalcontrol areas of the songbird brainrdquo Science vol 194 no 4261pp 211ndash213 1976

[36] F Nottebohm ldquoFrom bird song to neurogenesisrdquo ScientificAmerican vol 260 no 2 pp 74ndash79 1989

[37] A P Arnold and R A Gorski ldquoGonadal steroid induction ofstructural sex differences in the central nervous systemrdquoAnnualReview of Neuroscience vol 7 pp 413ndash442 1984

[38] P P C Graziadei M S Karlan G A M Graziadei and J JBernstein ldquoNeurogenesis of sensory neurons in the primateolfactory system after section of the fila olfactoriardquo BrainResearch vol 186 no 2 pp 289ndash300 1980

[39] D R Kornack and P Rakic ldquoThe generation migration anddifferentiation of olfactory neurons in the adult primate brainrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 98 no 8 pp 4752ndash4757 2001

[40] A Carleton L T Petreanu R Lansford A Alvarez-Buylla andP-M Lledo ldquoBecoming a new neuron in the adult olfactorybulbrdquo Nature Neuroscience vol 6 no 5 pp 507ndash518 2003

[41] M Sawada and K Sawamoto ldquoMechanisms of neurogenesis inthe normal and injured adult brainrdquo Keio Journal of Medicinevol 62 pp 13ndash28 2013

[42] P Rakic ldquoLimits of neurogenesis in primatesrdquo Science vol 227no 4690 pp 1054ndash1056 1985

[43] M F Eckenhoff and P Rakic ldquoNature and fate of proliferativecells in the hippocampal dentate gyrus during the life span ofthe rhesus monkeyrdquo Journal of Neuroscience vol 8 no 8 pp2729ndash2747 1988

[44] M W Miller and R S Nowakowski ldquoUse of bromodeox-yuridine-immunohistochemistry to examine the proliferationmigration and time of origin of cells in the central nervoussystemrdquo Brain Research vol 457 no 1 pp 44ndash52 1988

[45] H A Cameron ldquoAdult neurogenesis is regulated by adrenalsteroids in the dentate gyrusrdquo Neuroscience vol 61 no 2 pp203ndash209 1994

[46] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997

[47] Y Fan Z Y Huang C C Cao et al ldquoGenome of the Chinesetree shrewrdquo Nature Communications vol 4 article 1426 2013

[48] E Gould P Tanapat B S Mcewen G Flugge and E FuchsldquoProliferation of granule cell precursors in the dentate gyrusof adult monkeys is diminished by stressrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 95 no 6 pp 3168ndash3171 1998

[49] E Gould A J Reeves M Fallah P Tanapat C G Grossand E Fuchs ldquoHippocampal neurogenesis in adult Old Worldprimatesrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 9 pp 5263ndash5267 1999

[50] D R Kornack and P Rakic ldquoContinuation of neurogenesis inthe hippocampus of the adult macaque monkeyrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 96 no 10 pp 5768ndash5773 1999

[51] P S Eriksson E Perfilieva T Bjork-Eriksson et al ldquoNeurogen-esis in the adult human hippocampusrdquo Nature Medicine vol 4no 11 pp 1313ndash1317 1998

[52] G Kempermann and F H Gage ldquoNeurogenesis in the adulthippocampusrdquo Novartis Foundation Symposium vol 231 pp220ndash235 2000

[53] E Gould ldquoHow widespread is adult neurogenesis in mam-malsrdquo Nature Reviews Neuroscience vol 8 no 6 pp 481ndash4882007

[54] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 pp1219ndash1227 2013

[55] A Ernst K Alkass S Bernard et al ldquoNeurogenesis in thestriatum of the adult human brainrdquoCell vol 156 pp 1072ndash10832014

[56] G K H Zupanc ldquoNeurogenesis and neuronal regeneration inthe adult fish brainrdquo Journal of Comparative Physiology A vol192 no 6 pp 649ndash670 2006

[57] M Zhao S Momma K Delfani et al ldquoEvidence for neuroge-nesis in the adult mammalian substantia nigrardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 100 no 13 pp 7925ndash7930 2003

[58] I Amrein K Isler andH P Lipp ldquoComparing adult hippocam-pal neurogenesis in mammalian species and orders Influenceof chronological age and life history stagerdquo European Journal ofNeuroscience vol 34 no 6 pp 978ndash987 2011

[59] L A Voloboueva and R G Giffard ldquoInflammation mito-chondria and the inhibition of adult neurogenesisrdquo Journal ofNeuroscience Research vol 89 no 12 pp 1989ndash1996 2011

Neural Plasticity 9

[60] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003

[61] G Kempermann ldquoSeven principles in the regulation of adultneurogenesisrdquo European Journal of Neuroscience vol 33 no 6pp 1018ndash1024 2011

[62] P Tanapat N B Hastings A J Reeves and E Gould ldquoEstrogenstimulates a transient increase in the number of new neuronsin the dentate gyrus of the adult female ratrdquo Journal ofNeuroscience vol 19 no 14 pp 5792ndash5801 1999

[63] J L Pawluski S Brummelte C K Barha T M Crozier andL A M Galea ldquoEffects of steroid hormones on neurogenesisin the hippocampus of the adult female rodent during theestrous cycle pregnancy lactation and agingrdquo Frontiers inNeuroendocrinology vol 30 no 3 pp 343ndash357 2009

[64] M Sairanen G Lucas P Ernfors M Castren and E CastrenldquoBrain-derived neurotrophic factor and antidepressant drugshave different but coordinated effects on neuronal turnoverproliferation and survival in the adult dentate gyrusrdquo Journalof Neuroscience vol 25 no 5 pp 1089ndash1094 2005

[65] K Jin Y Zhu Y Sun X O Mao L Xie and D A Green-berg ldquoVascular endothelial growth factor (VEGF) stimulatesneurogenesis in vitro and in vivordquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no18 pp 11946ndash11950 2002

[66] K Fabel K Fabel B Tam et al ldquoVEGF is necessary for exercise-induced adult hippocampal neurogenesisrdquo European Journal ofNeuroscience vol 18 no 10 pp 2803ndash2812 2003

[67] H A Cameron B S McEwen and E Gould ldquoRegulation ofadult neurogenesis by excitatory input and NMDA receptoractivation in the dentate gyrusrdquo Journal of Neuroscience vol 15no 6 pp 4687ndash4692 1995

[68] B Seri J M Garcıa-Verdugo B S McEwen and A Alvarez-Buylla ldquoAstrocytes give rise to new neurons in the adultmammalian hippocampusrdquo Journal of Neuroscience vol 21 no18 pp 7153ndash7160 2001

[69] H Song C F Stevens and F H Gage ldquoAstroglia induceneurogenesis from adult neural stem cellsrdquo Nature vol 417 no6884 pp 39ndash44 2002

[70] C ZhaoWDeng and F H Gage ldquoMechanisms and FunctionalImplications of Adult Neurogenesisrdquo Cell vol 132 no 4 pp645ndash660 2008

[71] V M Heine S Maslam J Zareno M Joels and P J LucassenldquoSuppressed proliferation and apoptotic changes in the ratdentate gyrus after acute and chronic stress are reversiblerdquoEuropean Journal of Neuroscience vol 19 no 1 pp 131ndash1442004

[72] C L Coe M Kramer B Czeh et al ldquoPrenatal stress diminishesneurogenesis in the dentate gyrus of juvenile Rhesus monkeysrdquoBiological Psychiatry vol 54 no 10 pp 1025ndash1034 2003

[73] S C Tauber C Schlumbohm L Schilg E Fuchs R Nau and JGerber ldquoIntrauterine exposure to dexamethasone impairs pro-liferation but not neuronal differentiation in the dentate gyrusof newborn commonmarmosetmonkeysrdquoBrain Pathology vol16 no 3 pp 209ndash217 2006

[74] S C Tauber S Bunkowski C Schlumbohm et al ldquoNo long-term effect two years after intrauterine exposure to dexametha-sone on dentate gyrus volume neuronal proliferation and dif-ferentiation in common marmoset monkeysrdquo Brain Pathologyvol 18 no 4 pp 497ndash503 2008

[75] C A Oomen J L Mayer E R De Kloet M Joels and PJ Lucassen ldquoBrief treatment with the glucocorticoid receptor

antagonist mifepristone normalizes the reduction in neurogen-esis after chronic stressrdquo European Journal of Neuroscience vol26 no 12 pp 3395ndash3401 2007

[76] P Gass O Kretz D P Wolfer et al ldquoGenetic disruption ofmineralocorticoid receptor leads to impaired neurogenesis andgranule cell degeneration in the hippocampus of adult micerdquoEMBO Reports vol 1 no 5 pp 447ndash451 2000

[77] J E Malberg A J Eisch E J Nestler and R S DumanldquoChronic antidepressant treatment increases neurogenesis inadult rat hippocampusrdquo Journal of Neuroscience vol 20 no 24pp 9104ndash9110 2000

[78] C Anacker P A Zunszain A Cattaneo et al ldquoAntidepressantsincrease human hippocampal neurogenesis by activating theglucocorticoid receptorrdquoMolecular Psychiatry vol 16 no 7 pp738ndash750 2011

[79] M SawadaMMatsumoto andK Sawamoto ldquoVascular regula-tion of adult neurogenesis under physiological and pathologicalconditionsrdquo Frontiers in Neuroscience vol 8 article 53 2014

[80] H van Praag G Kempermann and F H Gage ldquoNeuralConsequences of environmental enrichmentrdquo Nature ReviewsNeuroscience vol 1 no 3 pp 191ndash198 2000

[81] E Gould P Tanapat N B Hastings and T J Shors ldquoNeurogen-esis in adulthood a posible role in learningrdquoTrends in CognitiveSciences vol 3 no 5 pp 186ndash192 1999

[82] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 pp 569ndash578 1999

[83] G Kempermann D Gast and F H Gage ldquoNeuroplasticityin old age sustained fivefold induction of hippocampal neu-rogenesis by long-term environmental enrichmentrdquo Annals ofNeurology vol 52 no 2 pp 135ndash143 2002

[84] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006

[85] M Koehl and D N Abrous ldquoA new chapter in the field ofmemory adult hippocampal neurogenesisrdquo European Journalof Neuroscience vol 33 no 6 pp 1101ndash1114 2011

[86] I Amrein D K N Dechmann Y Winter and H-P LippldquoAbsent or low rate of adult neurogenesis in the hippocampusof bats (Chiroptera)rdquo PLoS ONE vol 2 no 5 article e455 2007

[87] N Patzke M A Spocter K A Karlsson et al ldquoIn contrastto many other mammals cetaceans have relatively small hip-pocampi that appear to lack adult neurogenesisrdquoBrain Structureand Function 2013

[88] G Lepousez M T Valley and P M Lledo ldquoThe impact of adultneurogenesis on olfactory bulb circuits and computationsrdquoAnnual Review of Physiology vol 75 pp 339ndash363 2013

[89] Y I Sheline M H Gado and H C Kraemer ldquoUntreateddepression and hippocampal volume lossrdquo American Journal ofPsychiatry vol 160 no 8 pp 1516ndash1518 2003

[90] G Kempermann J Krebs and K Fabel ldquoThe contribution offailing adult hippocampal neurogenesis to psychiatric disor-dersrdquo Current Opinion in Psychiatry vol 21 no 3 pp 290ndash2952008

[91] A Reif S Fritzen M Finger et al ldquoNeural stem cell prolif-eration is decreased in schizophrenia but not in depressionrdquoMolecular Psychiatry vol 11 no 5 pp 514ndash522 2006

10 Neural Plasticity

[92] P J Lucassen P Meerlo A S Naylor et al ldquoRegulation ofadult neurogenesis by stress sleep disruption exercise andinflammation Implications for depression and antidepressantactionrdquo European Neuropsychopharmacology vol 20 no 1 pp1ndash17 2010

[93] M Boldrini M D Underwood R Hen et al ldquoAntidepressantsincrease neural progenitor cells in the human hippocampusrdquoNeuropsychopharmacology vol 34 no 11 pp 2376ndash2389 2009

[94] M Boldrini R Hen M D Underwood et al ldquoHippocampalangiogenesis and progenitor cell proliferation are increasedwith antidepressant use in major depressionrdquo Biological Psychi-atry vol 72 pp 562ndash571 2012

[95] M Boldrini A N Santiago R Hen et al ldquoHippocam-pal granule neuron number and dentate gyrus volume inantidepressant-treated and untreated major depressionrdquo Neu-ropsychopharmacology vol 38 pp 1068ndash1077 2013

[96] E Fuchs H Uno and G Flugge ldquoChronic psychosocial stressinduces morphological alterations in hippocampal pyramidalneurons of the tree shrewrdquo Brain Research vol 673 no 2 pp275ndash282 1995

[97] G Vollmann-Honsdorf Lichtmikroskopische und ultrastruk-turelle morphologische Veranderungen in der Hippocampusfor-mation von Tupaia (Tupaia belangeri) als Folge von chronischpsychosozialem Streszlig [PhD thesis] Faculty of Biology Univer-sity of Bielefeld 2001

[98] B SMcEwen ldquoBrain on stress how the social environment getsunder the skinrdquo Proceedings of the National Academy of Sciencesof theUnited States of America vol 109 supplement 2 pp 17180ndash17185 2012

Neural Plasticity 3

and extend axons into the mossy fiber pathway that projectsto the CA3 subfield [30ndash32] Another landmark was in theearly 1980s when substantial neurogenesis was demonstratedin a vocal control nucleus of the adult canary brain [33]and a functional link between behavior song learning andthe production of new neurons was established [34] Thefinding that in songbirds (canaries zebra finches) maleshave larger song control nuclei in their brains as comparedto females indicated that the number of neurons in thoseadult birds may change with the season [35] Indeed theneuron number in song control nuclei increases in springtime when male zebra finches begin to sing and newbornneuronswere also found in theHVC (hyperstriatum ventralepars caudalis) of adult canaries [36] Studies on the HVC inbirds showed that steroid hormones play important roles inthese processes of neuroplasticity in particular the gonadalhormone testosterone [35 37]

In line with these findings Cajalrsquos statement on the fixednumber of neurons in adult brainswas further challenged as itbecame clear that even inmammals parts of the adult centralnervous system are able to replace neurons In the olfactoryepithelium of themammalian nose sensory neurons are con-tinuously generated throughout the lifespan as first shown inadult squirrel monkeys [38] This electron microscopic studyclearly showed large numbers of newborn sensory neuronsthat are produced every day in the olfactory epithelium ofthe adult animals Later it was found that also neurons in theolfactory bulb (OB) of adult mammals can be replaced Thenew OB neurons derive from the subventricular zone at thelateral ventricle where neuroblasts are generated that migratethrough the rostral migratory stream to the OB (Figure 1)The neuroblasts differentiate to functional neurons in thatcase granule cells which form synapses with mitral cells ([3940] for review see [41]) However OB neurogenesis is easierto detect than hippocampal neurogenesis and it took severalyears until there was reliable evidence that hippocampalneurogenesis does exist in adult mammals

In particular neurogenesis could long not be demon-strated in the brains of adult nonhuman primates suchas rhesus monkeys thereby leading to the assumption thatneuronal replication is not tolerated in primates In an initialstudy Rakic [42] investigated neurogenesis in adult rhesusmonkeys using 3H-thymidine examining major structuresand subdivisions of the brain including the visual motor andthe associationneocortex hippocampus andOBRakic foundldquonot a single heavily labeled cell with the morphologicalcharacteristics of a neuron in any brain in any adult animalrdquoand concluded that ldquoall neurons of the rhesus monkey brainare generated during prenatal and early postnatal liferdquo [4243] Furthermore Rakic argued that ldquoa stable population ofneurons may be a biological necessity in an organism whosesurvival relies on learned behavior acquired over a longperiod of timerdquo These statements had a profound influenceon the development of the research field in that they formedthe basis for researchers of the time to show little interest todetect neurogenesis in the adult mammalian brain

A revolution in the field of neurogenesis research tookplace when the thymidine analog 5-bromo-21015840-deoxyuridine

(BrdU) and corresponding antibodies were introduced forlabeling newborn neurons by immunohistochemistry [44]Using this newmdashand in comparison to autoradiographymdashsimple and fast technique it became clear that adult hip-pocampal neurogenesis in mammals is not restricted torodents but has been conserved throughout mammalianevolution The formation of new granule neurons was forexample demonstrated in the dentate gyrus of adult rats andtree shrews [45 46] the later species is regarded as phylo-genetically located between insectivores and primates [47]Evidence of neurogenesis in the adult primate brain derivedfrom studies in marmoset monkeys [48] a small nonhumanprimate from South America and in macaques which aretypical representatives of the nonhumanOld-World primates[49 50] Finally the existence of neurogenesis in the adulthuman brain was shown in cancer patients who were injectedwith BrdU to monitor tumor cell proliferation Some of thesepatients died from their illness and small samples of theirhippocampi were evaluated for the presence of BrdU-labeledneurons Since BrdU had been systemically administered alldividing cells were supposed to be labeled Indeed newbornneurons were detected in the dentate gyrus granule celllayer of all individuals [51] These data unequivocally showedthat adult neurogenesis is a common phenomenon acrossmammalian species It thus became generally accepted thatadult neurogenesis not only does occur in the olfactorybulb and the gyrus dentatus of the hippocampal formationof mammals but can also be detected in ldquohigherrdquo brainregions such as the neocortex [52 53] However there arestill open questions regarding the extent of neurogenesis inhomologous brain regions of different mammalian species(see below)

To detect neurogenesis in brains of adult humans thegroup of J Frisen took advantage of the increased concentra-tion of 14C in the atmosphere after nuclear bomb tests [54]After a nuclear explosion this radioisotope is increasinglyincorporated into dividing cells of living organisms includinghumans Through the determination of 14C the authorsfound that about 700 new neurons are generated daily inthe hippocampal formation of adult humans Interestinglythe 14C analysis of human brains revealed adult neurogenesisin the striatum adjacent to a site at the lateral ventriclewhere neuronal precursor cells are generated and thereare indications that the neuroblasts in the human striatumdifferentiate to interneurons [55] Surprisingly no newbornneurons could be detected with the 14C technique in theadult humanOBThesemost recent findings clearly show thatspecies and brain-region specific processes of neurogenesisawait further elucidation

Adult neurogenesis does occur not only in mammalsand birds but also in amphibians reptiles and bony fishes(for references see [56]) Despite this omnipresence of adultneurogenesis within vertebrates comparative studies haverevealed significant differences between classes So far itappears that in most mammals the generation of newneurons in adult brains takes place in two regions thesubventricular zone and the dentate gyrus and the number

4 Neural Plasticity

(2) Neurogenesis in the dentategyrus (DG)

Hip

OB

ea b c d

(1) Generation of stem

subventricularzone (SVZ)

cells in the

Stimulation by olfactory

learning

Positive modulatorsEnvironmental stimuliLearningExercise (running)EstrogensAntidepressantsmiddot middot middot

Negative modulatorsAcute and chronic stressNMDA receptor activationAgingGlucocorticoidsmiddot middot middot

DGSVZ

RMS

II

Figure 1 A schematic view on adult neurogenesis Neuronal progenitor cells are generated in the subventricular zone (SVZ) and in the dentategyrus (DG) of the hippocampal formation (Hip) (1) In the SVZ neuroepithelial progenitor cells are generated that migrate through the RMS(rostral migratory stream) to the olfactory bulb (OB)They differentiate to mature neurons and are integrated as functional elements into theneuronal olfactory circuitry (2) In the DG quiescent neural progenitors (a) become amplifying neural progenitors (b) that differentiate firstto neuroblasts (c) then to immature neurons (d) and finally to functionally mature granule neurons (e)

of newly generated neurons is small compared to the totalnumber of brain cells (Figure 1) However there are alsoreports from studies in mice that new neurons can begenerated in the adult substantia nigra although with ldquoa slowphysiological turnover of neuronsrdquo [57] In contrast in fisha huge number of neurons are continuously produced inmany areas of the adult brain [56] Also important tomentionthat in comparison with fishes reptiles and birds the rate ofneurogenesis in adult mammals decreases with age [58]

5 Regulators of Adult Neurogenesis

The existence of neurogenesis in adult brains gives hope thateven damaged brain regions can be functionally repairedIndeed injury to the adult brain such as ischemic insults stim-ulates the proliferation of subventricular zone cells and thusthe formation of neuronal precursor cells These neuroblastsmigrate along blood vessels to the damaged region (for reviewsee [41]) However only a small percentage can survivein part because inflammatory processes that occur in theischemic brain region inhibit neurogenesis and the successfulintegration of new cells into a functional neuronal network[59] Anti-inflammatory drugs can restore neurogenesis asshown in rodentmodels of peripheral inflammation and afterirradiation [60]

Knowledge about the regulation of adult neurogenesis isdefinitely a prerequisite for future therapeutic interventionsthat may take advantage of the generation of new neurons inadult brains Kempermann [61] emphasized that there is anldquoimmense spectrum of neurogenic regulatorsrdquo which reflectldquothe sensitivity of adult neurogenesis to many different typesof stimulirdquo Respective regulatory elements that are so farknown include single molecules as well as environmentalconditions that lead to changes in a large number of fac-tors which themselves influence neurogenesis Among themolecular factors that were first identified as regulators of

adult neurogenesis are sex steroids such as estrogen whichcan at least transiently stimulate neurogenesis in the dentategyrus [62] Steroid hormones have pleiotropic effects on theexpression of many genes among which are also genes whichthemselves encode regulators of neurogenesis Accordinglyin female mammals effects of steroid hormones on adultneurogenesis depend on the estrous cycle and other stagesrelated to reproductive biology [63] It is not surprising thatgrowth factors such as BDNF (brain-derived neurotrophicfactor) and VEGF (peripheral vascular endothelial growthfactor) regulate adult neurogenesis [64ndash66] Also the neuro-transmitter glutamate and astroglia have an impact on adultneurogenesis probably by generating a distinct microen-vironment that may favor the generationdifferentiation ofneuroblasts [67ndash69]The large number of factors that regulateadult neurogenesis has been reviewed before [70]

Effects of stress on neurogenesis in the dentate gyrus(the so-called hippocampal neurogenesis) have been studiedby several groups Chronic social stress in tree shrewsand other adverse stress experiences in marmoset monkeysreduced hippocampal neurogenesis [23 46 48] The effectsof social and other forms of stress depend on the stressorrsquosintensity and its duration and they may be reversible [71]Prenatal stress in rhesus monkeys has persistent effects asa reduction in neurogenesis was observed in the adolescentindividuals [72] In newborn marmoset monkeys whichwere intrauterinely exposed to the synthetic glucocorticoiddexamethasone the proliferation of putative precursor cellsbut not the differentiation into mature cells was impaired[73] Interestingly this decreased proliferation rate observedin newborn monkeys was no longer detectable in their 2-year-old siblings suggesting no long-lasting effect of prenatalhyperexposure to dexamethasone on neuronal proliferationand differentiation in the dentate gyrus of marmoset mon-keys [74]

Several authors attributed the effects of stress on neuro-genesis to the actions of glucocorticoids which are elevated in

Neural Plasticity 5

(a) (b)

(c) (d)

Figure 2 Electron micrographs of pyramidal neuron nuclei in the hippocampus of control and stressed male tree shrews (a) controlCA1 (b) stress CA1 (c) control CA3 (d) stress CA3 Note the homogeneous nucleoplasma (NP) in the controls and the large numberof heterochromatin clusters (arrow) in nuclei of CA3 pyramidal neurons in stressed animals NL nucleolus Calibration bar 2 120583m

the blood of stressed individuals Corticosteroids do indeedregulate neurogenesis and the glucocorticoid receptor antag-onist mifepristone prevented the stress-induced reduction inhippocampal neurogenesis [75] Also the mineralocorticoidreceptor appears to play a particular role as indicated by thefact that a genetic disruption of the receptor impaired adulthippocampal neurogenesis in mice [76] However elementsof the glucocorticoid system are not the only regulatoryfactors of adult neurogenesis in stress Instead as pointedout above other components of the stress cascade such asenhanced excitatory neurotransmission (increased glutamaterelease) play also a role In several preclinical models ofdepression using stress to induce depressive-like symptomsin animals certain antidepressants restored the neurogenesisthat had been impaired by the stress (see eg [23 77])Thereare indications that antidepressants activate the glucocorti-coid receptor which may increase hippocampal neurogenesis[78] However it remains an enigma whether endogenous or

synthetic substances exist that can boost adult neurogenesisvia this receptor system

The formation of new neurons is regulated by substancesderived from blood vessels and is targeted by an enormousnumber of factors [61 79] Coinciding with this view arereports demonstrating that adult neurogenesis is enhanced byphysical activity such as running [80] by learning [81] or byenvironmental enrichment [82ndash84]

6 Functional Role of Adult Neurogenesis

Soon after the discovery of adult neurogenesis it was hypoth-esized that hippocampal neurogenesis (ie the neurogenesisin the subgranular zone of the dentate gyrus a region ofthe hippocampal formation) plays a crucial role in learningand memory [81] However experimental results on therole of different forms of memory in adult rodents (egspatial learning versus associative memory) were in part

6 Neural Plasticity

20

15

10

5

Control Stress Cortisol

CA1 CA3

Relat

ive n

umbe

rnu

cleus

20

15

10

5

Relat

ive n

umbe

rnu

cleuslowast lowast lowast

lowast lowast lowast

Control Stress Cortisol

Figure 3 Relative number of heterochromatin clusters in electron micrographs from nuclei of pyramidal cells in CA1 and CA3 Data aremean plusmn SEM (119875 le 00001)

contradictory In a comprehensive review Koehl and Abrous[85] came to the conclusion that adult neurogenesis inrodents is involved ldquowhen the task requires the establishmentof relationships amongmultiple environmental cues for theflexible use of acquired informationrdquo Whether this is truefor all mammals remains to be determined as a low rate oreven absence of neurogenesis was found in the hippocampalformation of adult bats [86] and in whales [87] species withan excellent spatial working memory In the OB adult-bornnew neurons are integrated into the neuronal circuits that areresponsible for olfaction and olfactory memory respectively(for review see [88])

The fact that in animal models of depression certainantidepressants restored normal neurogenesis that had beenimpaired by stress led to the hypothesis that the benefi-cial effects of antidepressants depend on the restoration ofnormal neurogenesis [77] The volume of the hippocampalformation is reduced in patients with major depression andantidepressants can normalize hippocampal volume [89]However the hippocampal shrinkage is probably not due to adecrease in neurogenesis but rather tomore complex changesin the neural network which involve dendritic axonal andpossibly also glial alterations [24] Kempermann et al [90]proposed that ldquofailing adult hippocampal neurogenesis maynot explain major depression addiction or schizophreniabut contributes to the hippocampal aspects of the diseasesrdquoA comparison of the neural stem-cell proliferation in postmortem brain samples from patients with major depres-sion bipolar affective disorder schizophrenia and controlsubjects revealed no evidence of reduced neurogenesis inthe dentate gyrus of depressed individuals Furthermoreantidepressant treatment did not increase neural stem-cellproliferation Unexpectedly significantly reduced numbersof newly formed cells were found only in schizophrenicpatients [91] Concerning impaired neurogenesis as presump-tive cause of depression a group of experts summarized that

ldquoa lasting reduction in neurogenesisrdquo (is) ldquounlikely toproduce the full mood disorderrdquo [92] However more recentreports based on post mortem studies showed decreasednumbers of neuronal progenitor cells in the dentate gyrusof depressed patients and a selective enhancing effect ofantidepressant treatment in the anterior and middle den-tate gyrus of depressed individuals [93ndash95] To overcomethe manifold limitations of post mortem studies a futureapproach to address the question of adult neurogenesis inhumans more precisely (possibly in longitudinal studies)could be the visualization of this process in live subjectsusing advanced in vivo imaging techniques Moreover thisapproach could help answer the open questions on the role ofneurogenesis in cognitive functions and its functional impactand contribution to the etiology of depression

7 Chromatin Changes

When searching for dead neurons in the hippocampal for-mation of male tree shrews standard histology showed thatchronic social stress does not lead to neuronal death butchanges the appearance of the nuclei in the hippocampal neu-rons [96] Closer investigations revealed that chronic stressincreases the formation of heterochromatin in the nuclei ofthe hippocampal neurons [97] In this study the nuclearultrastructure of hippocampal pyramidal neurons in maletree shrews that had been exposed to daily social stress duringfour weeks according to a standard stress paradigm wasanalyzed Electron microscopic analysis revealed that in thestressed animals the nucleoplasma of CA3 pyramidal neuronsdisplayed numerous heterochromatin clusters (Figure 2)Heterochromatin is a form of condensed chromatin whoseoccurrence indicates that transcription of genes is reducedin those cells Quantification of the clusters revealing areaslarger than 1 120583m2 in the hippocampal region CA3 showed

Neural Plasticity 7

that there was more heterochromatin in stressed animalscompared to controls In contrast in area CA1 the stress hadno effect on the density of heterochromatin clusters (Figure 3[97]) Although in those days it was totally unknown whichgenes in the hippocampal nuclei were ldquosilencedrdquo by thechronic stress these morphological data indicated alreadywhat was later called ldquoepigeneticsrdquo the phenomenon thatenvironmental factors change the structure of chromatininfluence transcription and induce changes in the genome[98] Since glucocorticoid hormones are often regarded asimportant factors that convey many effects of chronic stressit was tested whether a chronic cortisol treatment wouldhave the same effects on the chromatin as the chronic socialstress Interestingly chronic cortisol changed the number ofheterochromatin clusters only in hippocampal region CA1but not in CA3 the region that is targeted by stress (Figure 3)These results indicate a site and treatment specific reactionto stress and glucocorticoid treatment in the hippocampalformation The obvious differences between chronic stressand chronic glucocorticoid treatment must be kept in mindbecause they possibly reflect different cellular pathways acti-vated by the two treatments

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] F W Stahnisch and R Nitsch ldquoSantiago Ramon y Cajalrsquosconcept of neuronal plasticity the ambiguity lives onrdquo Trendsin Neurosciences vol 25 no 11 pp 589ndash591 2002

[2] K Zilles ldquoNeuronal plasticity as an adaptive property of thecentral nervous systemrdquo Annals of Anatomy vol 174 no 5 pp383ndash391 1992

[3] G Raisman ldquoNeuronal plasticity in the septal nuclei of the adultratrdquo Brain Research vol 14 no 1 pp 25ndash48 1969

[4] Y Watanabe E Gould and B S McEwen ldquoStress inducesatrophy of apical dendrites of hippocampal CA3 pyramidalneuronsrdquo Brain Research vol 588 no 2 pp 341ndash345 1992

[5] C S Woolley E Gould and B S McEwen ldquoExposure toexcess glucocorticoids alters dendritic morphology of adulthippocampal pyramidal neuronsrdquo Brain Research vol 531 no1-2 pp 225ndash231 1990

[6] A M Magarinos B S McEwen G Flugge and E FuchsldquoChronic psychosocial stress causes apical dendritic atrophyof hippocampal CA3 pyramidal neurons in subordinate treeshrewsrdquo Journal of Neuroscience vol 16 no 10 pp 3534ndash35401996

[7] M H Kole T Costoli J M Koolhaas and E Fuchs ldquoBidi-rectional shift in the cornu ammonis 3 pyramidal dendriticorganization following brief stressrdquo Neuroscience vol 125 no2 pp 337ndash347 2004

[8] S C Cook and C L Wellman ldquoChronic stress alters dendriticmorphology in rat medial prefrontal cortexrdquo Journal of Neuro-biology vol 60 no 2 pp 236ndash248 2004

[9] C Perez-Cruz J I H Muller-Keuker U Heilbronner E Fuchsand G Flugge ldquoMorphology of pyramidal neurons in the ratprefrontal cortex lateralized dendritic remodeling by chronic

stressrdquo Neural Plasticity vol 2007 Article ID 46276 14 pages2007

[10] C Perez-Cruz M Simon G Flugge E Fuchs and B CzehldquoDiurnal rhythm and stress regulate dendritic architecture andspine density of pyramidal neurons in the rat infralimbiccortexrdquo Behavioural Brain Research vol 205 no 2 pp 406ndash4132009

[11] A Vyas R Mitra B S Shankaranarayana Rao and S Chat-tarji ldquoChronic stress induces contrasting patterns of dendriticremodeling in hippocampal and amygdaloid neuronsrdquo Journalof Neuroscience vol 22 no 15 pp 6810ndash6818 2002

[12] C Sandi H A Davies M I Cordero J J Rodriguez V IPopov andM G Stewart ldquoRapid reversal of stress induced lossof synapses in CA3 of rat hippocampus following water mazetrainingrdquo European Journal of Neuroscience vol 17 no 11 pp2447ndash2456 2003

[13] Y Watanabe E Gould D C Daniels H Cameron and B SMcEwen ldquoTianeptine attenuates stress-induced morphologicalchanges in the hippocampusrdquo European Journal of Pharmacol-ogy vol 222 no 1 pp 157ndash162 1992

[14] T V P Bliss and T Lomo ldquoLong lasting potentiation ofsynaptic transmission in the dentate area of the anaesthetizedrabbit following stimulation of the perforant pathrdquo Journal ofPhysiology vol 232 no 2 pp 331ndash356 1973

[15] H G Kuhn T D Palmer and E Fuchs ldquoAdult neurogenesisa compensatory mechanism for neuronal damagerdquo EuropeanArchives of Psychiatry and Clinical Neuroscience vol 251 no 4pp 152ndash158 2001

[16] H Uno R Tarara J G ElseM A Suleman and RM SapolskyldquoHippocampal damage associated with prolonged and fatalstress in primatesrdquo Journal of Neuroscience vol 9 no 5 pp1705ndash1711 1989

[17] R M Sapolsky H Uno C S Rebert and C E Finch ldquoHip-pocampal damage associated with prolonged glucocorticoidexposure in primatesrdquo Journal of Neuroscience vol 10 no 9 pp2897ndash2902 1990

[18] J Cammermeyer ldquoArgentophil neuronal perikarya and neu-rofibrils induced by postmortem trauma and hypertonic per-fusatesrdquo Acta Anatomica vol 105 no 1 pp 9ndash24 1979

[19] G K Vollmann-Honsdorf G Flugge and E Fuchs ldquoChronicpsychosocial stress does not affect the number of pyramidalneurons in tree shrew hippocampusrdquo Neuroscience Letters vol233 no 2-3 pp 121ndash124 1997

[20] P J Lucassen G K Vollmann-HonsdorfMGleisberg B CzehE R De Kloet and E Fuchs ldquoChronic psychosocial stressdifferentially affects apoptosis in hippocampal subregions andcortex of the adult tree shrewrdquoEuropean Journal ofNeurosciencevol 14 no 1 pp 161ndash166 2001

[21] M BMuller P J Lucassen A YassouridisW J G HoogendijkF Holsboer and D F Swaab ldquoNeither major depression norglucocorticoid treatment affects the cellular integrity of thehuman hippocampusrdquo European Journal of Neuroscience vol14 no 10 pp 1603ndash1612 2001

[22] N Sousa M M Paula-Barbosa and O F X Almeida ldquoLigandand subfield specificity of corticoid-induced neuronal loss inthe rat hippocampal formationrdquoNeuroscience vol 89 no 4 pp1079ndash1087 1999

[23] B Czeh T Michaelis T Watanabe et al ldquoStress-inducedchanges in cerebral metabolites hippocampal volume and cellproliferation are prevented by antidepressant treatment withtianeptinerdquo Proceedings of the National Academy of Sciences of

8 Neural Plasticity

the United States of America vol 98 no 22 pp 12796ndash128012001

[24] B Czeh and P J Lucassen ldquoWhat causes the hippocampalvolume decrease in depression Are neurogenesis glial changesand apoptosis implicatedrdquo European Archives of Psychiatry andClinical Neuroscience vol 257 no 5 pp 250ndash260 2007

[25] P J Lucassen J Pruessner N Sousa et al ldquoNeuropathology ofstressrdquo Acta Neuropathologica vol 127 pp 109ndash135 2014

[26] R S Cajal Degeneration and Regeneration of the NervousSystem vol 2 Hafner New York NY USA 1959

[27] J Altman ldquoAre new neurons formed in the brains of adultmammalsrdquo Science vol 135 no 3509 pp 1127ndash1128 1962

[28] J Altman ldquoAutoradiographic investigation of cell proliferationin the brains of rats and catsrdquo The Anatomical record vol 145pp 573ndash591 1963

[29] J Altman and G D Das ldquoAutoradiographic and histologicalevidence of postnatal hippocampal neurogenesis in ratsrdquo Jour-nal of Comparative Neurology vol 124 no 3 pp 319ndash335 1965

[30] M S Kaplan and J W Hinds ldquoNeurogenesis in the adult ratelectronmicroscopic analysis of light radioautographsrdquo Sciencevol 197 no 4308 pp 1092ndash1094 1977

[31] M S Kaplan ldquoNeurogenesis in the 3-month-old rat visualcortexrdquo Journal of Comparative Neurology vol 195 no 2 pp323ndash338 1981

[32] B B Stanfield and J E Trice ldquoEvidence that granule cellsgenerated in the dentate gyrus of adult rats extend axonalprojectionsrdquo Experimental Brain Research vol 72 no 2 pp399ndash406 1988

[33] S A Goldman and F Nottebohm ldquoNeuronal productionmigration and differentiation in a vocal control nucleus of theadult female canary brainrdquo Proceedings of the National Academyof Sciences of the United States of America vol 80 no 8 pp2390ndash2394 1983

[34] A Alvarez-Buylla M Theelen and F Nottebohm ldquoBirth ofprojection neurons in the higher vocal center of the canaryforebrain before during and after song learningrdquoProceedings ofthe National Academy of Sciences of the United States of Americavol 85 no 22 pp 8722ndash8726 1988

[35] F Nottebohm and A P Arnold ldquoSexual dimorphism in vocalcontrol areas of the songbird brainrdquo Science vol 194 no 4261pp 211ndash213 1976

[36] F Nottebohm ldquoFrom bird song to neurogenesisrdquo ScientificAmerican vol 260 no 2 pp 74ndash79 1989

[37] A P Arnold and R A Gorski ldquoGonadal steroid induction ofstructural sex differences in the central nervous systemrdquoAnnualReview of Neuroscience vol 7 pp 413ndash442 1984

[38] P P C Graziadei M S Karlan G A M Graziadei and J JBernstein ldquoNeurogenesis of sensory neurons in the primateolfactory system after section of the fila olfactoriardquo BrainResearch vol 186 no 2 pp 289ndash300 1980

[39] D R Kornack and P Rakic ldquoThe generation migration anddifferentiation of olfactory neurons in the adult primate brainrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 98 no 8 pp 4752ndash4757 2001

[40] A Carleton L T Petreanu R Lansford A Alvarez-Buylla andP-M Lledo ldquoBecoming a new neuron in the adult olfactorybulbrdquo Nature Neuroscience vol 6 no 5 pp 507ndash518 2003

[41] M Sawada and K Sawamoto ldquoMechanisms of neurogenesis inthe normal and injured adult brainrdquo Keio Journal of Medicinevol 62 pp 13ndash28 2013

[42] P Rakic ldquoLimits of neurogenesis in primatesrdquo Science vol 227no 4690 pp 1054ndash1056 1985

[43] M F Eckenhoff and P Rakic ldquoNature and fate of proliferativecells in the hippocampal dentate gyrus during the life span ofthe rhesus monkeyrdquo Journal of Neuroscience vol 8 no 8 pp2729ndash2747 1988

[44] M W Miller and R S Nowakowski ldquoUse of bromodeox-yuridine-immunohistochemistry to examine the proliferationmigration and time of origin of cells in the central nervoussystemrdquo Brain Research vol 457 no 1 pp 44ndash52 1988

[45] H A Cameron ldquoAdult neurogenesis is regulated by adrenalsteroids in the dentate gyrusrdquo Neuroscience vol 61 no 2 pp203ndash209 1994

[46] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997

[47] Y Fan Z Y Huang C C Cao et al ldquoGenome of the Chinesetree shrewrdquo Nature Communications vol 4 article 1426 2013

[48] E Gould P Tanapat B S Mcewen G Flugge and E FuchsldquoProliferation of granule cell precursors in the dentate gyrusof adult monkeys is diminished by stressrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 95 no 6 pp 3168ndash3171 1998

[49] E Gould A J Reeves M Fallah P Tanapat C G Grossand E Fuchs ldquoHippocampal neurogenesis in adult Old Worldprimatesrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 9 pp 5263ndash5267 1999

[50] D R Kornack and P Rakic ldquoContinuation of neurogenesis inthe hippocampus of the adult macaque monkeyrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 96 no 10 pp 5768ndash5773 1999

[51] P S Eriksson E Perfilieva T Bjork-Eriksson et al ldquoNeurogen-esis in the adult human hippocampusrdquo Nature Medicine vol 4no 11 pp 1313ndash1317 1998

[52] G Kempermann and F H Gage ldquoNeurogenesis in the adulthippocampusrdquo Novartis Foundation Symposium vol 231 pp220ndash235 2000

[53] E Gould ldquoHow widespread is adult neurogenesis in mam-malsrdquo Nature Reviews Neuroscience vol 8 no 6 pp 481ndash4882007

[54] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 pp1219ndash1227 2013

[55] A Ernst K Alkass S Bernard et al ldquoNeurogenesis in thestriatum of the adult human brainrdquoCell vol 156 pp 1072ndash10832014

[56] G K H Zupanc ldquoNeurogenesis and neuronal regeneration inthe adult fish brainrdquo Journal of Comparative Physiology A vol192 no 6 pp 649ndash670 2006

[57] M Zhao S Momma K Delfani et al ldquoEvidence for neuroge-nesis in the adult mammalian substantia nigrardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 100 no 13 pp 7925ndash7930 2003

[58] I Amrein K Isler andH P Lipp ldquoComparing adult hippocam-pal neurogenesis in mammalian species and orders Influenceof chronological age and life history stagerdquo European Journal ofNeuroscience vol 34 no 6 pp 978ndash987 2011

[59] L A Voloboueva and R G Giffard ldquoInflammation mito-chondria and the inhibition of adult neurogenesisrdquo Journal ofNeuroscience Research vol 89 no 12 pp 1989ndash1996 2011

Neural Plasticity 9

[60] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003

[61] G Kempermann ldquoSeven principles in the regulation of adultneurogenesisrdquo European Journal of Neuroscience vol 33 no 6pp 1018ndash1024 2011

[62] P Tanapat N B Hastings A J Reeves and E Gould ldquoEstrogenstimulates a transient increase in the number of new neuronsin the dentate gyrus of the adult female ratrdquo Journal ofNeuroscience vol 19 no 14 pp 5792ndash5801 1999

[63] J L Pawluski S Brummelte C K Barha T M Crozier andL A M Galea ldquoEffects of steroid hormones on neurogenesisin the hippocampus of the adult female rodent during theestrous cycle pregnancy lactation and agingrdquo Frontiers inNeuroendocrinology vol 30 no 3 pp 343ndash357 2009

[64] M Sairanen G Lucas P Ernfors M Castren and E CastrenldquoBrain-derived neurotrophic factor and antidepressant drugshave different but coordinated effects on neuronal turnoverproliferation and survival in the adult dentate gyrusrdquo Journalof Neuroscience vol 25 no 5 pp 1089ndash1094 2005

[65] K Jin Y Zhu Y Sun X O Mao L Xie and D A Green-berg ldquoVascular endothelial growth factor (VEGF) stimulatesneurogenesis in vitro and in vivordquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no18 pp 11946ndash11950 2002

[66] K Fabel K Fabel B Tam et al ldquoVEGF is necessary for exercise-induced adult hippocampal neurogenesisrdquo European Journal ofNeuroscience vol 18 no 10 pp 2803ndash2812 2003

[67] H A Cameron B S McEwen and E Gould ldquoRegulation ofadult neurogenesis by excitatory input and NMDA receptoractivation in the dentate gyrusrdquo Journal of Neuroscience vol 15no 6 pp 4687ndash4692 1995

[68] B Seri J M Garcıa-Verdugo B S McEwen and A Alvarez-Buylla ldquoAstrocytes give rise to new neurons in the adultmammalian hippocampusrdquo Journal of Neuroscience vol 21 no18 pp 7153ndash7160 2001

[69] H Song C F Stevens and F H Gage ldquoAstroglia induceneurogenesis from adult neural stem cellsrdquo Nature vol 417 no6884 pp 39ndash44 2002

[70] C ZhaoWDeng and F H Gage ldquoMechanisms and FunctionalImplications of Adult Neurogenesisrdquo Cell vol 132 no 4 pp645ndash660 2008

[71] V M Heine S Maslam J Zareno M Joels and P J LucassenldquoSuppressed proliferation and apoptotic changes in the ratdentate gyrus after acute and chronic stress are reversiblerdquoEuropean Journal of Neuroscience vol 19 no 1 pp 131ndash1442004

[72] C L Coe M Kramer B Czeh et al ldquoPrenatal stress diminishesneurogenesis in the dentate gyrus of juvenile Rhesus monkeysrdquoBiological Psychiatry vol 54 no 10 pp 1025ndash1034 2003

[73] S C Tauber C Schlumbohm L Schilg E Fuchs R Nau and JGerber ldquoIntrauterine exposure to dexamethasone impairs pro-liferation but not neuronal differentiation in the dentate gyrusof newborn commonmarmosetmonkeysrdquoBrain Pathology vol16 no 3 pp 209ndash217 2006

[74] S C Tauber S Bunkowski C Schlumbohm et al ldquoNo long-term effect two years after intrauterine exposure to dexametha-sone on dentate gyrus volume neuronal proliferation and dif-ferentiation in common marmoset monkeysrdquo Brain Pathologyvol 18 no 4 pp 497ndash503 2008

[75] C A Oomen J L Mayer E R De Kloet M Joels and PJ Lucassen ldquoBrief treatment with the glucocorticoid receptor

antagonist mifepristone normalizes the reduction in neurogen-esis after chronic stressrdquo European Journal of Neuroscience vol26 no 12 pp 3395ndash3401 2007

[76] P Gass O Kretz D P Wolfer et al ldquoGenetic disruption ofmineralocorticoid receptor leads to impaired neurogenesis andgranule cell degeneration in the hippocampus of adult micerdquoEMBO Reports vol 1 no 5 pp 447ndash451 2000

[77] J E Malberg A J Eisch E J Nestler and R S DumanldquoChronic antidepressant treatment increases neurogenesis inadult rat hippocampusrdquo Journal of Neuroscience vol 20 no 24pp 9104ndash9110 2000

[78] C Anacker P A Zunszain A Cattaneo et al ldquoAntidepressantsincrease human hippocampal neurogenesis by activating theglucocorticoid receptorrdquoMolecular Psychiatry vol 16 no 7 pp738ndash750 2011

[79] M SawadaMMatsumoto andK Sawamoto ldquoVascular regula-tion of adult neurogenesis under physiological and pathologicalconditionsrdquo Frontiers in Neuroscience vol 8 article 53 2014

[80] H van Praag G Kempermann and F H Gage ldquoNeuralConsequences of environmental enrichmentrdquo Nature ReviewsNeuroscience vol 1 no 3 pp 191ndash198 2000

[81] E Gould P Tanapat N B Hastings and T J Shors ldquoNeurogen-esis in adulthood a posible role in learningrdquoTrends in CognitiveSciences vol 3 no 5 pp 186ndash192 1999

[82] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 pp 569ndash578 1999

[83] G Kempermann D Gast and F H Gage ldquoNeuroplasticityin old age sustained fivefold induction of hippocampal neu-rogenesis by long-term environmental enrichmentrdquo Annals ofNeurology vol 52 no 2 pp 135ndash143 2002

[84] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006

[85] M Koehl and D N Abrous ldquoA new chapter in the field ofmemory adult hippocampal neurogenesisrdquo European Journalof Neuroscience vol 33 no 6 pp 1101ndash1114 2011

[86] I Amrein D K N Dechmann Y Winter and H-P LippldquoAbsent or low rate of adult neurogenesis in the hippocampusof bats (Chiroptera)rdquo PLoS ONE vol 2 no 5 article e455 2007

[87] N Patzke M A Spocter K A Karlsson et al ldquoIn contrastto many other mammals cetaceans have relatively small hip-pocampi that appear to lack adult neurogenesisrdquoBrain Structureand Function 2013

[88] G Lepousez M T Valley and P M Lledo ldquoThe impact of adultneurogenesis on olfactory bulb circuits and computationsrdquoAnnual Review of Physiology vol 75 pp 339ndash363 2013

[89] Y I Sheline M H Gado and H C Kraemer ldquoUntreateddepression and hippocampal volume lossrdquo American Journal ofPsychiatry vol 160 no 8 pp 1516ndash1518 2003

[90] G Kempermann J Krebs and K Fabel ldquoThe contribution offailing adult hippocampal neurogenesis to psychiatric disor-dersrdquo Current Opinion in Psychiatry vol 21 no 3 pp 290ndash2952008

[91] A Reif S Fritzen M Finger et al ldquoNeural stem cell prolif-eration is decreased in schizophrenia but not in depressionrdquoMolecular Psychiatry vol 11 no 5 pp 514ndash522 2006

10 Neural Plasticity

[92] P J Lucassen P Meerlo A S Naylor et al ldquoRegulation ofadult neurogenesis by stress sleep disruption exercise andinflammation Implications for depression and antidepressantactionrdquo European Neuropsychopharmacology vol 20 no 1 pp1ndash17 2010

[93] M Boldrini M D Underwood R Hen et al ldquoAntidepressantsincrease neural progenitor cells in the human hippocampusrdquoNeuropsychopharmacology vol 34 no 11 pp 2376ndash2389 2009

[94] M Boldrini R Hen M D Underwood et al ldquoHippocampalangiogenesis and progenitor cell proliferation are increasedwith antidepressant use in major depressionrdquo Biological Psychi-atry vol 72 pp 562ndash571 2012

[95] M Boldrini A N Santiago R Hen et al ldquoHippocam-pal granule neuron number and dentate gyrus volume inantidepressant-treated and untreated major depressionrdquo Neu-ropsychopharmacology vol 38 pp 1068ndash1077 2013

[96] E Fuchs H Uno and G Flugge ldquoChronic psychosocial stressinduces morphological alterations in hippocampal pyramidalneurons of the tree shrewrdquo Brain Research vol 673 no 2 pp275ndash282 1995

[97] G Vollmann-Honsdorf Lichtmikroskopische und ultrastruk-turelle morphologische Veranderungen in der Hippocampusfor-mation von Tupaia (Tupaia belangeri) als Folge von chronischpsychosozialem Streszlig [PhD thesis] Faculty of Biology Univer-sity of Bielefeld 2001

[98] B SMcEwen ldquoBrain on stress how the social environment getsunder the skinrdquo Proceedings of the National Academy of Sciencesof theUnited States of America vol 109 supplement 2 pp 17180ndash17185 2012

4 Neural Plasticity

(2) Neurogenesis in the dentategyrus (DG)

Hip

OB

ea b c d

(1) Generation of stem

subventricularzone (SVZ)

cells in the

Stimulation by olfactory

learning

Positive modulatorsEnvironmental stimuliLearningExercise (running)EstrogensAntidepressantsmiddot middot middot

Negative modulatorsAcute and chronic stressNMDA receptor activationAgingGlucocorticoidsmiddot middot middot

DGSVZ

RMS

II

Figure 1 A schematic view on adult neurogenesis Neuronal progenitor cells are generated in the subventricular zone (SVZ) and in the dentategyrus (DG) of the hippocampal formation (Hip) (1) In the SVZ neuroepithelial progenitor cells are generated that migrate through the RMS(rostral migratory stream) to the olfactory bulb (OB)They differentiate to mature neurons and are integrated as functional elements into theneuronal olfactory circuitry (2) In the DG quiescent neural progenitors (a) become amplifying neural progenitors (b) that differentiate firstto neuroblasts (c) then to immature neurons (d) and finally to functionally mature granule neurons (e)

of newly generated neurons is small compared to the totalnumber of brain cells (Figure 1) However there are alsoreports from studies in mice that new neurons can begenerated in the adult substantia nigra although with ldquoa slowphysiological turnover of neuronsrdquo [57] In contrast in fisha huge number of neurons are continuously produced inmany areas of the adult brain [56] Also important tomentionthat in comparison with fishes reptiles and birds the rate ofneurogenesis in adult mammals decreases with age [58]

5 Regulators of Adult Neurogenesis

The existence of neurogenesis in adult brains gives hope thateven damaged brain regions can be functionally repairedIndeed injury to the adult brain such as ischemic insults stim-ulates the proliferation of subventricular zone cells and thusthe formation of neuronal precursor cells These neuroblastsmigrate along blood vessels to the damaged region (for reviewsee [41]) However only a small percentage can survivein part because inflammatory processes that occur in theischemic brain region inhibit neurogenesis and the successfulintegration of new cells into a functional neuronal network[59] Anti-inflammatory drugs can restore neurogenesis asshown in rodentmodels of peripheral inflammation and afterirradiation [60]

Knowledge about the regulation of adult neurogenesis isdefinitely a prerequisite for future therapeutic interventionsthat may take advantage of the generation of new neurons inadult brains Kempermann [61] emphasized that there is anldquoimmense spectrum of neurogenic regulatorsrdquo which reflectldquothe sensitivity of adult neurogenesis to many different typesof stimulirdquo Respective regulatory elements that are so farknown include single molecules as well as environmentalconditions that lead to changes in a large number of fac-tors which themselves influence neurogenesis Among themolecular factors that were first identified as regulators of

adult neurogenesis are sex steroids such as estrogen whichcan at least transiently stimulate neurogenesis in the dentategyrus [62] Steroid hormones have pleiotropic effects on theexpression of many genes among which are also genes whichthemselves encode regulators of neurogenesis Accordinglyin female mammals effects of steroid hormones on adultneurogenesis depend on the estrous cycle and other stagesrelated to reproductive biology [63] It is not surprising thatgrowth factors such as BDNF (brain-derived neurotrophicfactor) and VEGF (peripheral vascular endothelial growthfactor) regulate adult neurogenesis [64ndash66] Also the neuro-transmitter glutamate and astroglia have an impact on adultneurogenesis probably by generating a distinct microen-vironment that may favor the generationdifferentiation ofneuroblasts [67ndash69]The large number of factors that regulateadult neurogenesis has been reviewed before [70]

Effects of stress on neurogenesis in the dentate gyrus(the so-called hippocampal neurogenesis) have been studiedby several groups Chronic social stress in tree shrewsand other adverse stress experiences in marmoset monkeysreduced hippocampal neurogenesis [23 46 48] The effectsof social and other forms of stress depend on the stressorrsquosintensity and its duration and they may be reversible [71]Prenatal stress in rhesus monkeys has persistent effects asa reduction in neurogenesis was observed in the adolescentindividuals [72] In newborn marmoset monkeys whichwere intrauterinely exposed to the synthetic glucocorticoiddexamethasone the proliferation of putative precursor cellsbut not the differentiation into mature cells was impaired[73] Interestingly this decreased proliferation rate observedin newborn monkeys was no longer detectable in their 2-year-old siblings suggesting no long-lasting effect of prenatalhyperexposure to dexamethasone on neuronal proliferationand differentiation in the dentate gyrus of marmoset mon-keys [74]

Several authors attributed the effects of stress on neuro-genesis to the actions of glucocorticoids which are elevated in

Neural Plasticity 5

(a) (b)

(c) (d)

Figure 2 Electron micrographs of pyramidal neuron nuclei in the hippocampus of control and stressed male tree shrews (a) controlCA1 (b) stress CA1 (c) control CA3 (d) stress CA3 Note the homogeneous nucleoplasma (NP) in the controls and the large numberof heterochromatin clusters (arrow) in nuclei of CA3 pyramidal neurons in stressed animals NL nucleolus Calibration bar 2 120583m

the blood of stressed individuals Corticosteroids do indeedregulate neurogenesis and the glucocorticoid receptor antag-onist mifepristone prevented the stress-induced reduction inhippocampal neurogenesis [75] Also the mineralocorticoidreceptor appears to play a particular role as indicated by thefact that a genetic disruption of the receptor impaired adulthippocampal neurogenesis in mice [76] However elementsof the glucocorticoid system are not the only regulatoryfactors of adult neurogenesis in stress Instead as pointedout above other components of the stress cascade such asenhanced excitatory neurotransmission (increased glutamaterelease) play also a role In several preclinical models ofdepression using stress to induce depressive-like symptomsin animals certain antidepressants restored the neurogenesisthat had been impaired by the stress (see eg [23 77])Thereare indications that antidepressants activate the glucocorti-coid receptor which may increase hippocampal neurogenesis[78] However it remains an enigma whether endogenous or

synthetic substances exist that can boost adult neurogenesisvia this receptor system

The formation of new neurons is regulated by substancesderived from blood vessels and is targeted by an enormousnumber of factors [61 79] Coinciding with this view arereports demonstrating that adult neurogenesis is enhanced byphysical activity such as running [80] by learning [81] or byenvironmental enrichment [82ndash84]

6 Functional Role of Adult Neurogenesis

Soon after the discovery of adult neurogenesis it was hypoth-esized that hippocampal neurogenesis (ie the neurogenesisin the subgranular zone of the dentate gyrus a region ofthe hippocampal formation) plays a crucial role in learningand memory [81] However experimental results on therole of different forms of memory in adult rodents (egspatial learning versus associative memory) were in part

6 Neural Plasticity

20

15

10

5

Control Stress Cortisol

CA1 CA3

Relat

ive n

umbe

rnu

cleus

20

15

10

5

Relat

ive n

umbe

rnu

cleuslowast lowast lowast

lowast lowast lowast

Control Stress Cortisol

Figure 3 Relative number of heterochromatin clusters in electron micrographs from nuclei of pyramidal cells in CA1 and CA3 Data aremean plusmn SEM (119875 le 00001)

contradictory In a comprehensive review Koehl and Abrous[85] came to the conclusion that adult neurogenesis inrodents is involved ldquowhen the task requires the establishmentof relationships amongmultiple environmental cues for theflexible use of acquired informationrdquo Whether this is truefor all mammals remains to be determined as a low rate oreven absence of neurogenesis was found in the hippocampalformation of adult bats [86] and in whales [87] species withan excellent spatial working memory In the OB adult-bornnew neurons are integrated into the neuronal circuits that areresponsible for olfaction and olfactory memory respectively(for review see [88])

The fact that in animal models of depression certainantidepressants restored normal neurogenesis that had beenimpaired by stress led to the hypothesis that the benefi-cial effects of antidepressants depend on the restoration ofnormal neurogenesis [77] The volume of the hippocampalformation is reduced in patients with major depression andantidepressants can normalize hippocampal volume [89]However the hippocampal shrinkage is probably not due to adecrease in neurogenesis but rather tomore complex changesin the neural network which involve dendritic axonal andpossibly also glial alterations [24] Kempermann et al [90]proposed that ldquofailing adult hippocampal neurogenesis maynot explain major depression addiction or schizophreniabut contributes to the hippocampal aspects of the diseasesrdquoA comparison of the neural stem-cell proliferation in postmortem brain samples from patients with major depres-sion bipolar affective disorder schizophrenia and controlsubjects revealed no evidence of reduced neurogenesis inthe dentate gyrus of depressed individuals Furthermoreantidepressant treatment did not increase neural stem-cellproliferation Unexpectedly significantly reduced numbersof newly formed cells were found only in schizophrenicpatients [91] Concerning impaired neurogenesis as presump-tive cause of depression a group of experts summarized that

ldquoa lasting reduction in neurogenesisrdquo (is) ldquounlikely toproduce the full mood disorderrdquo [92] However more recentreports based on post mortem studies showed decreasednumbers of neuronal progenitor cells in the dentate gyrusof depressed patients and a selective enhancing effect ofantidepressant treatment in the anterior and middle den-tate gyrus of depressed individuals [93ndash95] To overcomethe manifold limitations of post mortem studies a futureapproach to address the question of adult neurogenesis inhumans more precisely (possibly in longitudinal studies)could be the visualization of this process in live subjectsusing advanced in vivo imaging techniques Moreover thisapproach could help answer the open questions on the role ofneurogenesis in cognitive functions and its functional impactand contribution to the etiology of depression

7 Chromatin Changes

When searching for dead neurons in the hippocampal for-mation of male tree shrews standard histology showed thatchronic social stress does not lead to neuronal death butchanges the appearance of the nuclei in the hippocampal neu-rons [96] Closer investigations revealed that chronic stressincreases the formation of heterochromatin in the nuclei ofthe hippocampal neurons [97] In this study the nuclearultrastructure of hippocampal pyramidal neurons in maletree shrews that had been exposed to daily social stress duringfour weeks according to a standard stress paradigm wasanalyzed Electron microscopic analysis revealed that in thestressed animals the nucleoplasma of CA3 pyramidal neuronsdisplayed numerous heterochromatin clusters (Figure 2)Heterochromatin is a form of condensed chromatin whoseoccurrence indicates that transcription of genes is reducedin those cells Quantification of the clusters revealing areaslarger than 1 120583m2 in the hippocampal region CA3 showed

Neural Plasticity 7

that there was more heterochromatin in stressed animalscompared to controls In contrast in area CA1 the stress hadno effect on the density of heterochromatin clusters (Figure 3[97]) Although in those days it was totally unknown whichgenes in the hippocampal nuclei were ldquosilencedrdquo by thechronic stress these morphological data indicated alreadywhat was later called ldquoepigeneticsrdquo the phenomenon thatenvironmental factors change the structure of chromatininfluence transcription and induce changes in the genome[98] Since glucocorticoid hormones are often regarded asimportant factors that convey many effects of chronic stressit was tested whether a chronic cortisol treatment wouldhave the same effects on the chromatin as the chronic socialstress Interestingly chronic cortisol changed the number ofheterochromatin clusters only in hippocampal region CA1but not in CA3 the region that is targeted by stress (Figure 3)These results indicate a site and treatment specific reactionto stress and glucocorticoid treatment in the hippocampalformation The obvious differences between chronic stressand chronic glucocorticoid treatment must be kept in mindbecause they possibly reflect different cellular pathways acti-vated by the two treatments

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] F W Stahnisch and R Nitsch ldquoSantiago Ramon y Cajalrsquosconcept of neuronal plasticity the ambiguity lives onrdquo Trendsin Neurosciences vol 25 no 11 pp 589ndash591 2002

[2] K Zilles ldquoNeuronal plasticity as an adaptive property of thecentral nervous systemrdquo Annals of Anatomy vol 174 no 5 pp383ndash391 1992

[3] G Raisman ldquoNeuronal plasticity in the septal nuclei of the adultratrdquo Brain Research vol 14 no 1 pp 25ndash48 1969

[4] Y Watanabe E Gould and B S McEwen ldquoStress inducesatrophy of apical dendrites of hippocampal CA3 pyramidalneuronsrdquo Brain Research vol 588 no 2 pp 341ndash345 1992

[5] C S Woolley E Gould and B S McEwen ldquoExposure toexcess glucocorticoids alters dendritic morphology of adulthippocampal pyramidal neuronsrdquo Brain Research vol 531 no1-2 pp 225ndash231 1990

[6] A M Magarinos B S McEwen G Flugge and E FuchsldquoChronic psychosocial stress causes apical dendritic atrophyof hippocampal CA3 pyramidal neurons in subordinate treeshrewsrdquo Journal of Neuroscience vol 16 no 10 pp 3534ndash35401996

[7] M H Kole T Costoli J M Koolhaas and E Fuchs ldquoBidi-rectional shift in the cornu ammonis 3 pyramidal dendriticorganization following brief stressrdquo Neuroscience vol 125 no2 pp 337ndash347 2004

[8] S C Cook and C L Wellman ldquoChronic stress alters dendriticmorphology in rat medial prefrontal cortexrdquo Journal of Neuro-biology vol 60 no 2 pp 236ndash248 2004

[9] C Perez-Cruz J I H Muller-Keuker U Heilbronner E Fuchsand G Flugge ldquoMorphology of pyramidal neurons in the ratprefrontal cortex lateralized dendritic remodeling by chronic

stressrdquo Neural Plasticity vol 2007 Article ID 46276 14 pages2007

[10] C Perez-Cruz M Simon G Flugge E Fuchs and B CzehldquoDiurnal rhythm and stress regulate dendritic architecture andspine density of pyramidal neurons in the rat infralimbiccortexrdquo Behavioural Brain Research vol 205 no 2 pp 406ndash4132009

[11] A Vyas R Mitra B S Shankaranarayana Rao and S Chat-tarji ldquoChronic stress induces contrasting patterns of dendriticremodeling in hippocampal and amygdaloid neuronsrdquo Journalof Neuroscience vol 22 no 15 pp 6810ndash6818 2002

[12] C Sandi H A Davies M I Cordero J J Rodriguez V IPopov andM G Stewart ldquoRapid reversal of stress induced lossof synapses in CA3 of rat hippocampus following water mazetrainingrdquo European Journal of Neuroscience vol 17 no 11 pp2447ndash2456 2003

[13] Y Watanabe E Gould D C Daniels H Cameron and B SMcEwen ldquoTianeptine attenuates stress-induced morphologicalchanges in the hippocampusrdquo European Journal of Pharmacol-ogy vol 222 no 1 pp 157ndash162 1992

[14] T V P Bliss and T Lomo ldquoLong lasting potentiation ofsynaptic transmission in the dentate area of the anaesthetizedrabbit following stimulation of the perforant pathrdquo Journal ofPhysiology vol 232 no 2 pp 331ndash356 1973

[15] H G Kuhn T D Palmer and E Fuchs ldquoAdult neurogenesisa compensatory mechanism for neuronal damagerdquo EuropeanArchives of Psychiatry and Clinical Neuroscience vol 251 no 4pp 152ndash158 2001

[16] H Uno R Tarara J G ElseM A Suleman and RM SapolskyldquoHippocampal damage associated with prolonged and fatalstress in primatesrdquo Journal of Neuroscience vol 9 no 5 pp1705ndash1711 1989

[17] R M Sapolsky H Uno C S Rebert and C E Finch ldquoHip-pocampal damage associated with prolonged glucocorticoidexposure in primatesrdquo Journal of Neuroscience vol 10 no 9 pp2897ndash2902 1990

[18] J Cammermeyer ldquoArgentophil neuronal perikarya and neu-rofibrils induced by postmortem trauma and hypertonic per-fusatesrdquo Acta Anatomica vol 105 no 1 pp 9ndash24 1979

[19] G K Vollmann-Honsdorf G Flugge and E Fuchs ldquoChronicpsychosocial stress does not affect the number of pyramidalneurons in tree shrew hippocampusrdquo Neuroscience Letters vol233 no 2-3 pp 121ndash124 1997

[20] P J Lucassen G K Vollmann-HonsdorfMGleisberg B CzehE R De Kloet and E Fuchs ldquoChronic psychosocial stressdifferentially affects apoptosis in hippocampal subregions andcortex of the adult tree shrewrdquoEuropean Journal ofNeurosciencevol 14 no 1 pp 161ndash166 2001

[21] M BMuller P J Lucassen A YassouridisW J G HoogendijkF Holsboer and D F Swaab ldquoNeither major depression norglucocorticoid treatment affects the cellular integrity of thehuman hippocampusrdquo European Journal of Neuroscience vol14 no 10 pp 1603ndash1612 2001

[22] N Sousa M M Paula-Barbosa and O F X Almeida ldquoLigandand subfield specificity of corticoid-induced neuronal loss inthe rat hippocampal formationrdquoNeuroscience vol 89 no 4 pp1079ndash1087 1999

[23] B Czeh T Michaelis T Watanabe et al ldquoStress-inducedchanges in cerebral metabolites hippocampal volume and cellproliferation are prevented by antidepressant treatment withtianeptinerdquo Proceedings of the National Academy of Sciences of

8 Neural Plasticity

the United States of America vol 98 no 22 pp 12796ndash128012001

[24] B Czeh and P J Lucassen ldquoWhat causes the hippocampalvolume decrease in depression Are neurogenesis glial changesand apoptosis implicatedrdquo European Archives of Psychiatry andClinical Neuroscience vol 257 no 5 pp 250ndash260 2007

[25] P J Lucassen J Pruessner N Sousa et al ldquoNeuropathology ofstressrdquo Acta Neuropathologica vol 127 pp 109ndash135 2014

[26] R S Cajal Degeneration and Regeneration of the NervousSystem vol 2 Hafner New York NY USA 1959

[27] J Altman ldquoAre new neurons formed in the brains of adultmammalsrdquo Science vol 135 no 3509 pp 1127ndash1128 1962

[28] J Altman ldquoAutoradiographic investigation of cell proliferationin the brains of rats and catsrdquo The Anatomical record vol 145pp 573ndash591 1963

[29] J Altman and G D Das ldquoAutoradiographic and histologicalevidence of postnatal hippocampal neurogenesis in ratsrdquo Jour-nal of Comparative Neurology vol 124 no 3 pp 319ndash335 1965

[30] M S Kaplan and J W Hinds ldquoNeurogenesis in the adult ratelectronmicroscopic analysis of light radioautographsrdquo Sciencevol 197 no 4308 pp 1092ndash1094 1977

[31] M S Kaplan ldquoNeurogenesis in the 3-month-old rat visualcortexrdquo Journal of Comparative Neurology vol 195 no 2 pp323ndash338 1981

[32] B B Stanfield and J E Trice ldquoEvidence that granule cellsgenerated in the dentate gyrus of adult rats extend axonalprojectionsrdquo Experimental Brain Research vol 72 no 2 pp399ndash406 1988

[33] S A Goldman and F Nottebohm ldquoNeuronal productionmigration and differentiation in a vocal control nucleus of theadult female canary brainrdquo Proceedings of the National Academyof Sciences of the United States of America vol 80 no 8 pp2390ndash2394 1983

[34] A Alvarez-Buylla M Theelen and F Nottebohm ldquoBirth ofprojection neurons in the higher vocal center of the canaryforebrain before during and after song learningrdquoProceedings ofthe National Academy of Sciences of the United States of Americavol 85 no 22 pp 8722ndash8726 1988

[35] F Nottebohm and A P Arnold ldquoSexual dimorphism in vocalcontrol areas of the songbird brainrdquo Science vol 194 no 4261pp 211ndash213 1976

[36] F Nottebohm ldquoFrom bird song to neurogenesisrdquo ScientificAmerican vol 260 no 2 pp 74ndash79 1989

[37] A P Arnold and R A Gorski ldquoGonadal steroid induction ofstructural sex differences in the central nervous systemrdquoAnnualReview of Neuroscience vol 7 pp 413ndash442 1984

[38] P P C Graziadei M S Karlan G A M Graziadei and J JBernstein ldquoNeurogenesis of sensory neurons in the primateolfactory system after section of the fila olfactoriardquo BrainResearch vol 186 no 2 pp 289ndash300 1980

[39] D R Kornack and P Rakic ldquoThe generation migration anddifferentiation of olfactory neurons in the adult primate brainrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 98 no 8 pp 4752ndash4757 2001

[40] A Carleton L T Petreanu R Lansford A Alvarez-Buylla andP-M Lledo ldquoBecoming a new neuron in the adult olfactorybulbrdquo Nature Neuroscience vol 6 no 5 pp 507ndash518 2003

[41] M Sawada and K Sawamoto ldquoMechanisms of neurogenesis inthe normal and injured adult brainrdquo Keio Journal of Medicinevol 62 pp 13ndash28 2013

[42] P Rakic ldquoLimits of neurogenesis in primatesrdquo Science vol 227no 4690 pp 1054ndash1056 1985

[43] M F Eckenhoff and P Rakic ldquoNature and fate of proliferativecells in the hippocampal dentate gyrus during the life span ofthe rhesus monkeyrdquo Journal of Neuroscience vol 8 no 8 pp2729ndash2747 1988

[44] M W Miller and R S Nowakowski ldquoUse of bromodeox-yuridine-immunohistochemistry to examine the proliferationmigration and time of origin of cells in the central nervoussystemrdquo Brain Research vol 457 no 1 pp 44ndash52 1988

[45] H A Cameron ldquoAdult neurogenesis is regulated by adrenalsteroids in the dentate gyrusrdquo Neuroscience vol 61 no 2 pp203ndash209 1994

[46] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997

[47] Y Fan Z Y Huang C C Cao et al ldquoGenome of the Chinesetree shrewrdquo Nature Communications vol 4 article 1426 2013

[48] E Gould P Tanapat B S Mcewen G Flugge and E FuchsldquoProliferation of granule cell precursors in the dentate gyrusof adult monkeys is diminished by stressrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 95 no 6 pp 3168ndash3171 1998

[49] E Gould A J Reeves M Fallah P Tanapat C G Grossand E Fuchs ldquoHippocampal neurogenesis in adult Old Worldprimatesrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 9 pp 5263ndash5267 1999

[50] D R Kornack and P Rakic ldquoContinuation of neurogenesis inthe hippocampus of the adult macaque monkeyrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 96 no 10 pp 5768ndash5773 1999

[51] P S Eriksson E Perfilieva T Bjork-Eriksson et al ldquoNeurogen-esis in the adult human hippocampusrdquo Nature Medicine vol 4no 11 pp 1313ndash1317 1998

[52] G Kempermann and F H Gage ldquoNeurogenesis in the adulthippocampusrdquo Novartis Foundation Symposium vol 231 pp220ndash235 2000

[53] E Gould ldquoHow widespread is adult neurogenesis in mam-malsrdquo Nature Reviews Neuroscience vol 8 no 6 pp 481ndash4882007

[54] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 pp1219ndash1227 2013

[55] A Ernst K Alkass S Bernard et al ldquoNeurogenesis in thestriatum of the adult human brainrdquoCell vol 156 pp 1072ndash10832014

[56] G K H Zupanc ldquoNeurogenesis and neuronal regeneration inthe adult fish brainrdquo Journal of Comparative Physiology A vol192 no 6 pp 649ndash670 2006

[57] M Zhao S Momma K Delfani et al ldquoEvidence for neuroge-nesis in the adult mammalian substantia nigrardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 100 no 13 pp 7925ndash7930 2003

[58] I Amrein K Isler andH P Lipp ldquoComparing adult hippocam-pal neurogenesis in mammalian species and orders Influenceof chronological age and life history stagerdquo European Journal ofNeuroscience vol 34 no 6 pp 978ndash987 2011

[59] L A Voloboueva and R G Giffard ldquoInflammation mito-chondria and the inhibition of adult neurogenesisrdquo Journal ofNeuroscience Research vol 89 no 12 pp 1989ndash1996 2011

Neural Plasticity 9

[60] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003

[61] G Kempermann ldquoSeven principles in the regulation of adultneurogenesisrdquo European Journal of Neuroscience vol 33 no 6pp 1018ndash1024 2011

[62] P Tanapat N B Hastings A J Reeves and E Gould ldquoEstrogenstimulates a transient increase in the number of new neuronsin the dentate gyrus of the adult female ratrdquo Journal ofNeuroscience vol 19 no 14 pp 5792ndash5801 1999

[63] J L Pawluski S Brummelte C K Barha T M Crozier andL A M Galea ldquoEffects of steroid hormones on neurogenesisin the hippocampus of the adult female rodent during theestrous cycle pregnancy lactation and agingrdquo Frontiers inNeuroendocrinology vol 30 no 3 pp 343ndash357 2009

[64] M Sairanen G Lucas P Ernfors M Castren and E CastrenldquoBrain-derived neurotrophic factor and antidepressant drugshave different but coordinated effects on neuronal turnoverproliferation and survival in the adult dentate gyrusrdquo Journalof Neuroscience vol 25 no 5 pp 1089ndash1094 2005

[65] K Jin Y Zhu Y Sun X O Mao L Xie and D A Green-berg ldquoVascular endothelial growth factor (VEGF) stimulatesneurogenesis in vitro and in vivordquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no18 pp 11946ndash11950 2002

[66] K Fabel K Fabel B Tam et al ldquoVEGF is necessary for exercise-induced adult hippocampal neurogenesisrdquo European Journal ofNeuroscience vol 18 no 10 pp 2803ndash2812 2003

[67] H A Cameron B S McEwen and E Gould ldquoRegulation ofadult neurogenesis by excitatory input and NMDA receptoractivation in the dentate gyrusrdquo Journal of Neuroscience vol 15no 6 pp 4687ndash4692 1995

[68] B Seri J M Garcıa-Verdugo B S McEwen and A Alvarez-Buylla ldquoAstrocytes give rise to new neurons in the adultmammalian hippocampusrdquo Journal of Neuroscience vol 21 no18 pp 7153ndash7160 2001

[69] H Song C F Stevens and F H Gage ldquoAstroglia induceneurogenesis from adult neural stem cellsrdquo Nature vol 417 no6884 pp 39ndash44 2002

[70] C ZhaoWDeng and F H Gage ldquoMechanisms and FunctionalImplications of Adult Neurogenesisrdquo Cell vol 132 no 4 pp645ndash660 2008

[71] V M Heine S Maslam J Zareno M Joels and P J LucassenldquoSuppressed proliferation and apoptotic changes in the ratdentate gyrus after acute and chronic stress are reversiblerdquoEuropean Journal of Neuroscience vol 19 no 1 pp 131ndash1442004

[72] C L Coe M Kramer B Czeh et al ldquoPrenatal stress diminishesneurogenesis in the dentate gyrus of juvenile Rhesus monkeysrdquoBiological Psychiatry vol 54 no 10 pp 1025ndash1034 2003

[73] S C Tauber C Schlumbohm L Schilg E Fuchs R Nau and JGerber ldquoIntrauterine exposure to dexamethasone impairs pro-liferation but not neuronal differentiation in the dentate gyrusof newborn commonmarmosetmonkeysrdquoBrain Pathology vol16 no 3 pp 209ndash217 2006

[74] S C Tauber S Bunkowski C Schlumbohm et al ldquoNo long-term effect two years after intrauterine exposure to dexametha-sone on dentate gyrus volume neuronal proliferation and dif-ferentiation in common marmoset monkeysrdquo Brain Pathologyvol 18 no 4 pp 497ndash503 2008

[75] C A Oomen J L Mayer E R De Kloet M Joels and PJ Lucassen ldquoBrief treatment with the glucocorticoid receptor

antagonist mifepristone normalizes the reduction in neurogen-esis after chronic stressrdquo European Journal of Neuroscience vol26 no 12 pp 3395ndash3401 2007

[76] P Gass O Kretz D P Wolfer et al ldquoGenetic disruption ofmineralocorticoid receptor leads to impaired neurogenesis andgranule cell degeneration in the hippocampus of adult micerdquoEMBO Reports vol 1 no 5 pp 447ndash451 2000

[77] J E Malberg A J Eisch E J Nestler and R S DumanldquoChronic antidepressant treatment increases neurogenesis inadult rat hippocampusrdquo Journal of Neuroscience vol 20 no 24pp 9104ndash9110 2000

[78] C Anacker P A Zunszain A Cattaneo et al ldquoAntidepressantsincrease human hippocampal neurogenesis by activating theglucocorticoid receptorrdquoMolecular Psychiatry vol 16 no 7 pp738ndash750 2011

[79] M SawadaMMatsumoto andK Sawamoto ldquoVascular regula-tion of adult neurogenesis under physiological and pathologicalconditionsrdquo Frontiers in Neuroscience vol 8 article 53 2014

[80] H van Praag G Kempermann and F H Gage ldquoNeuralConsequences of environmental enrichmentrdquo Nature ReviewsNeuroscience vol 1 no 3 pp 191ndash198 2000

[81] E Gould P Tanapat N B Hastings and T J Shors ldquoNeurogen-esis in adulthood a posible role in learningrdquoTrends in CognitiveSciences vol 3 no 5 pp 186ndash192 1999

[82] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 pp 569ndash578 1999

[83] G Kempermann D Gast and F H Gage ldquoNeuroplasticityin old age sustained fivefold induction of hippocampal neu-rogenesis by long-term environmental enrichmentrdquo Annals ofNeurology vol 52 no 2 pp 135ndash143 2002

[84] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006

[85] M Koehl and D N Abrous ldquoA new chapter in the field ofmemory adult hippocampal neurogenesisrdquo European Journalof Neuroscience vol 33 no 6 pp 1101ndash1114 2011

[86] I Amrein D K N Dechmann Y Winter and H-P LippldquoAbsent or low rate of adult neurogenesis in the hippocampusof bats (Chiroptera)rdquo PLoS ONE vol 2 no 5 article e455 2007

[87] N Patzke M A Spocter K A Karlsson et al ldquoIn contrastto many other mammals cetaceans have relatively small hip-pocampi that appear to lack adult neurogenesisrdquoBrain Structureand Function 2013

[88] G Lepousez M T Valley and P M Lledo ldquoThe impact of adultneurogenesis on olfactory bulb circuits and computationsrdquoAnnual Review of Physiology vol 75 pp 339ndash363 2013

[89] Y I Sheline M H Gado and H C Kraemer ldquoUntreateddepression and hippocampal volume lossrdquo American Journal ofPsychiatry vol 160 no 8 pp 1516ndash1518 2003

[90] G Kempermann J Krebs and K Fabel ldquoThe contribution offailing adult hippocampal neurogenesis to psychiatric disor-dersrdquo Current Opinion in Psychiatry vol 21 no 3 pp 290ndash2952008

[91] A Reif S Fritzen M Finger et al ldquoNeural stem cell prolif-eration is decreased in schizophrenia but not in depressionrdquoMolecular Psychiatry vol 11 no 5 pp 514ndash522 2006

10 Neural Plasticity

[92] P J Lucassen P Meerlo A S Naylor et al ldquoRegulation ofadult neurogenesis by stress sleep disruption exercise andinflammation Implications for depression and antidepressantactionrdquo European Neuropsychopharmacology vol 20 no 1 pp1ndash17 2010

[93] M Boldrini M D Underwood R Hen et al ldquoAntidepressantsincrease neural progenitor cells in the human hippocampusrdquoNeuropsychopharmacology vol 34 no 11 pp 2376ndash2389 2009

[94] M Boldrini R Hen M D Underwood et al ldquoHippocampalangiogenesis and progenitor cell proliferation are increasedwith antidepressant use in major depressionrdquo Biological Psychi-atry vol 72 pp 562ndash571 2012

[95] M Boldrini A N Santiago R Hen et al ldquoHippocam-pal granule neuron number and dentate gyrus volume inantidepressant-treated and untreated major depressionrdquo Neu-ropsychopharmacology vol 38 pp 1068ndash1077 2013

[96] E Fuchs H Uno and G Flugge ldquoChronic psychosocial stressinduces morphological alterations in hippocampal pyramidalneurons of the tree shrewrdquo Brain Research vol 673 no 2 pp275ndash282 1995

[97] G Vollmann-Honsdorf Lichtmikroskopische und ultrastruk-turelle morphologische Veranderungen in der Hippocampusfor-mation von Tupaia (Tupaia belangeri) als Folge von chronischpsychosozialem Streszlig [PhD thesis] Faculty of Biology Univer-sity of Bielefeld 2001

[98] B SMcEwen ldquoBrain on stress how the social environment getsunder the skinrdquo Proceedings of the National Academy of Sciencesof theUnited States of America vol 109 supplement 2 pp 17180ndash17185 2012

Neural Plasticity 5

(a) (b)

(c) (d)

Figure 2 Electron micrographs of pyramidal neuron nuclei in the hippocampus of control and stressed male tree shrews (a) controlCA1 (b) stress CA1 (c) control CA3 (d) stress CA3 Note the homogeneous nucleoplasma (NP) in the controls and the large numberof heterochromatin clusters (arrow) in nuclei of CA3 pyramidal neurons in stressed animals NL nucleolus Calibration bar 2 120583m

the blood of stressed individuals Corticosteroids do indeedregulate neurogenesis and the glucocorticoid receptor antag-onist mifepristone prevented the stress-induced reduction inhippocampal neurogenesis [75] Also the mineralocorticoidreceptor appears to play a particular role as indicated by thefact that a genetic disruption of the receptor impaired adulthippocampal neurogenesis in mice [76] However elementsof the glucocorticoid system are not the only regulatoryfactors of adult neurogenesis in stress Instead as pointedout above other components of the stress cascade such asenhanced excitatory neurotransmission (increased glutamaterelease) play also a role In several preclinical models ofdepression using stress to induce depressive-like symptomsin animals certain antidepressants restored the neurogenesisthat had been impaired by the stress (see eg [23 77])Thereare indications that antidepressants activate the glucocorti-coid receptor which may increase hippocampal neurogenesis[78] However it remains an enigma whether endogenous or

synthetic substances exist that can boost adult neurogenesisvia this receptor system

The formation of new neurons is regulated by substancesderived from blood vessels and is targeted by an enormousnumber of factors [61 79] Coinciding with this view arereports demonstrating that adult neurogenesis is enhanced byphysical activity such as running [80] by learning [81] or byenvironmental enrichment [82ndash84]

6 Functional Role of Adult Neurogenesis

Soon after the discovery of adult neurogenesis it was hypoth-esized that hippocampal neurogenesis (ie the neurogenesisin the subgranular zone of the dentate gyrus a region ofthe hippocampal formation) plays a crucial role in learningand memory [81] However experimental results on therole of different forms of memory in adult rodents (egspatial learning versus associative memory) were in part

6 Neural Plasticity

20

15

10

5

Control Stress Cortisol

CA1 CA3

Relat

ive n

umbe

rnu

cleus

20

15

10

5

Relat

ive n

umbe

rnu

cleuslowast lowast lowast

lowast lowast lowast

Control Stress Cortisol

Figure 3 Relative number of heterochromatin clusters in electron micrographs from nuclei of pyramidal cells in CA1 and CA3 Data aremean plusmn SEM (119875 le 00001)

contradictory In a comprehensive review Koehl and Abrous[85] came to the conclusion that adult neurogenesis inrodents is involved ldquowhen the task requires the establishmentof relationships amongmultiple environmental cues for theflexible use of acquired informationrdquo Whether this is truefor all mammals remains to be determined as a low rate oreven absence of neurogenesis was found in the hippocampalformation of adult bats [86] and in whales [87] species withan excellent spatial working memory In the OB adult-bornnew neurons are integrated into the neuronal circuits that areresponsible for olfaction and olfactory memory respectively(for review see [88])

The fact that in animal models of depression certainantidepressants restored normal neurogenesis that had beenimpaired by stress led to the hypothesis that the benefi-cial effects of antidepressants depend on the restoration ofnormal neurogenesis [77] The volume of the hippocampalformation is reduced in patients with major depression andantidepressants can normalize hippocampal volume [89]However the hippocampal shrinkage is probably not due to adecrease in neurogenesis but rather tomore complex changesin the neural network which involve dendritic axonal andpossibly also glial alterations [24] Kempermann et al [90]proposed that ldquofailing adult hippocampal neurogenesis maynot explain major depression addiction or schizophreniabut contributes to the hippocampal aspects of the diseasesrdquoA comparison of the neural stem-cell proliferation in postmortem brain samples from patients with major depres-sion bipolar affective disorder schizophrenia and controlsubjects revealed no evidence of reduced neurogenesis inthe dentate gyrus of depressed individuals Furthermoreantidepressant treatment did not increase neural stem-cellproliferation Unexpectedly significantly reduced numbersof newly formed cells were found only in schizophrenicpatients [91] Concerning impaired neurogenesis as presump-tive cause of depression a group of experts summarized that

ldquoa lasting reduction in neurogenesisrdquo (is) ldquounlikely toproduce the full mood disorderrdquo [92] However more recentreports based on post mortem studies showed decreasednumbers of neuronal progenitor cells in the dentate gyrusof depressed patients and a selective enhancing effect ofantidepressant treatment in the anterior and middle den-tate gyrus of depressed individuals [93ndash95] To overcomethe manifold limitations of post mortem studies a futureapproach to address the question of adult neurogenesis inhumans more precisely (possibly in longitudinal studies)could be the visualization of this process in live subjectsusing advanced in vivo imaging techniques Moreover thisapproach could help answer the open questions on the role ofneurogenesis in cognitive functions and its functional impactand contribution to the etiology of depression

7 Chromatin Changes

When searching for dead neurons in the hippocampal for-mation of male tree shrews standard histology showed thatchronic social stress does not lead to neuronal death butchanges the appearance of the nuclei in the hippocampal neu-rons [96] Closer investigations revealed that chronic stressincreases the formation of heterochromatin in the nuclei ofthe hippocampal neurons [97] In this study the nuclearultrastructure of hippocampal pyramidal neurons in maletree shrews that had been exposed to daily social stress duringfour weeks according to a standard stress paradigm wasanalyzed Electron microscopic analysis revealed that in thestressed animals the nucleoplasma of CA3 pyramidal neuronsdisplayed numerous heterochromatin clusters (Figure 2)Heterochromatin is a form of condensed chromatin whoseoccurrence indicates that transcription of genes is reducedin those cells Quantification of the clusters revealing areaslarger than 1 120583m2 in the hippocampal region CA3 showed

Neural Plasticity 7

that there was more heterochromatin in stressed animalscompared to controls In contrast in area CA1 the stress hadno effect on the density of heterochromatin clusters (Figure 3[97]) Although in those days it was totally unknown whichgenes in the hippocampal nuclei were ldquosilencedrdquo by thechronic stress these morphological data indicated alreadywhat was later called ldquoepigeneticsrdquo the phenomenon thatenvironmental factors change the structure of chromatininfluence transcription and induce changes in the genome[98] Since glucocorticoid hormones are often regarded asimportant factors that convey many effects of chronic stressit was tested whether a chronic cortisol treatment wouldhave the same effects on the chromatin as the chronic socialstress Interestingly chronic cortisol changed the number ofheterochromatin clusters only in hippocampal region CA1but not in CA3 the region that is targeted by stress (Figure 3)These results indicate a site and treatment specific reactionto stress and glucocorticoid treatment in the hippocampalformation The obvious differences between chronic stressand chronic glucocorticoid treatment must be kept in mindbecause they possibly reflect different cellular pathways acti-vated by the two treatments

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] F W Stahnisch and R Nitsch ldquoSantiago Ramon y Cajalrsquosconcept of neuronal plasticity the ambiguity lives onrdquo Trendsin Neurosciences vol 25 no 11 pp 589ndash591 2002

[2] K Zilles ldquoNeuronal plasticity as an adaptive property of thecentral nervous systemrdquo Annals of Anatomy vol 174 no 5 pp383ndash391 1992

[3] G Raisman ldquoNeuronal plasticity in the septal nuclei of the adultratrdquo Brain Research vol 14 no 1 pp 25ndash48 1969

[4] Y Watanabe E Gould and B S McEwen ldquoStress inducesatrophy of apical dendrites of hippocampal CA3 pyramidalneuronsrdquo Brain Research vol 588 no 2 pp 341ndash345 1992

[5] C S Woolley E Gould and B S McEwen ldquoExposure toexcess glucocorticoids alters dendritic morphology of adulthippocampal pyramidal neuronsrdquo Brain Research vol 531 no1-2 pp 225ndash231 1990

[6] A M Magarinos B S McEwen G Flugge and E FuchsldquoChronic psychosocial stress causes apical dendritic atrophyof hippocampal CA3 pyramidal neurons in subordinate treeshrewsrdquo Journal of Neuroscience vol 16 no 10 pp 3534ndash35401996

[7] M H Kole T Costoli J M Koolhaas and E Fuchs ldquoBidi-rectional shift in the cornu ammonis 3 pyramidal dendriticorganization following brief stressrdquo Neuroscience vol 125 no2 pp 337ndash347 2004

[8] S C Cook and C L Wellman ldquoChronic stress alters dendriticmorphology in rat medial prefrontal cortexrdquo Journal of Neuro-biology vol 60 no 2 pp 236ndash248 2004

[9] C Perez-Cruz J I H Muller-Keuker U Heilbronner E Fuchsand G Flugge ldquoMorphology of pyramidal neurons in the ratprefrontal cortex lateralized dendritic remodeling by chronic

stressrdquo Neural Plasticity vol 2007 Article ID 46276 14 pages2007

[10] C Perez-Cruz M Simon G Flugge E Fuchs and B CzehldquoDiurnal rhythm and stress regulate dendritic architecture andspine density of pyramidal neurons in the rat infralimbiccortexrdquo Behavioural Brain Research vol 205 no 2 pp 406ndash4132009

[11] A Vyas R Mitra B S Shankaranarayana Rao and S Chat-tarji ldquoChronic stress induces contrasting patterns of dendriticremodeling in hippocampal and amygdaloid neuronsrdquo Journalof Neuroscience vol 22 no 15 pp 6810ndash6818 2002

[12] C Sandi H A Davies M I Cordero J J Rodriguez V IPopov andM G Stewart ldquoRapid reversal of stress induced lossof synapses in CA3 of rat hippocampus following water mazetrainingrdquo European Journal of Neuroscience vol 17 no 11 pp2447ndash2456 2003

[13] Y Watanabe E Gould D C Daniels H Cameron and B SMcEwen ldquoTianeptine attenuates stress-induced morphologicalchanges in the hippocampusrdquo European Journal of Pharmacol-ogy vol 222 no 1 pp 157ndash162 1992

[14] T V P Bliss and T Lomo ldquoLong lasting potentiation ofsynaptic transmission in the dentate area of the anaesthetizedrabbit following stimulation of the perforant pathrdquo Journal ofPhysiology vol 232 no 2 pp 331ndash356 1973

[15] H G Kuhn T D Palmer and E Fuchs ldquoAdult neurogenesisa compensatory mechanism for neuronal damagerdquo EuropeanArchives of Psychiatry and Clinical Neuroscience vol 251 no 4pp 152ndash158 2001

[16] H Uno R Tarara J G ElseM A Suleman and RM SapolskyldquoHippocampal damage associated with prolonged and fatalstress in primatesrdquo Journal of Neuroscience vol 9 no 5 pp1705ndash1711 1989

[17] R M Sapolsky H Uno C S Rebert and C E Finch ldquoHip-pocampal damage associated with prolonged glucocorticoidexposure in primatesrdquo Journal of Neuroscience vol 10 no 9 pp2897ndash2902 1990

[18] J Cammermeyer ldquoArgentophil neuronal perikarya and neu-rofibrils induced by postmortem trauma and hypertonic per-fusatesrdquo Acta Anatomica vol 105 no 1 pp 9ndash24 1979

[19] G K Vollmann-Honsdorf G Flugge and E Fuchs ldquoChronicpsychosocial stress does not affect the number of pyramidalneurons in tree shrew hippocampusrdquo Neuroscience Letters vol233 no 2-3 pp 121ndash124 1997

[20] P J Lucassen G K Vollmann-HonsdorfMGleisberg B CzehE R De Kloet and E Fuchs ldquoChronic psychosocial stressdifferentially affects apoptosis in hippocampal subregions andcortex of the adult tree shrewrdquoEuropean Journal ofNeurosciencevol 14 no 1 pp 161ndash166 2001

[21] M BMuller P J Lucassen A YassouridisW J G HoogendijkF Holsboer and D F Swaab ldquoNeither major depression norglucocorticoid treatment affects the cellular integrity of thehuman hippocampusrdquo European Journal of Neuroscience vol14 no 10 pp 1603ndash1612 2001

[22] N Sousa M M Paula-Barbosa and O F X Almeida ldquoLigandand subfield specificity of corticoid-induced neuronal loss inthe rat hippocampal formationrdquoNeuroscience vol 89 no 4 pp1079ndash1087 1999

[23] B Czeh T Michaelis T Watanabe et al ldquoStress-inducedchanges in cerebral metabolites hippocampal volume and cellproliferation are prevented by antidepressant treatment withtianeptinerdquo Proceedings of the National Academy of Sciences of

8 Neural Plasticity

the United States of America vol 98 no 22 pp 12796ndash128012001

[24] B Czeh and P J Lucassen ldquoWhat causes the hippocampalvolume decrease in depression Are neurogenesis glial changesand apoptosis implicatedrdquo European Archives of Psychiatry andClinical Neuroscience vol 257 no 5 pp 250ndash260 2007

[25] P J Lucassen J Pruessner N Sousa et al ldquoNeuropathology ofstressrdquo Acta Neuropathologica vol 127 pp 109ndash135 2014

[26] R S Cajal Degeneration and Regeneration of the NervousSystem vol 2 Hafner New York NY USA 1959

[27] J Altman ldquoAre new neurons formed in the brains of adultmammalsrdquo Science vol 135 no 3509 pp 1127ndash1128 1962

[28] J Altman ldquoAutoradiographic investigation of cell proliferationin the brains of rats and catsrdquo The Anatomical record vol 145pp 573ndash591 1963

[29] J Altman and G D Das ldquoAutoradiographic and histologicalevidence of postnatal hippocampal neurogenesis in ratsrdquo Jour-nal of Comparative Neurology vol 124 no 3 pp 319ndash335 1965

[30] M S Kaplan and J W Hinds ldquoNeurogenesis in the adult ratelectronmicroscopic analysis of light radioautographsrdquo Sciencevol 197 no 4308 pp 1092ndash1094 1977

[31] M S Kaplan ldquoNeurogenesis in the 3-month-old rat visualcortexrdquo Journal of Comparative Neurology vol 195 no 2 pp323ndash338 1981

[32] B B Stanfield and J E Trice ldquoEvidence that granule cellsgenerated in the dentate gyrus of adult rats extend axonalprojectionsrdquo Experimental Brain Research vol 72 no 2 pp399ndash406 1988

[33] S A Goldman and F Nottebohm ldquoNeuronal productionmigration and differentiation in a vocal control nucleus of theadult female canary brainrdquo Proceedings of the National Academyof Sciences of the United States of America vol 80 no 8 pp2390ndash2394 1983

[34] A Alvarez-Buylla M Theelen and F Nottebohm ldquoBirth ofprojection neurons in the higher vocal center of the canaryforebrain before during and after song learningrdquoProceedings ofthe National Academy of Sciences of the United States of Americavol 85 no 22 pp 8722ndash8726 1988

[35] F Nottebohm and A P Arnold ldquoSexual dimorphism in vocalcontrol areas of the songbird brainrdquo Science vol 194 no 4261pp 211ndash213 1976

[36] F Nottebohm ldquoFrom bird song to neurogenesisrdquo ScientificAmerican vol 260 no 2 pp 74ndash79 1989

[37] A P Arnold and R A Gorski ldquoGonadal steroid induction ofstructural sex differences in the central nervous systemrdquoAnnualReview of Neuroscience vol 7 pp 413ndash442 1984

[38] P P C Graziadei M S Karlan G A M Graziadei and J JBernstein ldquoNeurogenesis of sensory neurons in the primateolfactory system after section of the fila olfactoriardquo BrainResearch vol 186 no 2 pp 289ndash300 1980

[39] D R Kornack and P Rakic ldquoThe generation migration anddifferentiation of olfactory neurons in the adult primate brainrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 98 no 8 pp 4752ndash4757 2001

[40] A Carleton L T Petreanu R Lansford A Alvarez-Buylla andP-M Lledo ldquoBecoming a new neuron in the adult olfactorybulbrdquo Nature Neuroscience vol 6 no 5 pp 507ndash518 2003

[41] M Sawada and K Sawamoto ldquoMechanisms of neurogenesis inthe normal and injured adult brainrdquo Keio Journal of Medicinevol 62 pp 13ndash28 2013

[42] P Rakic ldquoLimits of neurogenesis in primatesrdquo Science vol 227no 4690 pp 1054ndash1056 1985

[43] M F Eckenhoff and P Rakic ldquoNature and fate of proliferativecells in the hippocampal dentate gyrus during the life span ofthe rhesus monkeyrdquo Journal of Neuroscience vol 8 no 8 pp2729ndash2747 1988

[44] M W Miller and R S Nowakowski ldquoUse of bromodeox-yuridine-immunohistochemistry to examine the proliferationmigration and time of origin of cells in the central nervoussystemrdquo Brain Research vol 457 no 1 pp 44ndash52 1988

[45] H A Cameron ldquoAdult neurogenesis is regulated by adrenalsteroids in the dentate gyrusrdquo Neuroscience vol 61 no 2 pp203ndash209 1994

[46] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997

[47] Y Fan Z Y Huang C C Cao et al ldquoGenome of the Chinesetree shrewrdquo Nature Communications vol 4 article 1426 2013

[48] E Gould P Tanapat B S Mcewen G Flugge and E FuchsldquoProliferation of granule cell precursors in the dentate gyrusof adult monkeys is diminished by stressrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 95 no 6 pp 3168ndash3171 1998

[49] E Gould A J Reeves M Fallah P Tanapat C G Grossand E Fuchs ldquoHippocampal neurogenesis in adult Old Worldprimatesrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 9 pp 5263ndash5267 1999

[50] D R Kornack and P Rakic ldquoContinuation of neurogenesis inthe hippocampus of the adult macaque monkeyrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 96 no 10 pp 5768ndash5773 1999

[51] P S Eriksson E Perfilieva T Bjork-Eriksson et al ldquoNeurogen-esis in the adult human hippocampusrdquo Nature Medicine vol 4no 11 pp 1313ndash1317 1998

[52] G Kempermann and F H Gage ldquoNeurogenesis in the adulthippocampusrdquo Novartis Foundation Symposium vol 231 pp220ndash235 2000

[53] E Gould ldquoHow widespread is adult neurogenesis in mam-malsrdquo Nature Reviews Neuroscience vol 8 no 6 pp 481ndash4882007

[54] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 pp1219ndash1227 2013

[55] A Ernst K Alkass S Bernard et al ldquoNeurogenesis in thestriatum of the adult human brainrdquoCell vol 156 pp 1072ndash10832014

[56] G K H Zupanc ldquoNeurogenesis and neuronal regeneration inthe adult fish brainrdquo Journal of Comparative Physiology A vol192 no 6 pp 649ndash670 2006

[57] M Zhao S Momma K Delfani et al ldquoEvidence for neuroge-nesis in the adult mammalian substantia nigrardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 100 no 13 pp 7925ndash7930 2003

[58] I Amrein K Isler andH P Lipp ldquoComparing adult hippocam-pal neurogenesis in mammalian species and orders Influenceof chronological age and life history stagerdquo European Journal ofNeuroscience vol 34 no 6 pp 978ndash987 2011

[59] L A Voloboueva and R G Giffard ldquoInflammation mito-chondria and the inhibition of adult neurogenesisrdquo Journal ofNeuroscience Research vol 89 no 12 pp 1989ndash1996 2011

Neural Plasticity 9

[60] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003

[61] G Kempermann ldquoSeven principles in the regulation of adultneurogenesisrdquo European Journal of Neuroscience vol 33 no 6pp 1018ndash1024 2011

[62] P Tanapat N B Hastings A J Reeves and E Gould ldquoEstrogenstimulates a transient increase in the number of new neuronsin the dentate gyrus of the adult female ratrdquo Journal ofNeuroscience vol 19 no 14 pp 5792ndash5801 1999

[63] J L Pawluski S Brummelte C K Barha T M Crozier andL A M Galea ldquoEffects of steroid hormones on neurogenesisin the hippocampus of the adult female rodent during theestrous cycle pregnancy lactation and agingrdquo Frontiers inNeuroendocrinology vol 30 no 3 pp 343ndash357 2009

[64] M Sairanen G Lucas P Ernfors M Castren and E CastrenldquoBrain-derived neurotrophic factor and antidepressant drugshave different but coordinated effects on neuronal turnoverproliferation and survival in the adult dentate gyrusrdquo Journalof Neuroscience vol 25 no 5 pp 1089ndash1094 2005

[65] K Jin Y Zhu Y Sun X O Mao L Xie and D A Green-berg ldquoVascular endothelial growth factor (VEGF) stimulatesneurogenesis in vitro and in vivordquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no18 pp 11946ndash11950 2002

[66] K Fabel K Fabel B Tam et al ldquoVEGF is necessary for exercise-induced adult hippocampal neurogenesisrdquo European Journal ofNeuroscience vol 18 no 10 pp 2803ndash2812 2003

[67] H A Cameron B S McEwen and E Gould ldquoRegulation ofadult neurogenesis by excitatory input and NMDA receptoractivation in the dentate gyrusrdquo Journal of Neuroscience vol 15no 6 pp 4687ndash4692 1995

[68] B Seri J M Garcıa-Verdugo B S McEwen and A Alvarez-Buylla ldquoAstrocytes give rise to new neurons in the adultmammalian hippocampusrdquo Journal of Neuroscience vol 21 no18 pp 7153ndash7160 2001

[69] H Song C F Stevens and F H Gage ldquoAstroglia induceneurogenesis from adult neural stem cellsrdquo Nature vol 417 no6884 pp 39ndash44 2002

[70] C ZhaoWDeng and F H Gage ldquoMechanisms and FunctionalImplications of Adult Neurogenesisrdquo Cell vol 132 no 4 pp645ndash660 2008

[71] V M Heine S Maslam J Zareno M Joels and P J LucassenldquoSuppressed proliferation and apoptotic changes in the ratdentate gyrus after acute and chronic stress are reversiblerdquoEuropean Journal of Neuroscience vol 19 no 1 pp 131ndash1442004

[72] C L Coe M Kramer B Czeh et al ldquoPrenatal stress diminishesneurogenesis in the dentate gyrus of juvenile Rhesus monkeysrdquoBiological Psychiatry vol 54 no 10 pp 1025ndash1034 2003

[73] S C Tauber C Schlumbohm L Schilg E Fuchs R Nau and JGerber ldquoIntrauterine exposure to dexamethasone impairs pro-liferation but not neuronal differentiation in the dentate gyrusof newborn commonmarmosetmonkeysrdquoBrain Pathology vol16 no 3 pp 209ndash217 2006

[74] S C Tauber S Bunkowski C Schlumbohm et al ldquoNo long-term effect two years after intrauterine exposure to dexametha-sone on dentate gyrus volume neuronal proliferation and dif-ferentiation in common marmoset monkeysrdquo Brain Pathologyvol 18 no 4 pp 497ndash503 2008

[75] C A Oomen J L Mayer E R De Kloet M Joels and PJ Lucassen ldquoBrief treatment with the glucocorticoid receptor

antagonist mifepristone normalizes the reduction in neurogen-esis after chronic stressrdquo European Journal of Neuroscience vol26 no 12 pp 3395ndash3401 2007

[76] P Gass O Kretz D P Wolfer et al ldquoGenetic disruption ofmineralocorticoid receptor leads to impaired neurogenesis andgranule cell degeneration in the hippocampus of adult micerdquoEMBO Reports vol 1 no 5 pp 447ndash451 2000

[77] J E Malberg A J Eisch E J Nestler and R S DumanldquoChronic antidepressant treatment increases neurogenesis inadult rat hippocampusrdquo Journal of Neuroscience vol 20 no 24pp 9104ndash9110 2000

[78] C Anacker P A Zunszain A Cattaneo et al ldquoAntidepressantsincrease human hippocampal neurogenesis by activating theglucocorticoid receptorrdquoMolecular Psychiatry vol 16 no 7 pp738ndash750 2011

[79] M SawadaMMatsumoto andK Sawamoto ldquoVascular regula-tion of adult neurogenesis under physiological and pathologicalconditionsrdquo Frontiers in Neuroscience vol 8 article 53 2014

[80] H van Praag G Kempermann and F H Gage ldquoNeuralConsequences of environmental enrichmentrdquo Nature ReviewsNeuroscience vol 1 no 3 pp 191ndash198 2000

[81] E Gould P Tanapat N B Hastings and T J Shors ldquoNeurogen-esis in adulthood a posible role in learningrdquoTrends in CognitiveSciences vol 3 no 5 pp 186ndash192 1999

[82] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 pp 569ndash578 1999

[83] G Kempermann D Gast and F H Gage ldquoNeuroplasticityin old age sustained fivefold induction of hippocampal neu-rogenesis by long-term environmental enrichmentrdquo Annals ofNeurology vol 52 no 2 pp 135ndash143 2002

[84] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006

[85] M Koehl and D N Abrous ldquoA new chapter in the field ofmemory adult hippocampal neurogenesisrdquo European Journalof Neuroscience vol 33 no 6 pp 1101ndash1114 2011

[86] I Amrein D K N Dechmann Y Winter and H-P LippldquoAbsent or low rate of adult neurogenesis in the hippocampusof bats (Chiroptera)rdquo PLoS ONE vol 2 no 5 article e455 2007

[87] N Patzke M A Spocter K A Karlsson et al ldquoIn contrastto many other mammals cetaceans have relatively small hip-pocampi that appear to lack adult neurogenesisrdquoBrain Structureand Function 2013

[88] G Lepousez M T Valley and P M Lledo ldquoThe impact of adultneurogenesis on olfactory bulb circuits and computationsrdquoAnnual Review of Physiology vol 75 pp 339ndash363 2013

[89] Y I Sheline M H Gado and H C Kraemer ldquoUntreateddepression and hippocampal volume lossrdquo American Journal ofPsychiatry vol 160 no 8 pp 1516ndash1518 2003

[90] G Kempermann J Krebs and K Fabel ldquoThe contribution offailing adult hippocampal neurogenesis to psychiatric disor-dersrdquo Current Opinion in Psychiatry vol 21 no 3 pp 290ndash2952008

[91] A Reif S Fritzen M Finger et al ldquoNeural stem cell prolif-eration is decreased in schizophrenia but not in depressionrdquoMolecular Psychiatry vol 11 no 5 pp 514ndash522 2006

10 Neural Plasticity

[92] P J Lucassen P Meerlo A S Naylor et al ldquoRegulation ofadult neurogenesis by stress sleep disruption exercise andinflammation Implications for depression and antidepressantactionrdquo European Neuropsychopharmacology vol 20 no 1 pp1ndash17 2010

[93] M Boldrini M D Underwood R Hen et al ldquoAntidepressantsincrease neural progenitor cells in the human hippocampusrdquoNeuropsychopharmacology vol 34 no 11 pp 2376ndash2389 2009

[94] M Boldrini R Hen M D Underwood et al ldquoHippocampalangiogenesis and progenitor cell proliferation are increasedwith antidepressant use in major depressionrdquo Biological Psychi-atry vol 72 pp 562ndash571 2012

[95] M Boldrini A N Santiago R Hen et al ldquoHippocam-pal granule neuron number and dentate gyrus volume inantidepressant-treated and untreated major depressionrdquo Neu-ropsychopharmacology vol 38 pp 1068ndash1077 2013

[96] E Fuchs H Uno and G Flugge ldquoChronic psychosocial stressinduces morphological alterations in hippocampal pyramidalneurons of the tree shrewrdquo Brain Research vol 673 no 2 pp275ndash282 1995

[97] G Vollmann-Honsdorf Lichtmikroskopische und ultrastruk-turelle morphologische Veranderungen in der Hippocampusfor-mation von Tupaia (Tupaia belangeri) als Folge von chronischpsychosozialem Streszlig [PhD thesis] Faculty of Biology Univer-sity of Bielefeld 2001

[98] B SMcEwen ldquoBrain on stress how the social environment getsunder the skinrdquo Proceedings of the National Academy of Sciencesof theUnited States of America vol 109 supplement 2 pp 17180ndash17185 2012

6 Neural Plasticity

20

15

10

5

Control Stress Cortisol

CA1 CA3

Relat

ive n

umbe

rnu

cleus

20

15

10

5

Relat

ive n

umbe

rnu

cleuslowast lowast lowast

lowast lowast lowast

Control Stress Cortisol

Figure 3 Relative number of heterochromatin clusters in electron micrographs from nuclei of pyramidal cells in CA1 and CA3 Data aremean plusmn SEM (119875 le 00001)

contradictory In a comprehensive review Koehl and Abrous[85] came to the conclusion that adult neurogenesis inrodents is involved ldquowhen the task requires the establishmentof relationships amongmultiple environmental cues for theflexible use of acquired informationrdquo Whether this is truefor all mammals remains to be determined as a low rate oreven absence of neurogenesis was found in the hippocampalformation of adult bats [86] and in whales [87] species withan excellent spatial working memory In the OB adult-bornnew neurons are integrated into the neuronal circuits that areresponsible for olfaction and olfactory memory respectively(for review see [88])

The fact that in animal models of depression certainantidepressants restored normal neurogenesis that had beenimpaired by stress led to the hypothesis that the benefi-cial effects of antidepressants depend on the restoration ofnormal neurogenesis [77] The volume of the hippocampalformation is reduced in patients with major depression andantidepressants can normalize hippocampal volume [89]However the hippocampal shrinkage is probably not due to adecrease in neurogenesis but rather tomore complex changesin the neural network which involve dendritic axonal andpossibly also glial alterations [24] Kempermann et al [90]proposed that ldquofailing adult hippocampal neurogenesis maynot explain major depression addiction or schizophreniabut contributes to the hippocampal aspects of the diseasesrdquoA comparison of the neural stem-cell proliferation in postmortem brain samples from patients with major depres-sion bipolar affective disorder schizophrenia and controlsubjects revealed no evidence of reduced neurogenesis inthe dentate gyrus of depressed individuals Furthermoreantidepressant treatment did not increase neural stem-cellproliferation Unexpectedly significantly reduced numbersof newly formed cells were found only in schizophrenicpatients [91] Concerning impaired neurogenesis as presump-tive cause of depression a group of experts summarized that

ldquoa lasting reduction in neurogenesisrdquo (is) ldquounlikely toproduce the full mood disorderrdquo [92] However more recentreports based on post mortem studies showed decreasednumbers of neuronal progenitor cells in the dentate gyrusof depressed patients and a selective enhancing effect ofantidepressant treatment in the anterior and middle den-tate gyrus of depressed individuals [93ndash95] To overcomethe manifold limitations of post mortem studies a futureapproach to address the question of adult neurogenesis inhumans more precisely (possibly in longitudinal studies)could be the visualization of this process in live subjectsusing advanced in vivo imaging techniques Moreover thisapproach could help answer the open questions on the role ofneurogenesis in cognitive functions and its functional impactand contribution to the etiology of depression

7 Chromatin Changes

When searching for dead neurons in the hippocampal for-mation of male tree shrews standard histology showed thatchronic social stress does not lead to neuronal death butchanges the appearance of the nuclei in the hippocampal neu-rons [96] Closer investigations revealed that chronic stressincreases the formation of heterochromatin in the nuclei ofthe hippocampal neurons [97] In this study the nuclearultrastructure of hippocampal pyramidal neurons in maletree shrews that had been exposed to daily social stress duringfour weeks according to a standard stress paradigm wasanalyzed Electron microscopic analysis revealed that in thestressed animals the nucleoplasma of CA3 pyramidal neuronsdisplayed numerous heterochromatin clusters (Figure 2)Heterochromatin is a form of condensed chromatin whoseoccurrence indicates that transcription of genes is reducedin those cells Quantification of the clusters revealing areaslarger than 1 120583m2 in the hippocampal region CA3 showed

Neural Plasticity 7

that there was more heterochromatin in stressed animalscompared to controls In contrast in area CA1 the stress hadno effect on the density of heterochromatin clusters (Figure 3[97]) Although in those days it was totally unknown whichgenes in the hippocampal nuclei were ldquosilencedrdquo by thechronic stress these morphological data indicated alreadywhat was later called ldquoepigeneticsrdquo the phenomenon thatenvironmental factors change the structure of chromatininfluence transcription and induce changes in the genome[98] Since glucocorticoid hormones are often regarded asimportant factors that convey many effects of chronic stressit was tested whether a chronic cortisol treatment wouldhave the same effects on the chromatin as the chronic socialstress Interestingly chronic cortisol changed the number ofheterochromatin clusters only in hippocampal region CA1but not in CA3 the region that is targeted by stress (Figure 3)These results indicate a site and treatment specific reactionto stress and glucocorticoid treatment in the hippocampalformation The obvious differences between chronic stressand chronic glucocorticoid treatment must be kept in mindbecause they possibly reflect different cellular pathways acti-vated by the two treatments

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] F W Stahnisch and R Nitsch ldquoSantiago Ramon y Cajalrsquosconcept of neuronal plasticity the ambiguity lives onrdquo Trendsin Neurosciences vol 25 no 11 pp 589ndash591 2002

[2] K Zilles ldquoNeuronal plasticity as an adaptive property of thecentral nervous systemrdquo Annals of Anatomy vol 174 no 5 pp383ndash391 1992

[3] G Raisman ldquoNeuronal plasticity in the septal nuclei of the adultratrdquo Brain Research vol 14 no 1 pp 25ndash48 1969

[4] Y Watanabe E Gould and B S McEwen ldquoStress inducesatrophy of apical dendrites of hippocampal CA3 pyramidalneuronsrdquo Brain Research vol 588 no 2 pp 341ndash345 1992

[5] C S Woolley E Gould and B S McEwen ldquoExposure toexcess glucocorticoids alters dendritic morphology of adulthippocampal pyramidal neuronsrdquo Brain Research vol 531 no1-2 pp 225ndash231 1990

[6] A M Magarinos B S McEwen G Flugge and E FuchsldquoChronic psychosocial stress causes apical dendritic atrophyof hippocampal CA3 pyramidal neurons in subordinate treeshrewsrdquo Journal of Neuroscience vol 16 no 10 pp 3534ndash35401996

[7] M H Kole T Costoli J M Koolhaas and E Fuchs ldquoBidi-rectional shift in the cornu ammonis 3 pyramidal dendriticorganization following brief stressrdquo Neuroscience vol 125 no2 pp 337ndash347 2004

[8] S C Cook and C L Wellman ldquoChronic stress alters dendriticmorphology in rat medial prefrontal cortexrdquo Journal of Neuro-biology vol 60 no 2 pp 236ndash248 2004

[9] C Perez-Cruz J I H Muller-Keuker U Heilbronner E Fuchsand G Flugge ldquoMorphology of pyramidal neurons in the ratprefrontal cortex lateralized dendritic remodeling by chronic

stressrdquo Neural Plasticity vol 2007 Article ID 46276 14 pages2007

[10] C Perez-Cruz M Simon G Flugge E Fuchs and B CzehldquoDiurnal rhythm and stress regulate dendritic architecture andspine density of pyramidal neurons in the rat infralimbiccortexrdquo Behavioural Brain Research vol 205 no 2 pp 406ndash4132009

[11] A Vyas R Mitra B S Shankaranarayana Rao and S Chat-tarji ldquoChronic stress induces contrasting patterns of dendriticremodeling in hippocampal and amygdaloid neuronsrdquo Journalof Neuroscience vol 22 no 15 pp 6810ndash6818 2002

[12] C Sandi H A Davies M I Cordero J J Rodriguez V IPopov andM G Stewart ldquoRapid reversal of stress induced lossof synapses in CA3 of rat hippocampus following water mazetrainingrdquo European Journal of Neuroscience vol 17 no 11 pp2447ndash2456 2003

[13] Y Watanabe E Gould D C Daniels H Cameron and B SMcEwen ldquoTianeptine attenuates stress-induced morphologicalchanges in the hippocampusrdquo European Journal of Pharmacol-ogy vol 222 no 1 pp 157ndash162 1992

[14] T V P Bliss and T Lomo ldquoLong lasting potentiation ofsynaptic transmission in the dentate area of the anaesthetizedrabbit following stimulation of the perforant pathrdquo Journal ofPhysiology vol 232 no 2 pp 331ndash356 1973

[15] H G Kuhn T D Palmer and E Fuchs ldquoAdult neurogenesisa compensatory mechanism for neuronal damagerdquo EuropeanArchives of Psychiatry and Clinical Neuroscience vol 251 no 4pp 152ndash158 2001

[16] H Uno R Tarara J G ElseM A Suleman and RM SapolskyldquoHippocampal damage associated with prolonged and fatalstress in primatesrdquo Journal of Neuroscience vol 9 no 5 pp1705ndash1711 1989

[17] R M Sapolsky H Uno C S Rebert and C E Finch ldquoHip-pocampal damage associated with prolonged glucocorticoidexposure in primatesrdquo Journal of Neuroscience vol 10 no 9 pp2897ndash2902 1990

[18] J Cammermeyer ldquoArgentophil neuronal perikarya and neu-rofibrils induced by postmortem trauma and hypertonic per-fusatesrdquo Acta Anatomica vol 105 no 1 pp 9ndash24 1979

[19] G K Vollmann-Honsdorf G Flugge and E Fuchs ldquoChronicpsychosocial stress does not affect the number of pyramidalneurons in tree shrew hippocampusrdquo Neuroscience Letters vol233 no 2-3 pp 121ndash124 1997

[20] P J Lucassen G K Vollmann-HonsdorfMGleisberg B CzehE R De Kloet and E Fuchs ldquoChronic psychosocial stressdifferentially affects apoptosis in hippocampal subregions andcortex of the adult tree shrewrdquoEuropean Journal ofNeurosciencevol 14 no 1 pp 161ndash166 2001

[21] M BMuller P J Lucassen A YassouridisW J G HoogendijkF Holsboer and D F Swaab ldquoNeither major depression norglucocorticoid treatment affects the cellular integrity of thehuman hippocampusrdquo European Journal of Neuroscience vol14 no 10 pp 1603ndash1612 2001

[22] N Sousa M M Paula-Barbosa and O F X Almeida ldquoLigandand subfield specificity of corticoid-induced neuronal loss inthe rat hippocampal formationrdquoNeuroscience vol 89 no 4 pp1079ndash1087 1999

[23] B Czeh T Michaelis T Watanabe et al ldquoStress-inducedchanges in cerebral metabolites hippocampal volume and cellproliferation are prevented by antidepressant treatment withtianeptinerdquo Proceedings of the National Academy of Sciences of

8 Neural Plasticity

the United States of America vol 98 no 22 pp 12796ndash128012001

[24] B Czeh and P J Lucassen ldquoWhat causes the hippocampalvolume decrease in depression Are neurogenesis glial changesand apoptosis implicatedrdquo European Archives of Psychiatry andClinical Neuroscience vol 257 no 5 pp 250ndash260 2007

[25] P J Lucassen J Pruessner N Sousa et al ldquoNeuropathology ofstressrdquo Acta Neuropathologica vol 127 pp 109ndash135 2014

[26] R S Cajal Degeneration and Regeneration of the NervousSystem vol 2 Hafner New York NY USA 1959

[27] J Altman ldquoAre new neurons formed in the brains of adultmammalsrdquo Science vol 135 no 3509 pp 1127ndash1128 1962

[28] J Altman ldquoAutoradiographic investigation of cell proliferationin the brains of rats and catsrdquo The Anatomical record vol 145pp 573ndash591 1963

[29] J Altman and G D Das ldquoAutoradiographic and histologicalevidence of postnatal hippocampal neurogenesis in ratsrdquo Jour-nal of Comparative Neurology vol 124 no 3 pp 319ndash335 1965

[30] M S Kaplan and J W Hinds ldquoNeurogenesis in the adult ratelectronmicroscopic analysis of light radioautographsrdquo Sciencevol 197 no 4308 pp 1092ndash1094 1977

[31] M S Kaplan ldquoNeurogenesis in the 3-month-old rat visualcortexrdquo Journal of Comparative Neurology vol 195 no 2 pp323ndash338 1981

[32] B B Stanfield and J E Trice ldquoEvidence that granule cellsgenerated in the dentate gyrus of adult rats extend axonalprojectionsrdquo Experimental Brain Research vol 72 no 2 pp399ndash406 1988

[33] S A Goldman and F Nottebohm ldquoNeuronal productionmigration and differentiation in a vocal control nucleus of theadult female canary brainrdquo Proceedings of the National Academyof Sciences of the United States of America vol 80 no 8 pp2390ndash2394 1983

[34] A Alvarez-Buylla M Theelen and F Nottebohm ldquoBirth ofprojection neurons in the higher vocal center of the canaryforebrain before during and after song learningrdquoProceedings ofthe National Academy of Sciences of the United States of Americavol 85 no 22 pp 8722ndash8726 1988

[35] F Nottebohm and A P Arnold ldquoSexual dimorphism in vocalcontrol areas of the songbird brainrdquo Science vol 194 no 4261pp 211ndash213 1976

[36] F Nottebohm ldquoFrom bird song to neurogenesisrdquo ScientificAmerican vol 260 no 2 pp 74ndash79 1989

[37] A P Arnold and R A Gorski ldquoGonadal steroid induction ofstructural sex differences in the central nervous systemrdquoAnnualReview of Neuroscience vol 7 pp 413ndash442 1984

[38] P P C Graziadei M S Karlan G A M Graziadei and J JBernstein ldquoNeurogenesis of sensory neurons in the primateolfactory system after section of the fila olfactoriardquo BrainResearch vol 186 no 2 pp 289ndash300 1980

[39] D R Kornack and P Rakic ldquoThe generation migration anddifferentiation of olfactory neurons in the adult primate brainrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 98 no 8 pp 4752ndash4757 2001

[40] A Carleton L T Petreanu R Lansford A Alvarez-Buylla andP-M Lledo ldquoBecoming a new neuron in the adult olfactorybulbrdquo Nature Neuroscience vol 6 no 5 pp 507ndash518 2003

[41] M Sawada and K Sawamoto ldquoMechanisms of neurogenesis inthe normal and injured adult brainrdquo Keio Journal of Medicinevol 62 pp 13ndash28 2013

[42] P Rakic ldquoLimits of neurogenesis in primatesrdquo Science vol 227no 4690 pp 1054ndash1056 1985

[43] M F Eckenhoff and P Rakic ldquoNature and fate of proliferativecells in the hippocampal dentate gyrus during the life span ofthe rhesus monkeyrdquo Journal of Neuroscience vol 8 no 8 pp2729ndash2747 1988

[44] M W Miller and R S Nowakowski ldquoUse of bromodeox-yuridine-immunohistochemistry to examine the proliferationmigration and time of origin of cells in the central nervoussystemrdquo Brain Research vol 457 no 1 pp 44ndash52 1988

[45] H A Cameron ldquoAdult neurogenesis is regulated by adrenalsteroids in the dentate gyrusrdquo Neuroscience vol 61 no 2 pp203ndash209 1994

[46] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997

[47] Y Fan Z Y Huang C C Cao et al ldquoGenome of the Chinesetree shrewrdquo Nature Communications vol 4 article 1426 2013

[48] E Gould P Tanapat B S Mcewen G Flugge and E FuchsldquoProliferation of granule cell precursors in the dentate gyrusof adult monkeys is diminished by stressrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 95 no 6 pp 3168ndash3171 1998

[49] E Gould A J Reeves M Fallah P Tanapat C G Grossand E Fuchs ldquoHippocampal neurogenesis in adult Old Worldprimatesrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 9 pp 5263ndash5267 1999

[50] D R Kornack and P Rakic ldquoContinuation of neurogenesis inthe hippocampus of the adult macaque monkeyrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 96 no 10 pp 5768ndash5773 1999

[51] P S Eriksson E Perfilieva T Bjork-Eriksson et al ldquoNeurogen-esis in the adult human hippocampusrdquo Nature Medicine vol 4no 11 pp 1313ndash1317 1998

[52] G Kempermann and F H Gage ldquoNeurogenesis in the adulthippocampusrdquo Novartis Foundation Symposium vol 231 pp220ndash235 2000

[53] E Gould ldquoHow widespread is adult neurogenesis in mam-malsrdquo Nature Reviews Neuroscience vol 8 no 6 pp 481ndash4882007

[54] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 pp1219ndash1227 2013

[55] A Ernst K Alkass S Bernard et al ldquoNeurogenesis in thestriatum of the adult human brainrdquoCell vol 156 pp 1072ndash10832014

[56] G K H Zupanc ldquoNeurogenesis and neuronal regeneration inthe adult fish brainrdquo Journal of Comparative Physiology A vol192 no 6 pp 649ndash670 2006

[57] M Zhao S Momma K Delfani et al ldquoEvidence for neuroge-nesis in the adult mammalian substantia nigrardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 100 no 13 pp 7925ndash7930 2003

[58] I Amrein K Isler andH P Lipp ldquoComparing adult hippocam-pal neurogenesis in mammalian species and orders Influenceof chronological age and life history stagerdquo European Journal ofNeuroscience vol 34 no 6 pp 978ndash987 2011

[59] L A Voloboueva and R G Giffard ldquoInflammation mito-chondria and the inhibition of adult neurogenesisrdquo Journal ofNeuroscience Research vol 89 no 12 pp 1989ndash1996 2011

Neural Plasticity 9

[60] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003

[61] G Kempermann ldquoSeven principles in the regulation of adultneurogenesisrdquo European Journal of Neuroscience vol 33 no 6pp 1018ndash1024 2011

[62] P Tanapat N B Hastings A J Reeves and E Gould ldquoEstrogenstimulates a transient increase in the number of new neuronsin the dentate gyrus of the adult female ratrdquo Journal ofNeuroscience vol 19 no 14 pp 5792ndash5801 1999

[63] J L Pawluski S Brummelte C K Barha T M Crozier andL A M Galea ldquoEffects of steroid hormones on neurogenesisin the hippocampus of the adult female rodent during theestrous cycle pregnancy lactation and agingrdquo Frontiers inNeuroendocrinology vol 30 no 3 pp 343ndash357 2009

[64] M Sairanen G Lucas P Ernfors M Castren and E CastrenldquoBrain-derived neurotrophic factor and antidepressant drugshave different but coordinated effects on neuronal turnoverproliferation and survival in the adult dentate gyrusrdquo Journalof Neuroscience vol 25 no 5 pp 1089ndash1094 2005

[65] K Jin Y Zhu Y Sun X O Mao L Xie and D A Green-berg ldquoVascular endothelial growth factor (VEGF) stimulatesneurogenesis in vitro and in vivordquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no18 pp 11946ndash11950 2002

[66] K Fabel K Fabel B Tam et al ldquoVEGF is necessary for exercise-induced adult hippocampal neurogenesisrdquo European Journal ofNeuroscience vol 18 no 10 pp 2803ndash2812 2003

[67] H A Cameron B S McEwen and E Gould ldquoRegulation ofadult neurogenesis by excitatory input and NMDA receptoractivation in the dentate gyrusrdquo Journal of Neuroscience vol 15no 6 pp 4687ndash4692 1995

[68] B Seri J M Garcıa-Verdugo B S McEwen and A Alvarez-Buylla ldquoAstrocytes give rise to new neurons in the adultmammalian hippocampusrdquo Journal of Neuroscience vol 21 no18 pp 7153ndash7160 2001

[69] H Song C F Stevens and F H Gage ldquoAstroglia induceneurogenesis from adult neural stem cellsrdquo Nature vol 417 no6884 pp 39ndash44 2002

[70] C ZhaoWDeng and F H Gage ldquoMechanisms and FunctionalImplications of Adult Neurogenesisrdquo Cell vol 132 no 4 pp645ndash660 2008

[71] V M Heine S Maslam J Zareno M Joels and P J LucassenldquoSuppressed proliferation and apoptotic changes in the ratdentate gyrus after acute and chronic stress are reversiblerdquoEuropean Journal of Neuroscience vol 19 no 1 pp 131ndash1442004

[72] C L Coe M Kramer B Czeh et al ldquoPrenatal stress diminishesneurogenesis in the dentate gyrus of juvenile Rhesus monkeysrdquoBiological Psychiatry vol 54 no 10 pp 1025ndash1034 2003

[73] S C Tauber C Schlumbohm L Schilg E Fuchs R Nau and JGerber ldquoIntrauterine exposure to dexamethasone impairs pro-liferation but not neuronal differentiation in the dentate gyrusof newborn commonmarmosetmonkeysrdquoBrain Pathology vol16 no 3 pp 209ndash217 2006

[74] S C Tauber S Bunkowski C Schlumbohm et al ldquoNo long-term effect two years after intrauterine exposure to dexametha-sone on dentate gyrus volume neuronal proliferation and dif-ferentiation in common marmoset monkeysrdquo Brain Pathologyvol 18 no 4 pp 497ndash503 2008

[75] C A Oomen J L Mayer E R De Kloet M Joels and PJ Lucassen ldquoBrief treatment with the glucocorticoid receptor

antagonist mifepristone normalizes the reduction in neurogen-esis after chronic stressrdquo European Journal of Neuroscience vol26 no 12 pp 3395ndash3401 2007

[76] P Gass O Kretz D P Wolfer et al ldquoGenetic disruption ofmineralocorticoid receptor leads to impaired neurogenesis andgranule cell degeneration in the hippocampus of adult micerdquoEMBO Reports vol 1 no 5 pp 447ndash451 2000

[77] J E Malberg A J Eisch E J Nestler and R S DumanldquoChronic antidepressant treatment increases neurogenesis inadult rat hippocampusrdquo Journal of Neuroscience vol 20 no 24pp 9104ndash9110 2000

[78] C Anacker P A Zunszain A Cattaneo et al ldquoAntidepressantsincrease human hippocampal neurogenesis by activating theglucocorticoid receptorrdquoMolecular Psychiatry vol 16 no 7 pp738ndash750 2011

[79] M SawadaMMatsumoto andK Sawamoto ldquoVascular regula-tion of adult neurogenesis under physiological and pathologicalconditionsrdquo Frontiers in Neuroscience vol 8 article 53 2014

[80] H van Praag G Kempermann and F H Gage ldquoNeuralConsequences of environmental enrichmentrdquo Nature ReviewsNeuroscience vol 1 no 3 pp 191ndash198 2000

[81] E Gould P Tanapat N B Hastings and T J Shors ldquoNeurogen-esis in adulthood a posible role in learningrdquoTrends in CognitiveSciences vol 3 no 5 pp 186ndash192 1999

[82] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 pp 569ndash578 1999

[83] G Kempermann D Gast and F H Gage ldquoNeuroplasticityin old age sustained fivefold induction of hippocampal neu-rogenesis by long-term environmental enrichmentrdquo Annals ofNeurology vol 52 no 2 pp 135ndash143 2002

[84] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006

[85] M Koehl and D N Abrous ldquoA new chapter in the field ofmemory adult hippocampal neurogenesisrdquo European Journalof Neuroscience vol 33 no 6 pp 1101ndash1114 2011

[86] I Amrein D K N Dechmann Y Winter and H-P LippldquoAbsent or low rate of adult neurogenesis in the hippocampusof bats (Chiroptera)rdquo PLoS ONE vol 2 no 5 article e455 2007

[87] N Patzke M A Spocter K A Karlsson et al ldquoIn contrastto many other mammals cetaceans have relatively small hip-pocampi that appear to lack adult neurogenesisrdquoBrain Structureand Function 2013

[88] G Lepousez M T Valley and P M Lledo ldquoThe impact of adultneurogenesis on olfactory bulb circuits and computationsrdquoAnnual Review of Physiology vol 75 pp 339ndash363 2013

[89] Y I Sheline M H Gado and H C Kraemer ldquoUntreateddepression and hippocampal volume lossrdquo American Journal ofPsychiatry vol 160 no 8 pp 1516ndash1518 2003

[90] G Kempermann J Krebs and K Fabel ldquoThe contribution offailing adult hippocampal neurogenesis to psychiatric disor-dersrdquo Current Opinion in Psychiatry vol 21 no 3 pp 290ndash2952008

[91] A Reif S Fritzen M Finger et al ldquoNeural stem cell prolif-eration is decreased in schizophrenia but not in depressionrdquoMolecular Psychiatry vol 11 no 5 pp 514ndash522 2006

10 Neural Plasticity

[92] P J Lucassen P Meerlo A S Naylor et al ldquoRegulation ofadult neurogenesis by stress sleep disruption exercise andinflammation Implications for depression and antidepressantactionrdquo European Neuropsychopharmacology vol 20 no 1 pp1ndash17 2010

[93] M Boldrini M D Underwood R Hen et al ldquoAntidepressantsincrease neural progenitor cells in the human hippocampusrdquoNeuropsychopharmacology vol 34 no 11 pp 2376ndash2389 2009

[94] M Boldrini R Hen M D Underwood et al ldquoHippocampalangiogenesis and progenitor cell proliferation are increasedwith antidepressant use in major depressionrdquo Biological Psychi-atry vol 72 pp 562ndash571 2012

[95] M Boldrini A N Santiago R Hen et al ldquoHippocam-pal granule neuron number and dentate gyrus volume inantidepressant-treated and untreated major depressionrdquo Neu-ropsychopharmacology vol 38 pp 1068ndash1077 2013

[96] E Fuchs H Uno and G Flugge ldquoChronic psychosocial stressinduces morphological alterations in hippocampal pyramidalneurons of the tree shrewrdquo Brain Research vol 673 no 2 pp275ndash282 1995

[97] G Vollmann-Honsdorf Lichtmikroskopische und ultrastruk-turelle morphologische Veranderungen in der Hippocampusfor-mation von Tupaia (Tupaia belangeri) als Folge von chronischpsychosozialem Streszlig [PhD thesis] Faculty of Biology Univer-sity of Bielefeld 2001

[98] B SMcEwen ldquoBrain on stress how the social environment getsunder the skinrdquo Proceedings of the National Academy of Sciencesof theUnited States of America vol 109 supplement 2 pp 17180ndash17185 2012

Neural Plasticity 7

that there was more heterochromatin in stressed animalscompared to controls In contrast in area CA1 the stress hadno effect on the density of heterochromatin clusters (Figure 3[97]) Although in those days it was totally unknown whichgenes in the hippocampal nuclei were ldquosilencedrdquo by thechronic stress these morphological data indicated alreadywhat was later called ldquoepigeneticsrdquo the phenomenon thatenvironmental factors change the structure of chromatininfluence transcription and induce changes in the genome[98] Since glucocorticoid hormones are often regarded asimportant factors that convey many effects of chronic stressit was tested whether a chronic cortisol treatment wouldhave the same effects on the chromatin as the chronic socialstress Interestingly chronic cortisol changed the number ofheterochromatin clusters only in hippocampal region CA1but not in CA3 the region that is targeted by stress (Figure 3)These results indicate a site and treatment specific reactionto stress and glucocorticoid treatment in the hippocampalformation The obvious differences between chronic stressand chronic glucocorticoid treatment must be kept in mindbecause they possibly reflect different cellular pathways acti-vated by the two treatments

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] F W Stahnisch and R Nitsch ldquoSantiago Ramon y Cajalrsquosconcept of neuronal plasticity the ambiguity lives onrdquo Trendsin Neurosciences vol 25 no 11 pp 589ndash591 2002

[2] K Zilles ldquoNeuronal plasticity as an adaptive property of thecentral nervous systemrdquo Annals of Anatomy vol 174 no 5 pp383ndash391 1992

[3] G Raisman ldquoNeuronal plasticity in the septal nuclei of the adultratrdquo Brain Research vol 14 no 1 pp 25ndash48 1969

[4] Y Watanabe E Gould and B S McEwen ldquoStress inducesatrophy of apical dendrites of hippocampal CA3 pyramidalneuronsrdquo Brain Research vol 588 no 2 pp 341ndash345 1992

[5] C S Woolley E Gould and B S McEwen ldquoExposure toexcess glucocorticoids alters dendritic morphology of adulthippocampal pyramidal neuronsrdquo Brain Research vol 531 no1-2 pp 225ndash231 1990

[6] A M Magarinos B S McEwen G Flugge and E FuchsldquoChronic psychosocial stress causes apical dendritic atrophyof hippocampal CA3 pyramidal neurons in subordinate treeshrewsrdquo Journal of Neuroscience vol 16 no 10 pp 3534ndash35401996

[7] M H Kole T Costoli J M Koolhaas and E Fuchs ldquoBidi-rectional shift in the cornu ammonis 3 pyramidal dendriticorganization following brief stressrdquo Neuroscience vol 125 no2 pp 337ndash347 2004

[8] S C Cook and C L Wellman ldquoChronic stress alters dendriticmorphology in rat medial prefrontal cortexrdquo Journal of Neuro-biology vol 60 no 2 pp 236ndash248 2004

[9] C Perez-Cruz J I H Muller-Keuker U Heilbronner E Fuchsand G Flugge ldquoMorphology of pyramidal neurons in the ratprefrontal cortex lateralized dendritic remodeling by chronic

stressrdquo Neural Plasticity vol 2007 Article ID 46276 14 pages2007

[10] C Perez-Cruz M Simon G Flugge E Fuchs and B CzehldquoDiurnal rhythm and stress regulate dendritic architecture andspine density of pyramidal neurons in the rat infralimbiccortexrdquo Behavioural Brain Research vol 205 no 2 pp 406ndash4132009

[11] A Vyas R Mitra B S Shankaranarayana Rao and S Chat-tarji ldquoChronic stress induces contrasting patterns of dendriticremodeling in hippocampal and amygdaloid neuronsrdquo Journalof Neuroscience vol 22 no 15 pp 6810ndash6818 2002

[12] C Sandi H A Davies M I Cordero J J Rodriguez V IPopov andM G Stewart ldquoRapid reversal of stress induced lossof synapses in CA3 of rat hippocampus following water mazetrainingrdquo European Journal of Neuroscience vol 17 no 11 pp2447ndash2456 2003

[13] Y Watanabe E Gould D C Daniels H Cameron and B SMcEwen ldquoTianeptine attenuates stress-induced morphologicalchanges in the hippocampusrdquo European Journal of Pharmacol-ogy vol 222 no 1 pp 157ndash162 1992

[14] T V P Bliss and T Lomo ldquoLong lasting potentiation ofsynaptic transmission in the dentate area of the anaesthetizedrabbit following stimulation of the perforant pathrdquo Journal ofPhysiology vol 232 no 2 pp 331ndash356 1973

[15] H G Kuhn T D Palmer and E Fuchs ldquoAdult neurogenesisa compensatory mechanism for neuronal damagerdquo EuropeanArchives of Psychiatry and Clinical Neuroscience vol 251 no 4pp 152ndash158 2001

[16] H Uno R Tarara J G ElseM A Suleman and RM SapolskyldquoHippocampal damage associated with prolonged and fatalstress in primatesrdquo Journal of Neuroscience vol 9 no 5 pp1705ndash1711 1989

[17] R M Sapolsky H Uno C S Rebert and C E Finch ldquoHip-pocampal damage associated with prolonged glucocorticoidexposure in primatesrdquo Journal of Neuroscience vol 10 no 9 pp2897ndash2902 1990

[18] J Cammermeyer ldquoArgentophil neuronal perikarya and neu-rofibrils induced by postmortem trauma and hypertonic per-fusatesrdquo Acta Anatomica vol 105 no 1 pp 9ndash24 1979

[19] G K Vollmann-Honsdorf G Flugge and E Fuchs ldquoChronicpsychosocial stress does not affect the number of pyramidalneurons in tree shrew hippocampusrdquo Neuroscience Letters vol233 no 2-3 pp 121ndash124 1997

[20] P J Lucassen G K Vollmann-HonsdorfMGleisberg B CzehE R De Kloet and E Fuchs ldquoChronic psychosocial stressdifferentially affects apoptosis in hippocampal subregions andcortex of the adult tree shrewrdquoEuropean Journal ofNeurosciencevol 14 no 1 pp 161ndash166 2001

[21] M BMuller P J Lucassen A YassouridisW J G HoogendijkF Holsboer and D F Swaab ldquoNeither major depression norglucocorticoid treatment affects the cellular integrity of thehuman hippocampusrdquo European Journal of Neuroscience vol14 no 10 pp 1603ndash1612 2001

[22] N Sousa M M Paula-Barbosa and O F X Almeida ldquoLigandand subfield specificity of corticoid-induced neuronal loss inthe rat hippocampal formationrdquoNeuroscience vol 89 no 4 pp1079ndash1087 1999

[23] B Czeh T Michaelis T Watanabe et al ldquoStress-inducedchanges in cerebral metabolites hippocampal volume and cellproliferation are prevented by antidepressant treatment withtianeptinerdquo Proceedings of the National Academy of Sciences of

8 Neural Plasticity

the United States of America vol 98 no 22 pp 12796ndash128012001

[24] B Czeh and P J Lucassen ldquoWhat causes the hippocampalvolume decrease in depression Are neurogenesis glial changesand apoptosis implicatedrdquo European Archives of Psychiatry andClinical Neuroscience vol 257 no 5 pp 250ndash260 2007

[25] P J Lucassen J Pruessner N Sousa et al ldquoNeuropathology ofstressrdquo Acta Neuropathologica vol 127 pp 109ndash135 2014

[26] R S Cajal Degeneration and Regeneration of the NervousSystem vol 2 Hafner New York NY USA 1959

[27] J Altman ldquoAre new neurons formed in the brains of adultmammalsrdquo Science vol 135 no 3509 pp 1127ndash1128 1962

[28] J Altman ldquoAutoradiographic investigation of cell proliferationin the brains of rats and catsrdquo The Anatomical record vol 145pp 573ndash591 1963

[29] J Altman and G D Das ldquoAutoradiographic and histologicalevidence of postnatal hippocampal neurogenesis in ratsrdquo Jour-nal of Comparative Neurology vol 124 no 3 pp 319ndash335 1965

[30] M S Kaplan and J W Hinds ldquoNeurogenesis in the adult ratelectronmicroscopic analysis of light radioautographsrdquo Sciencevol 197 no 4308 pp 1092ndash1094 1977

[31] M S Kaplan ldquoNeurogenesis in the 3-month-old rat visualcortexrdquo Journal of Comparative Neurology vol 195 no 2 pp323ndash338 1981

[32] B B Stanfield and J E Trice ldquoEvidence that granule cellsgenerated in the dentate gyrus of adult rats extend axonalprojectionsrdquo Experimental Brain Research vol 72 no 2 pp399ndash406 1988

[33] S A Goldman and F Nottebohm ldquoNeuronal productionmigration and differentiation in a vocal control nucleus of theadult female canary brainrdquo Proceedings of the National Academyof Sciences of the United States of America vol 80 no 8 pp2390ndash2394 1983

[34] A Alvarez-Buylla M Theelen and F Nottebohm ldquoBirth ofprojection neurons in the higher vocal center of the canaryforebrain before during and after song learningrdquoProceedings ofthe National Academy of Sciences of the United States of Americavol 85 no 22 pp 8722ndash8726 1988

[35] F Nottebohm and A P Arnold ldquoSexual dimorphism in vocalcontrol areas of the songbird brainrdquo Science vol 194 no 4261pp 211ndash213 1976

[36] F Nottebohm ldquoFrom bird song to neurogenesisrdquo ScientificAmerican vol 260 no 2 pp 74ndash79 1989

[37] A P Arnold and R A Gorski ldquoGonadal steroid induction ofstructural sex differences in the central nervous systemrdquoAnnualReview of Neuroscience vol 7 pp 413ndash442 1984

[38] P P C Graziadei M S Karlan G A M Graziadei and J JBernstein ldquoNeurogenesis of sensory neurons in the primateolfactory system after section of the fila olfactoriardquo BrainResearch vol 186 no 2 pp 289ndash300 1980

[39] D R Kornack and P Rakic ldquoThe generation migration anddifferentiation of olfactory neurons in the adult primate brainrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 98 no 8 pp 4752ndash4757 2001

[40] A Carleton L T Petreanu R Lansford A Alvarez-Buylla andP-M Lledo ldquoBecoming a new neuron in the adult olfactorybulbrdquo Nature Neuroscience vol 6 no 5 pp 507ndash518 2003

[41] M Sawada and K Sawamoto ldquoMechanisms of neurogenesis inthe normal and injured adult brainrdquo Keio Journal of Medicinevol 62 pp 13ndash28 2013

[42] P Rakic ldquoLimits of neurogenesis in primatesrdquo Science vol 227no 4690 pp 1054ndash1056 1985

[43] M F Eckenhoff and P Rakic ldquoNature and fate of proliferativecells in the hippocampal dentate gyrus during the life span ofthe rhesus monkeyrdquo Journal of Neuroscience vol 8 no 8 pp2729ndash2747 1988

[44] M W Miller and R S Nowakowski ldquoUse of bromodeox-yuridine-immunohistochemistry to examine the proliferationmigration and time of origin of cells in the central nervoussystemrdquo Brain Research vol 457 no 1 pp 44ndash52 1988

[45] H A Cameron ldquoAdult neurogenesis is regulated by adrenalsteroids in the dentate gyrusrdquo Neuroscience vol 61 no 2 pp203ndash209 1994

[46] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997

[47] Y Fan Z Y Huang C C Cao et al ldquoGenome of the Chinesetree shrewrdquo Nature Communications vol 4 article 1426 2013

[48] E Gould P Tanapat B S Mcewen G Flugge and E FuchsldquoProliferation of granule cell precursors in the dentate gyrusof adult monkeys is diminished by stressrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 95 no 6 pp 3168ndash3171 1998

[49] E Gould A J Reeves M Fallah P Tanapat C G Grossand E Fuchs ldquoHippocampal neurogenesis in adult Old Worldprimatesrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 9 pp 5263ndash5267 1999

[50] D R Kornack and P Rakic ldquoContinuation of neurogenesis inthe hippocampus of the adult macaque monkeyrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 96 no 10 pp 5768ndash5773 1999

[51] P S Eriksson E Perfilieva T Bjork-Eriksson et al ldquoNeurogen-esis in the adult human hippocampusrdquo Nature Medicine vol 4no 11 pp 1313ndash1317 1998

[52] G Kempermann and F H Gage ldquoNeurogenesis in the adulthippocampusrdquo Novartis Foundation Symposium vol 231 pp220ndash235 2000

[53] E Gould ldquoHow widespread is adult neurogenesis in mam-malsrdquo Nature Reviews Neuroscience vol 8 no 6 pp 481ndash4882007

[54] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 pp1219ndash1227 2013

[55] A Ernst K Alkass S Bernard et al ldquoNeurogenesis in thestriatum of the adult human brainrdquoCell vol 156 pp 1072ndash10832014

[56] G K H Zupanc ldquoNeurogenesis and neuronal regeneration inthe adult fish brainrdquo Journal of Comparative Physiology A vol192 no 6 pp 649ndash670 2006

[57] M Zhao S Momma K Delfani et al ldquoEvidence for neuroge-nesis in the adult mammalian substantia nigrardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 100 no 13 pp 7925ndash7930 2003

[58] I Amrein K Isler andH P Lipp ldquoComparing adult hippocam-pal neurogenesis in mammalian species and orders Influenceof chronological age and life history stagerdquo European Journal ofNeuroscience vol 34 no 6 pp 978ndash987 2011

[59] L A Voloboueva and R G Giffard ldquoInflammation mito-chondria and the inhibition of adult neurogenesisrdquo Journal ofNeuroscience Research vol 89 no 12 pp 1989ndash1996 2011

Neural Plasticity 9

[60] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003

[61] G Kempermann ldquoSeven principles in the regulation of adultneurogenesisrdquo European Journal of Neuroscience vol 33 no 6pp 1018ndash1024 2011

[62] P Tanapat N B Hastings A J Reeves and E Gould ldquoEstrogenstimulates a transient increase in the number of new neuronsin the dentate gyrus of the adult female ratrdquo Journal ofNeuroscience vol 19 no 14 pp 5792ndash5801 1999

[63] J L Pawluski S Brummelte C K Barha T M Crozier andL A M Galea ldquoEffects of steroid hormones on neurogenesisin the hippocampus of the adult female rodent during theestrous cycle pregnancy lactation and agingrdquo Frontiers inNeuroendocrinology vol 30 no 3 pp 343ndash357 2009

[64] M Sairanen G Lucas P Ernfors M Castren and E CastrenldquoBrain-derived neurotrophic factor and antidepressant drugshave different but coordinated effects on neuronal turnoverproliferation and survival in the adult dentate gyrusrdquo Journalof Neuroscience vol 25 no 5 pp 1089ndash1094 2005

[65] K Jin Y Zhu Y Sun X O Mao L Xie and D A Green-berg ldquoVascular endothelial growth factor (VEGF) stimulatesneurogenesis in vitro and in vivordquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no18 pp 11946ndash11950 2002

[66] K Fabel K Fabel B Tam et al ldquoVEGF is necessary for exercise-induced adult hippocampal neurogenesisrdquo European Journal ofNeuroscience vol 18 no 10 pp 2803ndash2812 2003

[67] H A Cameron B S McEwen and E Gould ldquoRegulation ofadult neurogenesis by excitatory input and NMDA receptoractivation in the dentate gyrusrdquo Journal of Neuroscience vol 15no 6 pp 4687ndash4692 1995

[68] B Seri J M Garcıa-Verdugo B S McEwen and A Alvarez-Buylla ldquoAstrocytes give rise to new neurons in the adultmammalian hippocampusrdquo Journal of Neuroscience vol 21 no18 pp 7153ndash7160 2001

[69] H Song C F Stevens and F H Gage ldquoAstroglia induceneurogenesis from adult neural stem cellsrdquo Nature vol 417 no6884 pp 39ndash44 2002

[70] C ZhaoWDeng and F H Gage ldquoMechanisms and FunctionalImplications of Adult Neurogenesisrdquo Cell vol 132 no 4 pp645ndash660 2008

[71] V M Heine S Maslam J Zareno M Joels and P J LucassenldquoSuppressed proliferation and apoptotic changes in the ratdentate gyrus after acute and chronic stress are reversiblerdquoEuropean Journal of Neuroscience vol 19 no 1 pp 131ndash1442004

[72] C L Coe M Kramer B Czeh et al ldquoPrenatal stress diminishesneurogenesis in the dentate gyrus of juvenile Rhesus monkeysrdquoBiological Psychiatry vol 54 no 10 pp 1025ndash1034 2003

[73] S C Tauber C Schlumbohm L Schilg E Fuchs R Nau and JGerber ldquoIntrauterine exposure to dexamethasone impairs pro-liferation but not neuronal differentiation in the dentate gyrusof newborn commonmarmosetmonkeysrdquoBrain Pathology vol16 no 3 pp 209ndash217 2006

[74] S C Tauber S Bunkowski C Schlumbohm et al ldquoNo long-term effect two years after intrauterine exposure to dexametha-sone on dentate gyrus volume neuronal proliferation and dif-ferentiation in common marmoset monkeysrdquo Brain Pathologyvol 18 no 4 pp 497ndash503 2008

[75] C A Oomen J L Mayer E R De Kloet M Joels and PJ Lucassen ldquoBrief treatment with the glucocorticoid receptor

antagonist mifepristone normalizes the reduction in neurogen-esis after chronic stressrdquo European Journal of Neuroscience vol26 no 12 pp 3395ndash3401 2007

[76] P Gass O Kretz D P Wolfer et al ldquoGenetic disruption ofmineralocorticoid receptor leads to impaired neurogenesis andgranule cell degeneration in the hippocampus of adult micerdquoEMBO Reports vol 1 no 5 pp 447ndash451 2000

[77] J E Malberg A J Eisch E J Nestler and R S DumanldquoChronic antidepressant treatment increases neurogenesis inadult rat hippocampusrdquo Journal of Neuroscience vol 20 no 24pp 9104ndash9110 2000

[78] C Anacker P A Zunszain A Cattaneo et al ldquoAntidepressantsincrease human hippocampal neurogenesis by activating theglucocorticoid receptorrdquoMolecular Psychiatry vol 16 no 7 pp738ndash750 2011

[79] M SawadaMMatsumoto andK Sawamoto ldquoVascular regula-tion of adult neurogenesis under physiological and pathologicalconditionsrdquo Frontiers in Neuroscience vol 8 article 53 2014

[80] H van Praag G Kempermann and F H Gage ldquoNeuralConsequences of environmental enrichmentrdquo Nature ReviewsNeuroscience vol 1 no 3 pp 191ndash198 2000

[81] E Gould P Tanapat N B Hastings and T J Shors ldquoNeurogen-esis in adulthood a posible role in learningrdquoTrends in CognitiveSciences vol 3 no 5 pp 186ndash192 1999

[82] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 pp 569ndash578 1999

[83] G Kempermann D Gast and F H Gage ldquoNeuroplasticityin old age sustained fivefold induction of hippocampal neu-rogenesis by long-term environmental enrichmentrdquo Annals ofNeurology vol 52 no 2 pp 135ndash143 2002

[84] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006

[85] M Koehl and D N Abrous ldquoA new chapter in the field ofmemory adult hippocampal neurogenesisrdquo European Journalof Neuroscience vol 33 no 6 pp 1101ndash1114 2011

[86] I Amrein D K N Dechmann Y Winter and H-P LippldquoAbsent or low rate of adult neurogenesis in the hippocampusof bats (Chiroptera)rdquo PLoS ONE vol 2 no 5 article e455 2007

[87] N Patzke M A Spocter K A Karlsson et al ldquoIn contrastto many other mammals cetaceans have relatively small hip-pocampi that appear to lack adult neurogenesisrdquoBrain Structureand Function 2013

[88] G Lepousez M T Valley and P M Lledo ldquoThe impact of adultneurogenesis on olfactory bulb circuits and computationsrdquoAnnual Review of Physiology vol 75 pp 339ndash363 2013

[89] Y I Sheline M H Gado and H C Kraemer ldquoUntreateddepression and hippocampal volume lossrdquo American Journal ofPsychiatry vol 160 no 8 pp 1516ndash1518 2003

[90] G Kempermann J Krebs and K Fabel ldquoThe contribution offailing adult hippocampal neurogenesis to psychiatric disor-dersrdquo Current Opinion in Psychiatry vol 21 no 3 pp 290ndash2952008

[91] A Reif S Fritzen M Finger et al ldquoNeural stem cell prolif-eration is decreased in schizophrenia but not in depressionrdquoMolecular Psychiatry vol 11 no 5 pp 514ndash522 2006

10 Neural Plasticity

[92] P J Lucassen P Meerlo A S Naylor et al ldquoRegulation ofadult neurogenesis by stress sleep disruption exercise andinflammation Implications for depression and antidepressantactionrdquo European Neuropsychopharmacology vol 20 no 1 pp1ndash17 2010

[93] M Boldrini M D Underwood R Hen et al ldquoAntidepressantsincrease neural progenitor cells in the human hippocampusrdquoNeuropsychopharmacology vol 34 no 11 pp 2376ndash2389 2009

[94] M Boldrini R Hen M D Underwood et al ldquoHippocampalangiogenesis and progenitor cell proliferation are increasedwith antidepressant use in major depressionrdquo Biological Psychi-atry vol 72 pp 562ndash571 2012

[95] M Boldrini A N Santiago R Hen et al ldquoHippocam-pal granule neuron number and dentate gyrus volume inantidepressant-treated and untreated major depressionrdquo Neu-ropsychopharmacology vol 38 pp 1068ndash1077 2013

[96] E Fuchs H Uno and G Flugge ldquoChronic psychosocial stressinduces morphological alterations in hippocampal pyramidalneurons of the tree shrewrdquo Brain Research vol 673 no 2 pp275ndash282 1995

[97] G Vollmann-Honsdorf Lichtmikroskopische und ultrastruk-turelle morphologische Veranderungen in der Hippocampusfor-mation von Tupaia (Tupaia belangeri) als Folge von chronischpsychosozialem Streszlig [PhD thesis] Faculty of Biology Univer-sity of Bielefeld 2001

[98] B SMcEwen ldquoBrain on stress how the social environment getsunder the skinrdquo Proceedings of the National Academy of Sciencesof theUnited States of America vol 109 supplement 2 pp 17180ndash17185 2012

8 Neural Plasticity

the United States of America vol 98 no 22 pp 12796ndash128012001

[24] B Czeh and P J Lucassen ldquoWhat causes the hippocampalvolume decrease in depression Are neurogenesis glial changesand apoptosis implicatedrdquo European Archives of Psychiatry andClinical Neuroscience vol 257 no 5 pp 250ndash260 2007

[25] P J Lucassen J Pruessner N Sousa et al ldquoNeuropathology ofstressrdquo Acta Neuropathologica vol 127 pp 109ndash135 2014

[26] R S Cajal Degeneration and Regeneration of the NervousSystem vol 2 Hafner New York NY USA 1959

[27] J Altman ldquoAre new neurons formed in the brains of adultmammalsrdquo Science vol 135 no 3509 pp 1127ndash1128 1962

[28] J Altman ldquoAutoradiographic investigation of cell proliferationin the brains of rats and catsrdquo The Anatomical record vol 145pp 573ndash591 1963

[29] J Altman and G D Das ldquoAutoradiographic and histologicalevidence of postnatal hippocampal neurogenesis in ratsrdquo Jour-nal of Comparative Neurology vol 124 no 3 pp 319ndash335 1965

[30] M S Kaplan and J W Hinds ldquoNeurogenesis in the adult ratelectronmicroscopic analysis of light radioautographsrdquo Sciencevol 197 no 4308 pp 1092ndash1094 1977

[31] M S Kaplan ldquoNeurogenesis in the 3-month-old rat visualcortexrdquo Journal of Comparative Neurology vol 195 no 2 pp323ndash338 1981

[32] B B Stanfield and J E Trice ldquoEvidence that granule cellsgenerated in the dentate gyrus of adult rats extend axonalprojectionsrdquo Experimental Brain Research vol 72 no 2 pp399ndash406 1988

[33] S A Goldman and F Nottebohm ldquoNeuronal productionmigration and differentiation in a vocal control nucleus of theadult female canary brainrdquo Proceedings of the National Academyof Sciences of the United States of America vol 80 no 8 pp2390ndash2394 1983

[34] A Alvarez-Buylla M Theelen and F Nottebohm ldquoBirth ofprojection neurons in the higher vocal center of the canaryforebrain before during and after song learningrdquoProceedings ofthe National Academy of Sciences of the United States of Americavol 85 no 22 pp 8722ndash8726 1988

[35] F Nottebohm and A P Arnold ldquoSexual dimorphism in vocalcontrol areas of the songbird brainrdquo Science vol 194 no 4261pp 211ndash213 1976

[36] F Nottebohm ldquoFrom bird song to neurogenesisrdquo ScientificAmerican vol 260 no 2 pp 74ndash79 1989

[37] A P Arnold and R A Gorski ldquoGonadal steroid induction ofstructural sex differences in the central nervous systemrdquoAnnualReview of Neuroscience vol 7 pp 413ndash442 1984

[38] P P C Graziadei M S Karlan G A M Graziadei and J JBernstein ldquoNeurogenesis of sensory neurons in the primateolfactory system after section of the fila olfactoriardquo BrainResearch vol 186 no 2 pp 289ndash300 1980

[39] D R Kornack and P Rakic ldquoThe generation migration anddifferentiation of olfactory neurons in the adult primate brainrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 98 no 8 pp 4752ndash4757 2001

[40] A Carleton L T Petreanu R Lansford A Alvarez-Buylla andP-M Lledo ldquoBecoming a new neuron in the adult olfactorybulbrdquo Nature Neuroscience vol 6 no 5 pp 507ndash518 2003

[41] M Sawada and K Sawamoto ldquoMechanisms of neurogenesis inthe normal and injured adult brainrdquo Keio Journal of Medicinevol 62 pp 13ndash28 2013

[42] P Rakic ldquoLimits of neurogenesis in primatesrdquo Science vol 227no 4690 pp 1054ndash1056 1985

[43] M F Eckenhoff and P Rakic ldquoNature and fate of proliferativecells in the hippocampal dentate gyrus during the life span ofthe rhesus monkeyrdquo Journal of Neuroscience vol 8 no 8 pp2729ndash2747 1988

[44] M W Miller and R S Nowakowski ldquoUse of bromodeox-yuridine-immunohistochemistry to examine the proliferationmigration and time of origin of cells in the central nervoussystemrdquo Brain Research vol 457 no 1 pp 44ndash52 1988

[45] H A Cameron ldquoAdult neurogenesis is regulated by adrenalsteroids in the dentate gyrusrdquo Neuroscience vol 61 no 2 pp203ndash209 1994

[46] E Gould B S McEwen P Tanapat L A M Galea and EFuchs ldquoNeurogenesis in the dentate gyrus of the adult treeshrew is regulated by psychosocial stress and NMDA receptoractivationrdquo Journal of Neuroscience vol 17 no 7 pp 2492ndash24981997

[47] Y Fan Z Y Huang C C Cao et al ldquoGenome of the Chinesetree shrewrdquo Nature Communications vol 4 article 1426 2013

[48] E Gould P Tanapat B S Mcewen G Flugge and E FuchsldquoProliferation of granule cell precursors in the dentate gyrusof adult monkeys is diminished by stressrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 95 no 6 pp 3168ndash3171 1998

[49] E Gould A J Reeves M Fallah P Tanapat C G Grossand E Fuchs ldquoHippocampal neurogenesis in adult Old Worldprimatesrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 9 pp 5263ndash5267 1999

[50] D R Kornack and P Rakic ldquoContinuation of neurogenesis inthe hippocampus of the adult macaque monkeyrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 96 no 10 pp 5768ndash5773 1999

[51] P S Eriksson E Perfilieva T Bjork-Eriksson et al ldquoNeurogen-esis in the adult human hippocampusrdquo Nature Medicine vol 4no 11 pp 1313ndash1317 1998

[52] G Kempermann and F H Gage ldquoNeurogenesis in the adulthippocampusrdquo Novartis Foundation Symposium vol 231 pp220ndash235 2000

[53] E Gould ldquoHow widespread is adult neurogenesis in mam-malsrdquo Nature Reviews Neuroscience vol 8 no 6 pp 481ndash4882007

[54] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 pp1219ndash1227 2013

[55] A Ernst K Alkass S Bernard et al ldquoNeurogenesis in thestriatum of the adult human brainrdquoCell vol 156 pp 1072ndash10832014

[56] G K H Zupanc ldquoNeurogenesis and neuronal regeneration inthe adult fish brainrdquo Journal of Comparative Physiology A vol192 no 6 pp 649ndash670 2006

[57] M Zhao S Momma K Delfani et al ldquoEvidence for neuroge-nesis in the adult mammalian substantia nigrardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 100 no 13 pp 7925ndash7930 2003

[58] I Amrein K Isler andH P Lipp ldquoComparing adult hippocam-pal neurogenesis in mammalian species and orders Influenceof chronological age and life history stagerdquo European Journal ofNeuroscience vol 34 no 6 pp 978ndash987 2011

[59] L A Voloboueva and R G Giffard ldquoInflammation mito-chondria and the inhibition of adult neurogenesisrdquo Journal ofNeuroscience Research vol 89 no 12 pp 1989ndash1996 2011

Neural Plasticity 9

[60] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003

[61] G Kempermann ldquoSeven principles in the regulation of adultneurogenesisrdquo European Journal of Neuroscience vol 33 no 6pp 1018ndash1024 2011

[62] P Tanapat N B Hastings A J Reeves and E Gould ldquoEstrogenstimulates a transient increase in the number of new neuronsin the dentate gyrus of the adult female ratrdquo Journal ofNeuroscience vol 19 no 14 pp 5792ndash5801 1999

[63] J L Pawluski S Brummelte C K Barha T M Crozier andL A M Galea ldquoEffects of steroid hormones on neurogenesisin the hippocampus of the adult female rodent during theestrous cycle pregnancy lactation and agingrdquo Frontiers inNeuroendocrinology vol 30 no 3 pp 343ndash357 2009

[64] M Sairanen G Lucas P Ernfors M Castren and E CastrenldquoBrain-derived neurotrophic factor and antidepressant drugshave different but coordinated effects on neuronal turnoverproliferation and survival in the adult dentate gyrusrdquo Journalof Neuroscience vol 25 no 5 pp 1089ndash1094 2005

[65] K Jin Y Zhu Y Sun X O Mao L Xie and D A Green-berg ldquoVascular endothelial growth factor (VEGF) stimulatesneurogenesis in vitro and in vivordquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no18 pp 11946ndash11950 2002

[66] K Fabel K Fabel B Tam et al ldquoVEGF is necessary for exercise-induced adult hippocampal neurogenesisrdquo European Journal ofNeuroscience vol 18 no 10 pp 2803ndash2812 2003

[67] H A Cameron B S McEwen and E Gould ldquoRegulation ofadult neurogenesis by excitatory input and NMDA receptoractivation in the dentate gyrusrdquo Journal of Neuroscience vol 15no 6 pp 4687ndash4692 1995

[68] B Seri J M Garcıa-Verdugo B S McEwen and A Alvarez-Buylla ldquoAstrocytes give rise to new neurons in the adultmammalian hippocampusrdquo Journal of Neuroscience vol 21 no18 pp 7153ndash7160 2001

[69] H Song C F Stevens and F H Gage ldquoAstroglia induceneurogenesis from adult neural stem cellsrdquo Nature vol 417 no6884 pp 39ndash44 2002

[70] C ZhaoWDeng and F H Gage ldquoMechanisms and FunctionalImplications of Adult Neurogenesisrdquo Cell vol 132 no 4 pp645ndash660 2008

[71] V M Heine S Maslam J Zareno M Joels and P J LucassenldquoSuppressed proliferation and apoptotic changes in the ratdentate gyrus after acute and chronic stress are reversiblerdquoEuropean Journal of Neuroscience vol 19 no 1 pp 131ndash1442004

[72] C L Coe M Kramer B Czeh et al ldquoPrenatal stress diminishesneurogenesis in the dentate gyrus of juvenile Rhesus monkeysrdquoBiological Psychiatry vol 54 no 10 pp 1025ndash1034 2003

[73] S C Tauber C Schlumbohm L Schilg E Fuchs R Nau and JGerber ldquoIntrauterine exposure to dexamethasone impairs pro-liferation but not neuronal differentiation in the dentate gyrusof newborn commonmarmosetmonkeysrdquoBrain Pathology vol16 no 3 pp 209ndash217 2006

[74] S C Tauber S Bunkowski C Schlumbohm et al ldquoNo long-term effect two years after intrauterine exposure to dexametha-sone on dentate gyrus volume neuronal proliferation and dif-ferentiation in common marmoset monkeysrdquo Brain Pathologyvol 18 no 4 pp 497ndash503 2008

[75] C A Oomen J L Mayer E R De Kloet M Joels and PJ Lucassen ldquoBrief treatment with the glucocorticoid receptor

antagonist mifepristone normalizes the reduction in neurogen-esis after chronic stressrdquo European Journal of Neuroscience vol26 no 12 pp 3395ndash3401 2007

[76] P Gass O Kretz D P Wolfer et al ldquoGenetic disruption ofmineralocorticoid receptor leads to impaired neurogenesis andgranule cell degeneration in the hippocampus of adult micerdquoEMBO Reports vol 1 no 5 pp 447ndash451 2000

[77] J E Malberg A J Eisch E J Nestler and R S DumanldquoChronic antidepressant treatment increases neurogenesis inadult rat hippocampusrdquo Journal of Neuroscience vol 20 no 24pp 9104ndash9110 2000

[78] C Anacker P A Zunszain A Cattaneo et al ldquoAntidepressantsincrease human hippocampal neurogenesis by activating theglucocorticoid receptorrdquoMolecular Psychiatry vol 16 no 7 pp738ndash750 2011

[79] M SawadaMMatsumoto andK Sawamoto ldquoVascular regula-tion of adult neurogenesis under physiological and pathologicalconditionsrdquo Frontiers in Neuroscience vol 8 article 53 2014

[80] H van Praag G Kempermann and F H Gage ldquoNeuralConsequences of environmental enrichmentrdquo Nature ReviewsNeuroscience vol 1 no 3 pp 191ndash198 2000

[81] E Gould P Tanapat N B Hastings and T J Shors ldquoNeurogen-esis in adulthood a posible role in learningrdquoTrends in CognitiveSciences vol 3 no 5 pp 186ndash192 1999

[82] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 pp 569ndash578 1999

[83] G Kempermann D Gast and F H Gage ldquoNeuroplasticityin old age sustained fivefold induction of hippocampal neu-rogenesis by long-term environmental enrichmentrdquo Annals ofNeurology vol 52 no 2 pp 135ndash143 2002

[84] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006

[85] M Koehl and D N Abrous ldquoA new chapter in the field ofmemory adult hippocampal neurogenesisrdquo European Journalof Neuroscience vol 33 no 6 pp 1101ndash1114 2011

[86] I Amrein D K N Dechmann Y Winter and H-P LippldquoAbsent or low rate of adult neurogenesis in the hippocampusof bats (Chiroptera)rdquo PLoS ONE vol 2 no 5 article e455 2007

[87] N Patzke M A Spocter K A Karlsson et al ldquoIn contrastto many other mammals cetaceans have relatively small hip-pocampi that appear to lack adult neurogenesisrdquoBrain Structureand Function 2013

[88] G Lepousez M T Valley and P M Lledo ldquoThe impact of adultneurogenesis on olfactory bulb circuits and computationsrdquoAnnual Review of Physiology vol 75 pp 339ndash363 2013

[89] Y I Sheline M H Gado and H C Kraemer ldquoUntreateddepression and hippocampal volume lossrdquo American Journal ofPsychiatry vol 160 no 8 pp 1516ndash1518 2003

[90] G Kempermann J Krebs and K Fabel ldquoThe contribution offailing adult hippocampal neurogenesis to psychiatric disor-dersrdquo Current Opinion in Psychiatry vol 21 no 3 pp 290ndash2952008

[91] A Reif S Fritzen M Finger et al ldquoNeural stem cell prolif-eration is decreased in schizophrenia but not in depressionrdquoMolecular Psychiatry vol 11 no 5 pp 514ndash522 2006

10 Neural Plasticity

[92] P J Lucassen P Meerlo A S Naylor et al ldquoRegulation ofadult neurogenesis by stress sleep disruption exercise andinflammation Implications for depression and antidepressantactionrdquo European Neuropsychopharmacology vol 20 no 1 pp1ndash17 2010

[93] M Boldrini M D Underwood R Hen et al ldquoAntidepressantsincrease neural progenitor cells in the human hippocampusrdquoNeuropsychopharmacology vol 34 no 11 pp 2376ndash2389 2009

[94] M Boldrini R Hen M D Underwood et al ldquoHippocampalangiogenesis and progenitor cell proliferation are increasedwith antidepressant use in major depressionrdquo Biological Psychi-atry vol 72 pp 562ndash571 2012

[95] M Boldrini A N Santiago R Hen et al ldquoHippocam-pal granule neuron number and dentate gyrus volume inantidepressant-treated and untreated major depressionrdquo Neu-ropsychopharmacology vol 38 pp 1068ndash1077 2013

[96] E Fuchs H Uno and G Flugge ldquoChronic psychosocial stressinduces morphological alterations in hippocampal pyramidalneurons of the tree shrewrdquo Brain Research vol 673 no 2 pp275ndash282 1995

[97] G Vollmann-Honsdorf Lichtmikroskopische und ultrastruk-turelle morphologische Veranderungen in der Hippocampusfor-mation von Tupaia (Tupaia belangeri) als Folge von chronischpsychosozialem Streszlig [PhD thesis] Faculty of Biology Univer-sity of Bielefeld 2001

[98] B SMcEwen ldquoBrain on stress how the social environment getsunder the skinrdquo Proceedings of the National Academy of Sciencesof theUnited States of America vol 109 supplement 2 pp 17180ndash17185 2012

Neural Plasticity 9

[60] M L Monje H Toda and T D Palmer ldquoInflammatoryblockade restores adult hippocampal neurogenesisrdquo Sciencevol 302 no 5651 pp 1760ndash1765 2003

[61] G Kempermann ldquoSeven principles in the regulation of adultneurogenesisrdquo European Journal of Neuroscience vol 33 no 6pp 1018ndash1024 2011

[62] P Tanapat N B Hastings A J Reeves and E Gould ldquoEstrogenstimulates a transient increase in the number of new neuronsin the dentate gyrus of the adult female ratrdquo Journal ofNeuroscience vol 19 no 14 pp 5792ndash5801 1999

[63] J L Pawluski S Brummelte C K Barha T M Crozier andL A M Galea ldquoEffects of steroid hormones on neurogenesisin the hippocampus of the adult female rodent during theestrous cycle pregnancy lactation and agingrdquo Frontiers inNeuroendocrinology vol 30 no 3 pp 343ndash357 2009

[64] M Sairanen G Lucas P Ernfors M Castren and E CastrenldquoBrain-derived neurotrophic factor and antidepressant drugshave different but coordinated effects on neuronal turnoverproliferation and survival in the adult dentate gyrusrdquo Journalof Neuroscience vol 25 no 5 pp 1089ndash1094 2005

[65] K Jin Y Zhu Y Sun X O Mao L Xie and D A Green-berg ldquoVascular endothelial growth factor (VEGF) stimulatesneurogenesis in vitro and in vivordquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no18 pp 11946ndash11950 2002

[66] K Fabel K Fabel B Tam et al ldquoVEGF is necessary for exercise-induced adult hippocampal neurogenesisrdquo European Journal ofNeuroscience vol 18 no 10 pp 2803ndash2812 2003

[67] H A Cameron B S McEwen and E Gould ldquoRegulation ofadult neurogenesis by excitatory input and NMDA receptoractivation in the dentate gyrusrdquo Journal of Neuroscience vol 15no 6 pp 4687ndash4692 1995

[68] B Seri J M Garcıa-Verdugo B S McEwen and A Alvarez-Buylla ldquoAstrocytes give rise to new neurons in the adultmammalian hippocampusrdquo Journal of Neuroscience vol 21 no18 pp 7153ndash7160 2001

[69] H Song C F Stevens and F H Gage ldquoAstroglia induceneurogenesis from adult neural stem cellsrdquo Nature vol 417 no6884 pp 39ndash44 2002

[70] C ZhaoWDeng and F H Gage ldquoMechanisms and FunctionalImplications of Adult Neurogenesisrdquo Cell vol 132 no 4 pp645ndash660 2008

[71] V M Heine S Maslam J Zareno M Joels and P J LucassenldquoSuppressed proliferation and apoptotic changes in the ratdentate gyrus after acute and chronic stress are reversiblerdquoEuropean Journal of Neuroscience vol 19 no 1 pp 131ndash1442004

[72] C L Coe M Kramer B Czeh et al ldquoPrenatal stress diminishesneurogenesis in the dentate gyrus of juvenile Rhesus monkeysrdquoBiological Psychiatry vol 54 no 10 pp 1025ndash1034 2003

[73] S C Tauber C Schlumbohm L Schilg E Fuchs R Nau and JGerber ldquoIntrauterine exposure to dexamethasone impairs pro-liferation but not neuronal differentiation in the dentate gyrusof newborn commonmarmosetmonkeysrdquoBrain Pathology vol16 no 3 pp 209ndash217 2006

[74] S C Tauber S Bunkowski C Schlumbohm et al ldquoNo long-term effect two years after intrauterine exposure to dexametha-sone on dentate gyrus volume neuronal proliferation and dif-ferentiation in common marmoset monkeysrdquo Brain Pathologyvol 18 no 4 pp 497ndash503 2008

[75] C A Oomen J L Mayer E R De Kloet M Joels and PJ Lucassen ldquoBrief treatment with the glucocorticoid receptor

antagonist mifepristone normalizes the reduction in neurogen-esis after chronic stressrdquo European Journal of Neuroscience vol26 no 12 pp 3395ndash3401 2007

[76] P Gass O Kretz D P Wolfer et al ldquoGenetic disruption ofmineralocorticoid receptor leads to impaired neurogenesis andgranule cell degeneration in the hippocampus of adult micerdquoEMBO Reports vol 1 no 5 pp 447ndash451 2000

[77] J E Malberg A J Eisch E J Nestler and R S DumanldquoChronic antidepressant treatment increases neurogenesis inadult rat hippocampusrdquo Journal of Neuroscience vol 20 no 24pp 9104ndash9110 2000

[78] C Anacker P A Zunszain A Cattaneo et al ldquoAntidepressantsincrease human hippocampal neurogenesis by activating theglucocorticoid receptorrdquoMolecular Psychiatry vol 16 no 7 pp738ndash750 2011

[79] M SawadaMMatsumoto andK Sawamoto ldquoVascular regula-tion of adult neurogenesis under physiological and pathologicalconditionsrdquo Frontiers in Neuroscience vol 8 article 53 2014

[80] H van Praag G Kempermann and F H Gage ldquoNeuralConsequences of environmental enrichmentrdquo Nature ReviewsNeuroscience vol 1 no 3 pp 191ndash198 2000

[81] E Gould P Tanapat N B Hastings and T J Shors ldquoNeurogen-esis in adulthood a posible role in learningrdquoTrends in CognitiveSciences vol 3 no 5 pp 186ndash192 1999

[82] M Nilsson E Perfilieva U Johansson O Orwar and P SEriksson ldquoEnriched environment increases neurogenesis in theadult rat dentate gyrus and improves spatial memoryrdquo Journalof Neurobiology vol 39 pp 569ndash578 1999

[83] G Kempermann D Gast and F H Gage ldquoNeuroplasticityin old age sustained fivefold induction of hippocampal neu-rogenesis by long-term environmental enrichmentrdquo Annals ofNeurology vol 52 no 2 pp 135ndash143 2002

[84] C Rossi A Angelucci L Costantin et al ldquoBrain-derivedneurotrophic factor (BDNF) is required for the enhancementof hippocampal neurogenesis following environmental enrich-mentrdquo European Journal of Neuroscience vol 24 no 7 pp 1850ndash1856 2006

[85] M Koehl and D N Abrous ldquoA new chapter in the field ofmemory adult hippocampal neurogenesisrdquo European Journalof Neuroscience vol 33 no 6 pp 1101ndash1114 2011

[86] I Amrein D K N Dechmann Y Winter and H-P LippldquoAbsent or low rate of adult neurogenesis in the hippocampusof bats (Chiroptera)rdquo PLoS ONE vol 2 no 5 article e455 2007

[87] N Patzke M A Spocter K A Karlsson et al ldquoIn contrastto many other mammals cetaceans have relatively small hip-pocampi that appear to lack adult neurogenesisrdquoBrain Structureand Function 2013

[88] G Lepousez M T Valley and P M Lledo ldquoThe impact of adultneurogenesis on olfactory bulb circuits and computationsrdquoAnnual Review of Physiology vol 75 pp 339ndash363 2013

[89] Y I Sheline M H Gado and H C Kraemer ldquoUntreateddepression and hippocampal volume lossrdquo American Journal ofPsychiatry vol 160 no 8 pp 1516ndash1518 2003

[90] G Kempermann J Krebs and K Fabel ldquoThe contribution offailing adult hippocampal neurogenesis to psychiatric disor-dersrdquo Current Opinion in Psychiatry vol 21 no 3 pp 290ndash2952008

[91] A Reif S Fritzen M Finger et al ldquoNeural stem cell prolif-eration is decreased in schizophrenia but not in depressionrdquoMolecular Psychiatry vol 11 no 5 pp 514ndash522 2006

10 Neural Plasticity

[92] P J Lucassen P Meerlo A S Naylor et al ldquoRegulation ofadult neurogenesis by stress sleep disruption exercise andinflammation Implications for depression and antidepressantactionrdquo European Neuropsychopharmacology vol 20 no 1 pp1ndash17 2010

[93] M Boldrini M D Underwood R Hen et al ldquoAntidepressantsincrease neural progenitor cells in the human hippocampusrdquoNeuropsychopharmacology vol 34 no 11 pp 2376ndash2389 2009

[94] M Boldrini R Hen M D Underwood et al ldquoHippocampalangiogenesis and progenitor cell proliferation are increasedwith antidepressant use in major depressionrdquo Biological Psychi-atry vol 72 pp 562ndash571 2012

[95] M Boldrini A N Santiago R Hen et al ldquoHippocam-pal granule neuron number and dentate gyrus volume inantidepressant-treated and untreated major depressionrdquo Neu-ropsychopharmacology vol 38 pp 1068ndash1077 2013

[96] E Fuchs H Uno and G Flugge ldquoChronic psychosocial stressinduces morphological alterations in hippocampal pyramidalneurons of the tree shrewrdquo Brain Research vol 673 no 2 pp275ndash282 1995

[97] G Vollmann-Honsdorf Lichtmikroskopische und ultrastruk-turelle morphologische Veranderungen in der Hippocampusfor-mation von Tupaia (Tupaia belangeri) als Folge von chronischpsychosozialem Streszlig [PhD thesis] Faculty of Biology Univer-sity of Bielefeld 2001

[98] B SMcEwen ldquoBrain on stress how the social environment getsunder the skinrdquo Proceedings of the National Academy of Sciencesof theUnited States of America vol 109 supplement 2 pp 17180ndash17185 2012

10 Neural Plasticity

[92] P J Lucassen P Meerlo A S Naylor et al ldquoRegulation ofadult neurogenesis by stress sleep disruption exercise andinflammation Implications for depression and antidepressantactionrdquo European Neuropsychopharmacology vol 20 no 1 pp1ndash17 2010

[93] M Boldrini M D Underwood R Hen et al ldquoAntidepressantsincrease neural progenitor cells in the human hippocampusrdquoNeuropsychopharmacology vol 34 no 11 pp 2376ndash2389 2009

[94] M Boldrini R Hen M D Underwood et al ldquoHippocampalangiogenesis and progenitor cell proliferation are increasedwith antidepressant use in major depressionrdquo Biological Psychi-atry vol 72 pp 562ndash571 2012

[95] M Boldrini A N Santiago R Hen et al ldquoHippocam-pal granule neuron number and dentate gyrus volume inantidepressant-treated and untreated major depressionrdquo Neu-ropsychopharmacology vol 38 pp 1068ndash1077 2013

[96] E Fuchs H Uno and G Flugge ldquoChronic psychosocial stressinduces morphological alterations in hippocampal pyramidalneurons of the tree shrewrdquo Brain Research vol 673 no 2 pp275ndash282 1995

[97] G Vollmann-Honsdorf Lichtmikroskopische und ultrastruk-turelle morphologische Veranderungen in der Hippocampusfor-mation von Tupaia (Tupaia belangeri) als Folge von chronischpsychosozialem Streszlig [PhD thesis] Faculty of Biology Univer-sity of Bielefeld 2001

[98] B SMcEwen ldquoBrain on stress how the social environment getsunder the skinrdquo Proceedings of the National Academy of Sciencesof theUnited States of America vol 109 supplement 2 pp 17180ndash17185 2012