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3 From Indifference to Ardor: The Onset, Maintenance,and Meaning of the Maternal BrainG Gonzalez-Mariscal, CINVESTAV-Universidad Autonoma de Tlaxcala, Tlaxcala, Mexico

C H Kinsley, University of Richmond, Richmond, VA, USA

� 2009 Elsevier Inc. All rights reserved.

Chapter Outline

3.1 Introduction 2

3.2 Endocrine Control 2

3.2.1 Prepartum Activities 2

3.2.1.1 Nest-building 2

3.2.1.2 Maternal aggression and isolation behavior 3

3.2.1.3 Food intake 3

3.2.2 Behaviors at Parturition 3

3.2.3 Postpartum Activities 4

3.2.3.1 Nursing 4

3.2.3.2 Maternal behavior without nursing 5

3.3 Neural Control 5

3.3.1 Cortex, Trigeminal Complex, and Olfactory Circuit 5

3.3.2 Septum and Bed Nucleus of the Stria Terminalis 6

3.3.3 MPOA and Its Connections 7

3.3.3.1 Studies using lesion and deafferentation techniques 7

3.3.3.2 Studies using implantation of hormones and detection of their receptors 8

3.3.4 Midbrain Tegmentum, Paraventricular Nucleus, and Habenular Complex 9

3.3.5 Sampling the Active Parental Brain 10

3.3.5.1 The expression of immediate early genes 10

3.3.5.2 Other methods 12

3.4 Epigenetic, Intergenerational Transmission of Mothering Styles:

Its Impact on Offspring Development 12

3.5 Impact of Maternal Behavior on the Mother: Effects on Cognition and

Neuroplasticity 15

3.5.1 Theoretical Context 15

3.5.2 Fear and Anxiety Regulation 16

3.5.2.1 Behaviors affected 16

3.5.2.2 Brain mechanisms 16

3.5.3 Regulation of Cognitive Effects 17

3.5.3.1 Learning and memory 17

3.5.3.2 Neural regulation of cognitive effects 17

3.6 Conclusions and Perspectives 19

References 20

Further Reading 28

Glossaryg0005 dendritic spines Tiny protuberances arising from

the pinching-off and extension of the

dendrite of neurons, which are sensitive

to presynaptic stimulation, neurotrophic

factors, and selected hormones. Such

spines provide substantial increases to

the surface area of an individual neuron,

and therefore differential changes to its

information processing capacity.

g0010maternal behavior A constellation of behaviors

that is designed to ensure the survival and

1

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These results coincide with the observation that therabbit MPOA has a high concentration of receptorsfor estrogens (ERa; Caba et al., 2003a) and for pro-gestins (PRs; Caba et al., 2003b). In sows receptorsfor PGF2a have been reported in the brain (Burne,2000). Surprisingly, few studies have explored thehormonal control of nest-building in rodents. In rats(Denenberg et al., 1969), mice (Lisk, 1971), and ham-sters (Swanson and Campbell, 1979), some combi-nations of estradiol and progesterone promote theaccumulation of shredded material but, to our knowl-edge, the brain sites where these hormones act topromote nest-building are unknown.

s0025 3.2.1.2 Maternal aggression and isolation

behaviorp0015 Several rodents show aggression to intruders in late

pregnancy; estradiol and progesterone are some ofthe factors involved in stimulating this activity (forreview, see Numan et al. (2006)), which is maximalacross lactation (see below). Shortly before parturi-tion ungulates (i.e., sheep, goats, and sows) isolatethemselves from the herd, show restlessness and agi-tation, and they emit vocalizations (Poindron et al.,2007a,b; Algers and Uvnas-Moberg, 2007). Althoughthe participation of hormones in these activities hasnot been directly explored, their occurrence close toparturition suggests an involvement of the hormonesthat time and control delivery.

s0030 3.2.1.3 Food intakep0020 Changes in this parameter have been reported during

the peripartum period in some species, both in termsof quantity (food intake declines by about 60% onprepartum day 1 in rabbits; Gonzalez-Mariscal et al.,1994) and quality (meaty foodstuffs are consumed byrodents (Gregg and Wynne-Edwards, 2006; Kristal,1991) and rabbits (Melo and Gonzalez-Mariscal,2003); amniotic fluid is consumed by ungulates(Poindron et al., 2007a)). There is evidence that and-rogens decrease food intake in rabbits (Gonzalez-Mariscal et al., 2003) but hardly anything is knownabout the hormonal factors modulating food prefer-ences around delivery in any species.

s0035 3.2.2 Behaviors at Parturition

p0025 Placentophagia and amniotic fluid ingestion are con-sistently observed following delivery in most mam-mals studied (Poindron et al., 2007a; Gregg andWynne-Edwards, 2006; Kristal, 1991; Melo andGonzalez-Mariscal, 2003). Little is known about the

consequences of placentophagia on the mother,although an analgesic effect has been shown in rats(Kristal, 1991); for the newborn the licking theyreceive from the mother as she consumes the amni-otic fluid that bathes them stimulates their breathing,dries their fur, and promotes later learning abilities.The hormonal control of placentophagia is unknown,but likely involves steroid hormones.

p0030The interaction between mother and offspring atparturition is critical to ensure the establishment ofmaternal responsiveness across lactation, especiallyin primiparous females. Clear evidence in rabbits(Gonzalez-Mariscal et al., 1998), rats (Bridges, 1975),sheep (Poindron et al., 2007a), and goats (Poindronet al., 2007b) has shown that interfering with mother/young contact at this time disrupts or seriously altersmaternal behavior. A similar interference in earlylactation provokes milder effects. These resultssuggest that the particular conditions that exist atparturition – in terms of changes in the concentrationof several hormones in blood (e.g., oxytocin (OT);PGF2a; corticosteroids; PRL; progesterone; estra-diol; for review, see Gonzalez-Mariscal and Poindron(2002)), contractions of the uterus, changes in thedistribution, and/or number of receptors for specifichormones and neurotransmitters in the brain, simul-taneously with the multisensorial perception of sti-muli from the newborn – favor the consolidation anddirect the responsiveness of the mother to the young.In the case of ungulates an additional process takesplace at this time: the recognition of the mother’s ownoffspring which determines the exclusive nursing of aparticular lamb or kid across lactation (see the follow-ing section). Although parturition has been longrecognized as a critical period for the consolidationof maternal behavior, little is known about the factorsunderlying this process. Yet, some results obtained inrats suggest that a pathway similar to learning oper-ates at this time. Thus: (1) there is direct relationshipbetween the duration of the maternal experience andthe duration of its retention following separationfrom the litter (Bridges, 1977); (2) drugs that blockprotein synthesis and interfere with several formsof learning disrupt maternal behavior (Fleminget al., 1996), especially when placed directly into theshell of the nucleus accumbens (Li and Fleming,2003); (3) removing corticosteroids, which are knownto favor the consolidation of some forms of learning,prior to parturition (by adrenalectomy in late preg-nancy) reduces maternal responsiveness followingseparation from the litter for several days (Grahamet al., 2006).

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s0040 3.2.3 Postpartum Activities

s0045 3.2.3.1 Nursingp0035 This is undoubtedly the main behavior displayed by

all mammalian mothers toward their progeny fromparturition until weaning. Yet, the specific character-istics of nursing and the display of activities thatsurround it vary greatly among species. For instance,in rodents, nursing is preceded by retrieving the pupsthat have strayed away and grouping them in thenest. Rabbits and sows neither retrieve their young(despite their small size) nor do ewes or goats (whoproduce large, well-developed offspring). The pre-dictable, unfailing display of nursing and its asso-ciated behaviors depends on several factors thatact from late pregnancy and throughout lactation.Among the former, PRL released before parturitionin rats (Andrews and Grattan, 2002) and rabbits(Gonzalez-Mariscal et al., 2000) plays a criticalrole in promoting maternal responsiveness: prevent-ing PRL secretion (by intracerebroventricular (ICV)injection of bromocryptine) in the last 5 days ofpregnancy prevents the display of nursing from par-turition onward in rabbits (Gonzalez-Mariscal et al.,2004). This result agrees with the observation that anincrease in the density of the long form of the PRLreceptor occurs in specific brain regions (notably, theMPOA) at the end of pregnancy in rats (Bakowskaand Morrell, 1997).

p0040 At parturition, vaginocervical stimulation (VCS)plays a major role in the establishment of maternalbehavior in ewes and goats: peridural anesthesiaresults in the failure to accept the suckling attemptsof the newborn in primiparous sheep and goats(Poindron et al., 2007a,b). Moreover, cesarean sectionprovokes a similar effect in sheep and rats. Experi-mental evidence suggests that these effects may bemediated by the release of OT occurring at parturi-tion: in rats, ICV injections of an OTantagonist at thistime prevent the onset of maternal behavior (VanLeengoed et al., 1987), and in sheep, the disruptiveeffect of peridural anesthesia is partly overcome byICV injection of OT (Krehbiel et al., 1987). Similarresults have been obtained in nonpregnant animals:VCS (Kendrick et al., 1991) or ICV OT injections(Kendrick et al., 1987) promote maternal behavior inmultiparous ewes primed with ovarian steroids; con-versely, an OT antiserum reduces the facilitation ofmaternal behavior normally seen in virgin rats primedwith ovarian steroids (Pedersen et al., 1985). Theabove evidence supports the idea that the concur-rence of specific somatosensory and hormonal factors

at parturition is critical for the onset of maternalresponsiveness across lactation. In contrast, the obser-vation that neither OT antagonist in rats (Fahrbachet al., 1985) nor bromocryptine in rats (Stern, 1977) orrabbits (Gonzalez-Mariscal et al., 2000) antagonizematernal behavior when given in early lactation sug-gests that the maintenance of responsiveness to theyoung does not involve OTor PRL.

p0045The fine-tuning of maternal behavior, that is, thedisplay of nursing with its associated species-typicalethogram throughout lactation, depends largely onsomatosensory factors. Thus, in species that givebirth to multiple young (like rodents, rabbits, andpigs), recognition of the mother’s own progeny isirrelevant as they effectively nurse young otherthan their own (Algers and Uvnas-Moberg, 2007;Gonzalez-Mariscal and Gallegos, 2007; Rosenblattand Lehrman, 1963). In these animals stimuli comingfrom the progeny regulate other aspects of maternalbehavior. Specifically, in rats the adoption of a high-crouch nursing posture critically depends on thequantity and quality of the ventral stimulation pro-vided by the suckling pups (Stern and Johnson, 1990;Stern et al., 1992). Moreover, in rats the number andduration of nursing bouts per day declines from mid-lactation onward (as does the amount ofmilk produced)in relation to the intensity of suckling, which becomesmore vigorous as the pups grow (Mena andGrosvenor,1972). Furthermore, suckling stimulation is critical formaintaining thehigh levels of aggression seen inmotherrats across lactation: pup removal leads to a decline inthis behavior within 24 h (Erskine et al., 1978).

p0050In rabbits, nipple stimulation plays a major role inregulating the duration of nursing: the normalc. 3 min day–1 (Gonzalez-Mariscal et al., 1994;Zarrow et al., 1965) requires a minimum litter sizeof three. When a single pup is provided, the timeinside the nest box (during which nursing occurs) isgreatly increased. A similar effect is observed whenthe mother’s nipples are covered or removed (thelect-omy) or when the pups’ mouths are covered (Gonza-lez-Mariscal, 2007). In sows, suckling stimulation fromthe piglets modulates a specific component of thematernal ethogram: the mother’s grunting (Algersand Uvnas-Moberg, 2007). As the sow lies down toinitiate nursing, she emits a type of grunting thatsignals the piglets to her teats. Their suckling pro-motes the initial release of OTwhich, in turn, triggersa change in the type of maternal grunting: the pigletsrespond to it by suckling more vigorously, thus initiat-ing milk letdown.

4 From Indifference to Ardor: The Onset, Maintenance, and Meaning of the Maternal Brain

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p0055 In contrast to the above species, ewes and goatsshow selective nursing throughout lactation, that is,they will accept at the udder only their own lamb orkid and actively reject alien ones (Poindron et al.,2007a,b). The recognition of the mother’s own off-spring in these species depends on the perceptionof the olfactory signature of the newborn at parturi-tion and its consolidation as an olfactory memory(Levy et al., 2004). As lactation progresses, visualand acoustic cues begin to play an important rolein the mother’s recognition of her progeny andalso in the reciprocal process, that is, in the capa-city of the young to recognize their own mother(Poindron et al., 2007a,b; Nowak et al., 2007). Thismutual recognition is essential to adjust the physiol-ogy and behavior of both parties to each otheracross lactation.

s0050 3.2.3.2 Maternal behavior without nursingp0060 Although the hormones of pregnancy prime the

maternal brain to effectively respond to the stimulishe receives from the young starting at parturition,nonpregnant, nonlactating rodents and rabbits canbehave maternally under specific conditions. Thus,rats, hamsters, gerbils, and laboratory (but not wild)mice gradually behave maternally to foster youngafter several days of cohabitation with them (for areview, see Gonzalez-Mariscal and Poindron (2002)).This so-called sensitization process does not occurin intact rabbits (Gonzalez-Mariscal et al., 2004). Yet,in both rats (Fleming and Rosenblatt, 1974a,b) andrabbits (Gonzalez-Mariscal et al., 2004; Chirino et al.,2007), lesions to the main olfactory system (MOS) orthe accessory olfactory system (AOS) stimulate thedisplay of maternal behavior. In rats this effect isfacilitated by estrogens (reduced latency to becomematernal; Mayer and Rosenblatt, 1979), whereasin rabbits estrogens are essential (absent in OVXanimals; Gonzalez-Mariscal et al., 2004; Chirinoet al., 2007).

p0065 These results indicate that the neural circuitsunderlying the motivation to interact with the prog-eny and the regulation of species-typical behaviorsare present in all female rats and rabbits, regardless oftheir reproductive status, but are tonically inhibitedby the MOS and AOS. The way through which that

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proposed that this behavior is under a multisensorialcontrol because the elimination of either vision,olfaction, or tactile sensitivity of the snout and peri-oral region did not interfere with the retrieval of pups.Later work (Benuck and Rowe, 1975; Herrenkohl andRosenberg, 1972; Herrenkohl and Sachs, 1972) hasconfirmed the lack of effect of anosmia, blindness,and deafness of lactating rats on maternal behavior.More recent studies in which the perioral region wasdesensitized by either injecting a local anesthetic intothe mystacial pads or by sectioning the infraorbitalbranch of the trigeminal nerve found that these pro-cedures interfere with pup retrieval (Kenyon et al.,1981, 1983; Stern and Kolunie, 1989). The discrep-ancy between these results and those of Beach andJaynes (1956) may have been due to the fact thatBeach and Jayne allowed several weeks between thesnout desensitization and testing for maternal behav-ior, a period during which re-innervation of the peri-oral region may have occurred.

p0080 In hamsters, the total removal of the neocortexdoes not eliminate maternal behavior, but when thisprocedure is accompanied by lesions of the cingulatecortex and the underlying hippocampus, maternalbehavior is abolished (Murphy et al., 1981). In pri-mates, lesions to either the prefrontal cortex orthe anterior temporal cortex (performed at around2 months postpartum) severely disrupt the mother’sactive search for her young and provoke a loss of theprotective retrieval of the infant faced with threaten-ing situations (Bucher, 1970; Franzen and Myers,1973; Myers et al., 1973). Xerri et al. (1994) havereported that the somatosensory cortex of mothersoccupies more surface area than that of nulliparousfemales, an indication that as ever greater demandsare placed up on the mother’s responsivity to heroffspring, the brain responds by becoming more sen-sitive to their many sensory cues, including suckling,tactile, etc. This inherent neuroplasticity is an exam-ple of the expression of the female’s maternal behav-ioral state.

p0085 Lesions of the amygdala (a structure that receivesmajor input from the MOS and AOS) do not disruptmaternal behavior in lactating mice (Slotnick andNigrosh, 1975) and lesions to the stria terminalis(the major efferent pathway of the amygdala) haveno effect on the maternal care of lactating rats(Numan, 1974). By contrast, lesions of the cortico-medial amygdala (Del Cerro et al., 1991; Fleminget al., 1980; Numan et al., 1993), bed nucleus of theaccessory olfactory tract (Del Cerro et al., 1991), or

stria terminalis in virgin rats stimulate maternalbehavior (Fleming et al., 1980) while kindling-typeelectrical stimulation of the medial amygdala delaysthe onset of maternal responsiveness to foster pups inexperienced mother rats (Morgan et al., 1999).

p0090On the other hand, activity in the amygdalaappears to be related to the support of the requisitematernal behaviors a mother displays in supportof the care and maintenance of her litter. Wartellaet al. (2003) reported less activation of basolateralamygdala (BLA) in response to stressful situationsin parous (and pregnant (primi/multigravid)) com-pared to age-matched nulliparous females. Rasia-Filho et al. (2004), examining Golgi-stained neurons,reported that neuronal complexity was enhanced inthe medial amygdala in parous females. Together,these data suggest that reproductive experience mayregulate the structure and function of behavior-mediating neural substrates in ways that benefit theforaging and offspring defense capabilities of themother. A female thus equipped may be betterprepared to face the exigencies of her natural envi-ronment than the nulliparous female, whose neuralsubstrate has not yet undergone the hormonal andpup-induced changes that occur with pregnancy andits aftermath.

s00653.3.2 Septum and Bed Nucleus ofthe Stria Terminalis

p0095The septal area has been lesioned in motherrats (Fleischer and Slotnick, 1978; Terlecki andSainsbury, 1978), mice (Carlson and Thomas, 1968;Slotnick and Nigrosh, 1975), and rabbits (Cruz andBeyer, 1972). In rodents, these lesions do not abolishmaternal motivation but provoke a spatial disorgani-zation of maternal behavior: mothers pick up pups,carry them around, drop them at random (thus alter-ing crouching and nursing), and they may alsobuild several small nests where they retrieve young(Terlecki and Sainsbury, 1978). Excitotoxic aminoacid lesions of the bed nucleus of the stria termi-nalis disrupt retrieval behavior in postpartum rats(Numan, 1996). Rats lesioned in the septal regionalso show increased defensiveness, an alteration pro-posed to explain the disorganization of maternalbehavior (Sheehan et al., 2000). In contrast, thebehavior of rabbits is severely altered in all its aspectsfollowing septal lesions; mothers do not build nestsand refuse to enter the nest box for nursing (Cruz andBeyer, 1972).


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s0070 3.3.3 MPOA and Its Connections

s0075 3.3.3.1 Studies using lesion and

deafferentation techniquesp0100 Much evidence has accumulated to identify the

MPOA as a critical site for the expression of maternalbehavior. Electrolytic or radiofrequency lesions of thisregion disrupt retrieving, nest-building, and nursing inlactating rats (Gray and Brooks, 1984; Jacobson et al.,1980; Numan, 1974; Numan et al., 1977) and hamsters(Marques et al., 1979; Miceli and Malsbury, 1982).A similar effect is provoked by injecting N-methyl-D-aspartate (NMDA), which selectively destroys cellbodies but spares fibers of passage, into the MPOA oflactating rats (Numan et al., 1988). Moreover, virginfemales (ovariectomized or intact) lesioned in theMPOA do not show maternal behavior despite manydays of exposure to pups (Gray and Brooks, 1984;Miceli et al., 1983; Numan et al., 1977). Furthermore,the facilitation of maternal behavior provoked invirgin rats by lesioning the corticomedial amygdaladoes not occur if such females have also beenlesioned in the MPOA (Fleming et al., 1983). Incontrast, by applying kindling-type electrical stimu-lation to the MPOA maternal responsiveness to fos-ter pups is promoted in both experienced mothersand virgins (Morgan et al., 1999), a finding support-ing the idea that activity of this brain structure iscritical for the performance of maternal behavior.Furthermore, this brain region also seems to mediatethe reinforcing properties of young pups in postpar-tum and in sensitized virgin rats: electrolytic lesionsto the MPOA disrupt maternal behavior in thehome cage and decrease the rate of bar-pressing forpups in an operant reinforcement paradigm (Leeet al., 2000).

p0105 Adifferent experimental approach has been used toinvestigate the connections of the MPOA which maybe part of a circuit regulating specific aspects of mater-nal behavior. By selectively severing the rostral, cau-dal, lateral, or dorsal connections of the MPOA andassessing the effects of such procedures on the mater-nal behavior of lactating rats, a series of experiments(Franz et al., 1986; Miceli et al., 1983; Numan, 1974;Numan and Callahan, 1980; Numan and Corodimas,1985; Terkel et al., 1979) have revealed that the lateralprojections of the MPOA exert the most importantinfluence. Knife cuts interrupting such connectionsseverely disrupt the oral components of maternalbehavior (i.e., retrieving and nest-building) and pro-voke moderate alterations in crouching and nursing.Such deficits are long-lasting, being still apparent

1 month after the knife cuts are performed ( JakubowskiandTerkel, 1986; Numan, 1990). It is important to notethat the observed deficits in pup retrieval are not aconsequence of a general inability to retrieve anything,because lesioned females readily hoard candy (Numanand Corodimas, 1985). It must also be emphasized thatthe disruption in maternal behavior that followsMPOA lesions is not an indirect consequence of altera-tions in pituitary function because: (1) this effect occurseven in hormonally primed rats (Numan andCallahan,1980); (2) such lesions disrupt the maintenance ofmaternal behavior in lactating ( Jacobson et al., 1980;Miceli et al., 1983; Numan, 1974; Numan andCallahan, 1980; Terkel et al., 1979) and in virgin(i.e., sensitized; Gray and Brooks, 1984; Miceli et al.,1983; Numan et al., 1977) rats, known to be largelyindependent of hormones.

p0110To further define the elements and pathways com-prised in a maternal circuit, Numan and colleaguesperformed a systematic series of studies involvingthe selective destruction of specific brain areas andneural connections and the determination of theireffects on the maternal behavior of lactating rats.As stated earlier, severing the lateral projections ofthe MPOA disrupts maternal behavior, an effect alsoseen after lesioning the lateral hypothalamus (Avarand Monos, 1966, 1967, 1969a,b). These lateralMPOA projections travel to the ventral tegmentalarea (VTA) by one of two routes: a direct one andan indirect one involving a synapse in the lateralpreoptic area (LPOA; Barone et al., 1981; Conradand Pfaff, 1976; Swanson, 1976). Numan has pro-posed that the VTA may be important in regulatingongoing maternal behavior because some of theascending projections of this region reach the stria-tum and are involved in the control of oral motorresponses. Indeed, bilateral electrolytic (though notNMDA) lesions of the VTA severely disrupt mater-nal behavior in postpartum rats (Gaffori and LeMoal, 1979; Numan and Smith, 1984). Bilateralknife cuts through the lateral hypothalamus disruptmaternal behavior only when performed at a level(dorsal) in which fibers coming from neurons in thelateral hypothalamus and going to the VTA are sev-ered. When cuts are made ventrally, the connectionsdisrupted are those from MPOA neurons projectingdirectly to the VTA and this procedure has no effecton maternal behavior (Numan et al., 1985). Severealterations in maternal behavior are also obtainedwhen unilateral electrolytic lesions of the VTA arecombined with contralateral knife cuts of the lateral


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projections of the MPOA, thus indicating that intactbilateral connections between the MPOA and theVTA are essential for the adequate display of mater-nal behavior.

p0115 To distinguish which of the two routes connectingMPOA and VTA (i.e., the direct one or the one with arelay in the LPOA) is part of the maternal circuit,Numan et al. (1988) performed radiofrequency orNMDA lesions in the LPOA and found that bothprocedures provoked severe disruptions in maternalbehavior. This was not observed when NMDA lesionswere performed in the lateral hypothalamus. Theseresults are consistent with the finding that fiberspassing through the lateral hypothalamus (and whichare crucial for maternal behavior) come mainly fromcell bodies located in the LPOA and bed nucleus ofthe stria terminalis (Numan et al., 1985). In summary,these studies support the existence, in rats, of amaternal circuit involving the MPOA, LPOA, andafferent fibers passing through the lateral hypothala-mus and the VTA.

s0080 3.3.3.2 Studies using implantation of

hormones and detection of their receptorsp0120 Diluted estradiol was implanted into the MPOA of

rats that were ovariectomized and hysterectomizedon pregnancy day 16 (Numan et al., 1977). Thisprocedure effectively stimulated maternal behaviorand the results were confirmed in a later study(Fahrbach and Pfaff, 1986). These findings coincidewith the observation that many cells that concentrateestradiol and project to or through the ventral mid-brain are located in the MPOA, LPOA, and bednucleus of the stria terminalis, as determined by thecombined use of a fluorescent retrograde tracer(injected into the ventral midbrain) plus 3H-estradiolautoradiography (Fahrbach and Pfaff, 1986). More-over, toward the end of pregnancy there is an increasein the number of estrogen receptors in the MPOA, asdetermined by the binding of 3H-estradiol to cytosoland nuclear receptors extracted from this region(Giordano et al., 1989, 1990) and by the detection ofmRNA specific for the a-form of the ER (Wagnerand Morrell, 1996; Wagner et al., 1998).

p0125 It is unclear if progesterone acts on the MPOAto regulate maternal behavior because hormoneimplants in this region fail to inhibit maternal behav-ior induced by estradiol injections given to ovariecto-mized/hysterectomized late pregnant rats (Numan,1978). Yet, PRs are found at highest levels in latepregnancy in the MPOA and ventral part of the bednucleus of the stria terminalis, among other regions

(rat: Numan et al. (1999); guinea pig: Blausteinand Turcotte (1989), Blaustein et al. (1988), andWarembourg et al. (1986, 1989)). In sheep, the distri-bution of PRs is similar to that of other species (Scottet al., 2000), but their possible role in the control ofmaternal behavior remains unexplored.

p0130Support for an action of PRL on the MPOA tofacilitate maternal behavior comes from the find-ings of Bridges and colleagues. These investigatorsfound that implants of ovine or rat PRL, placentallactogen-I, or growth hormone into the MPOA ofovariectomized, bromocryptine-treated rats, givenprogesterone and then estradiol, readily facilitatematernal behavior (Bridges and Freemark, 1995;Bridges and Mann, 1994; Bridges et al., 1990, 1997).PRL binding sites were initially detected in thehypothalamus by the binding of 125I-ovine PRL toneuronal membranes (Muccioli and Di Carlo, 1994).Later studies have detected estrogen-induced PRLreceptors in the MPOA using immunocytochemistry(Pi and Grattan, 1998), and in situ hybridization(Pi and Grattan, 1999a). Moreover, the mRNA forthis receptor is expressed most abundantly at the endof pregnancy (Bakowska and Morrell, 1997) and dur-ing lactation (Pi and Grattan, 1999a,b,c) in severalbrain regions, including the MPOA. In rabbits, PRLbinding sites have been detected in: (1) the hypothal-amus of intact females by measuring the affinitylabeling of 125I-ovine PRL to membranes obtainedfrom the hypothalamus (Di Carlo and Muccioli,1981); (2) the MPOA and several hypothalamicnuclei (e.g., paraventricular, supraoptic, suprachias-matic, and arcuate) of intact females by autoradiogra-phy of 125I-ovine PRL (Walsh et al., 1990).

p0135The MPOA also demonstrates plasticity of a morenatural form with regard to the onset and mainte-nance of maternal behavior. Keyser-Marcus et al.(2001) reported that neurons in the MPOA becomemore complex under the hormonal stimulationof pregnancy or a pregnancy mimic. For example,whereas there was no difference between OVX anddiestrous females, both had smaller somal areas com-pared to progesterone- and estradiol-treated andlate-pregnant females. Interestingly, the area of thesoma returned to diestrus/OVX levels in lactatingfemales. Further, the authors found a significantlygreater number of dendritic branches, and signifi-cantly longer cumulative dendritic length, in preg-nant and hormone-treated groups compared to OVX,diestrous, and lactating females. The increase insomal area may indicate increased cellular activity(Miller and Erskine, 1995) and stimulatory effects on


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additional neuronal structural variables may repre-sent modifications in the information-processingcapacity of this set of neurons. Therefore, pregnancyand its attendant hormonal exposure may stimulateneurons in the MPOA which then contribute (in anas-yet undetermined manner) to the display of mater-nal behavior. During the postpartum, lactationalperiod, when cues from pups primarily maintainmaternal attention, the neuronal soma appears toreturn to a prepregnancy, nonhormonally dependentstate (but still sensitive to pup cues as transducedthrough other means: see Macbeth et al. (2008), whodetected marked alterations of brain-derived neuro-trophic factor (BDNF) in parous females). These datademonstrate a striking plasticity in the brains offemales that may be reflected in modifications inpup-directed behaviors.

s0085 3.3.4 Midbrain Tegmentum,Paraventricular Nucleus, and HabenularComplex

p0140 The lateral midbrain tegmentum, which includes theperipeduncular nucleus, receives input from descend-ing preoptic efferents and also from trigeminal sen-sory pathways that pass through the VTA and carryinput from the perioral region (Nadaud et al., 1984;Smith, 1973). Lesions in this area abolish maternalaggression toward males, block milk ejection, but donot interfere with nursing behavior (Hansen andFerreira, 1986; Hansen andGummesson, 1982; Hansenand Kohler, 1984). However, knife cuts made cau-dal to the VTA (thus disrupting ascending anddescending pathways traveling through the mesen-cephalon) abolish maternal behavior (Numan andNuman, 1991). These results indicate that fiberspassing through the VTA and relevant for maternalbehavior terminate at levels lower than the mesen-cephalon (e.g., caudal periaqueductal gray (PAG)and central tegmental field). Interesting recentwork by Felicio and his colleagues has implicatedthe PAG in a form of behavioral switching, in whichthe mechanism for a decision-making apparatusappears to involve differential activation of thedorsal and ventral PAG. As the maternal femaledecides to hunt versus acting maternal, there iscoincident alteration of the activity of the PAG (asmeasured by c-fos activity) that shifts her attentionaway/toward pups/prey objects (Felicio and Canteras,2008). The data suggest that the PAG may weigh therelative merits of chasing prey (insects in the Felicioand Canteras work) versus being maternal, based

on concurrent internal states, status of the pups, envi-ronmental constraints, etc. It may play a role in decid-ing the cost:benefit ratio that follows a choice inthe mother’s day-to-day, minute-by-minute care ofher young.

p0145The paraventricular nucleus (PVN) seems to par-ticipate in the onset of maternal behavior in severalspecies through the release of OTand its parvocellularextra-hypothalamic projections. Thus, in rats: (1) OTis released in the supraoptic nucleus (SON) and thePVN at parturition (Neumann et al., 1993); (2) ultra-structural changes are observed in the SON and PVN,such as glial retraction and an increase in direct neu-ronal coupling, in the last 24 h preceding parturition(Hatton and Ellisman, 1982; Perlmutter et al., 1984;Theodosis and Poulain, 1984; Theodosis et al., 1981);(3) most of these changes disappear within 10–30 daysafter weaning (Modney and Hatton, 1990); (4) similarchanges can be observed in sensitized virgins (Salmet al., 1988) following ICV injection of OT (Theodosiset al., 1986) or in response to electrical stimulation ofthe olfactory pathways in brain slice preparations(Hatton and Yang, 1989, 1990); (5) isolation of themediobasal hypothalamus, a procedure that leavesthe PVN and its extra-hypothalamic connectionsintact but severs pathways between the PVN and themedial basal hypothalamus, abolishes milk output butdoes not affect maternal behavior (Herrenkohl andRosenberg, 1974); (6) lesions to the PVN disrupt ratmaternal behavior, although only if performed beforeits onset (Insel and Harbaugh, 1989; Numan andCorodimas, 1985); if performed after parturitionPVN lesions significantly reduce maternal aggression(Consiglio and Lucion, 1996). On the other hand,kainic acid-induced lesions of the PVN on pospartumday 2 affect retrieving behavior (but not other mater-nal behavior components (Olazabal and Ferreira,1997)), while lesions performed on day 5 postpartumwith ibotenic acid (a procedure that preferentiallylesions parvocellular neurons) or infusion of anti-sense oligonucleotides against OT increase maternalaggression (Giovenardi et al., 1997, 1998).

p0150In sheep there is strong evidence for the partici-pation of OT from the PVN in the activation ofmaternal behavior. Thus: (1) OT is released in thisstructure during parturition and retrodialysis of thispeptide induces maternal behavior in nonpregnantsteroid primed females (Da Costa et al., 1996a);(2) birth or VCS activates the PVN (as determinedby expression of the FOS protein), where oxytociner-gic neurons and fibers as well as OT receptors havebeen found (Kendrick et al., 1997); (3) the number of


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OT immunoreactive neurons and mRNA transcriptsfor the OT receptor are increased in the PVN atparturition and following progesterone/estradiolpriming (Broad et al., 1993); (4) previous maternalexperience further enhances the expression of OTreceptor mRNA in the PVN (Broad et al., 1999).From this evidence, it has been proposed that atparturition OT facilitates its own release (by actingon autoreceptors), not only in the PVN itself but alsoin the brain regions it projects to, for example, MPOAand olfactory bulbs (Kendrick et al., 1997).

p0155 The lateral habenular complex is necessary for thehormonal onset of maternal behavior because cyto-toxic lesions in this region produce deficits in pupretrieval, nest-building, and nursing in rats thatwere ovariectomized/hysterectomized and injectedwith estrogen on pregnancy day 16 (Corodimaset al., 1993; Matthews-Felton et al., 1995). However,implants of estradiol in the lateral habenula fail tostimulate maternal behavior in rats that were ovari-ectomized/hysterectomized on pregnancy day 16(Matthews-Felton et al., 1999) despite the fact thatERs have been found in this region by autoradio-graphy (Pfaff and Keiner, 1973) and in situ hybridiza-tion (Wagner et al., 1998).

s0090 3.3.5 Sampling the Active Parental Brain

s0095 3.3.5.1 The expression of immediate

early genesp0160 The protein products of c-fos, fosB, egr-1, and zif-268

(examples of the so-called immediate early genes)participate in regulating the transcription of late-responding genes. A large amount of evidence sup-ports the idea that an increased production ofthe mRNA or the protein products of such genesindicates neuronal stimulation (Dacoit et al., 1990;Morgan and Curran, 1991; Wisden et al., 1990). Thus,the quantification of such gene products has beenused to measure neuronal activity in specific brainregions under a variety of experimental conditions.Because several antibodies for the FOS protein arereadily available, most studies have used the detec-tion of this protein by means of immunocytochemis-try to explore the brain regions activated during thedisplay of maternal behavior. By using this approach,Numan and Numan (1994) found that lactating ratsexposed to pups (following a 3-day separation) showedsignificantly higher numbers of FOS-immunoreactive(IR) neurons in the MPOA, ventral (though notdorsal) bed nucleus of the stria terminalis, anteriorcortical and posterodorsal medial amygdaloid nuclei,

compared to lactating rats that were given candyinstead of pups on the day of testing. Very similarchanges were observed in virgin rats behaving mater-nally after having been exposed to pups for severaldays, with respect to females also given pups for thesame number of days but not yet behaving maternally.No differences in the number of FOS-IR neuronsbetween maternal and nonmaternal rats were notedin other brain regions (e.g., ventromedial hypo-thalamic nucleus, BAOT, and anterior medial orposteroventral medial amygdaloid nuclei). Similarly,Fleming et al. (1994b) found that postpartum ratsexposed to pups showed many more FOS-IR neuronsin: MPOA, piriform cortex, and medial and corticalamygdala than mothers exposed to a familiar adultfemale or to food. The active display of maternalbehavior in lactating rats was also associated with anincrease in the number of fosB and egr-1 immuno-reactive neurons in theMPOAandventral bed nucleusof the stria terminalis, though the temporal course ofexpression of these proteins was different from thatobservedwith the c-FOS protein (Numan et al., 1998).The same group of investigators (Stack and Numan,2000) has shown that immunoreactivity to the c-FOSand fosB proteins is maintained in the MPOA, ventralbed nucleus of the stria terminalis, and PVN (anterior,magnocellular region) as long as mothers interact withtheir pups (maximal time studied was 47 h). In otherregions explored (e.g., posterodorsal medial amygdala,lateral habenula, posterior PVN, and ventromedialhypothalamic nucleus), immunoreactivity declinedover time despite continuous mother–litter interac-tion (Stack and Numan, 2000). Because the MPOAand ventral bed nucleus of the stria terminalis areessential for the display of maternal behavior in rats(see earlier), these authors have proposed that thecontinuous expression of the c-FOS and fosB genesmay be necessary to maintain the activity of theseareas. In addition, sensitized adult virgin rats alsoshowan increased number of neurons immunoreactiveto both c-FOS and fosB proteins in the MPOA andventral bed nucleus of the stria terminalis following a2-h interaction with pups (Kalinichev et al., 2000).

p0165Despite these clear results, the interpretation ofchanges in the number of FOS-immunoreactive neu-rons is not unequivocal because, in the context of abehavior that is stimulated by pup cues, a given brainregion may be activated by either: (1) the perceptionof such cues, (2) the expression of maternal behaviorper se, or (3) the occurrence of events not related withmaternal behavior (e.g., neuroendocrine secretion).To distinguish among these possibilities, strategies


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have been used to selectively block the perception ofspecific cues from the pups and then assess theimpact of such manipulations on the expressionof FOS in particular brain regions. The removal ofnipples (thelectomy) did not modify the number ofFOS-IR neurons in the MPOA (Numan and Numan,1995; Walsh et al., 1996) or ventral bed nucleus of thestria terminalis (Numan and Numan, 1995) and theapplication of a local anesthetic in the ventrumreduced FOS expression only in the somatosensorycortex (Walsh et al., 1996). Similarly, the surgicalremoval of the olfactory bulbs (Numan and Numan,1995; Walsh et al., 1996) or the spraying of ZnSO4

into the olfactory epithelium (Fleming and Walsh,1994; Walsh et al., 1996) did not modify the numberof FOS-IR neurons in the MPOA of lactatingmothers but reduced it in structures related withthe olfactory system (e.g., medial amygdala and piri-form cortex). Moreover, the number of FOS-IR neu-rons in the MPOA following an interaction with thelitter remained unchanged even after the combinedapplication of local anesthetic to the ventrum plusZnSO4 to the olfactory epithelium (Fleming andWalsh, 1994; Walsh et al., 1996). However, the com-bined surgical removal of nipples and main olfactorybulbs reduced (but did not eliminate) the number ofFOS-IR neurons in the MPOA and ventral bednucleus of the stria terminalis (Numan and Numan,1995). From these results, it has been proposed thatneurons expressing FOS following an interactionwith the litter represent mostly the efferent outputfrom the MPOA and are related with the perfor-mance of maternal behavior (Numan and Numan,1995; Walsh et al., 1996). In a detailed study involvingthe quantification of FOS-immunoreactive neuronsin 20 brain regions, Lonstein et al. (1998) found thatthe degree of neuronal activation provoked by inter-acting with a suckling litter was not significantlydifferent from that observed following an interactionwith pups that had their snouts anesthetized andwere, therefore, unable to suckle. The single areawhere FOS expression was significantly greater fol-lowing suckling (vs. nonsuckling) stimulation wasthe caudal PAG (lateral and ventrolateral portions;Lonstein and Stern, 1997). Because only sucklingpups elicit the upright crouch (kyphosis) characteris-tic of normal nursing (Stern, 1996) and electrolyticlesions to the caudal PAG disrupt it (Lonstein andStern, 1997), these authors have suggested that adiscrete population of FOS-IR neurons in this regionis related with the sensorimotor control of kyphoticnursing. Indeed, unilateral thelectomy reduced both

the proportion of time spent in the kyphotic posture(in relation to the total time spent over the litter)and the number of FOS-IR neurons found in thecaudal PAG on the side ipsilateral to the thelectomy(Lonstein and Stern, 1999).

p0170To further understand the significance of changesin the number of FOS-IR neurons associated with thedisplay of maternal behavior, Lonstein and De Vries(2000) analyzed brain sections co-stained with FOSand an antiserum against GAD67 (an isoform of therate-limiting synthesizing enzyme for GABA, foundin the cytoplasm; Martin and Rimvall, 1993). Theyfound that, in lactating rats, interaction with pupsincreased the number of co-labeled neurons in theMPOA, ventral bed nucleus of the stria terminalis,and caudal PAG (ventrolateral region), a result sug-gesting that GABAergic neurons may promote spe-cific aspects of maternal behavior by removing tonicinhibitory influences. By using a similar experimen-tal strategy, Lonstein et al. (2000) reported that lac-tating rats allowed to interact with pups showed anincreased number of neurons co-stained with FOSand an antibody against the ERa than did mothersnot given young. These differences were particularlyevident in the MPOA, lateral habenula, and ventralbed nucleus of the stria terminalis.

p0175In virgin Balb/c mice a single brief (30min) expo-sure to pups increased the number of FOS-IR neuronsin the MPOA, corticomedial amygdala, entorhinaland piriform cortex, and anterior olfactory nucleus,regardless of whether females were intact or ovariec-tomized (Calamandrei and Keverne, 1994). Inter-estingly, the presentation of pups inside a dark,perforated box (that allowed females to perceiveonly olfactory and auditory signals from the young)stimulated FOS expression in the olfactory areas butnot in the MPOA. In contrast, the depletion of nor-adrenaline in the olfactory bulb (provoked by inject-ing 6-hydroxy-dopamine into the medial olfactorystria) reduced FOS expression only in the anteriorolfactory nucleus and the piriform cortex. Theseresults coincide with those obtained in rats and sup-port the notion that FOS expression in the MPOAoccurs as a result of the active display of maternalbehavior.

p0180In multiparous sheep, the interaction betweenthe mother and her lamb for the first 30min afterparturition stimulated c-fos mRNA transcription(detected by in situ hybridization) in the cerebralcortex (e.g., entorhinal, piriform, and somatosensory),habenula, hippocampus (CA3 region, dentate gyrus),limbic system (e.g., bed nucleus of the stria


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terminalis, lateral septum, and olfactory bulb),MPOA, and several hypothalamic nuclei (e.g., PVNand SON). Very similar changes were observed innonpregnant multiparous ewes treated with estrogenand progesterone and given 5min of VCS. In contrast,zif-268 mRNA transcription was noted in only a fewareas (entorhinal and orbitofrontal cortex; dentategyrus) of postpartum sheep (Da Costa et al., 1997).

s0100 3.3.5.2 Other methodsp0185 The uptake of 14C-2-deoxy-glucose (2DG) has been

used as an index of activity in neuronal terminals butnot cell bodies (Nudo andMasterton, 1986; Sharp et al.,1988). At parturition, mother rats showed an increa-sed uptake of 2DG in the MPOA and VTA, while insensitized virgins displaying maternal behavior adecreased 2DG uptake was observed in several struc-tures of the accessory olfactory system (i.e., accessoryolfactory bulb, medial amygdaloid nucleus, and bednucleus of the accessory olfactory tract; Del Cerroet al., 1995). These results coincide with the proposi-tion that the facilitation of maternal behavior in virginrats occurs as a consequence of reducing the impact ofaversive olfactory stimulation coming from the pups.To distinguish between excitatory and disinhibitorysynaptic relations in specific brain areas, associatedwith the display of maternal behavior, the same groupof investigators combined the 2DG method with theimmunocytochemical detection of FOS (Komisaruket al., 2000). In the three models of maternal behaviorexplored (parturient, sensitized virgins, and rats hys-terectomized on pregnancyday 16), theMPOA showedincreased uptake of 2DG and increased expression ofFOS. This indicates that the expression of maternalbehavior (regardless of how it is induced) involvesexcitatory input to the MPOA and excitatory outputfrom it. A different pattern was observed in structuresof the olfactory system (e.g., BAOT and medial amyg-dala): while parturient rats showed increased 2DGuptake and increased FOS expression (i.e., excitatory/excitatory relations), in sensitized virgins 2DG uptakedecreased and FOS increased. This observation furthersupports the notion that the expression of maternalbehavior through sensitization in virgin rats involvesa reduction in the activity of the olfactory system.

p0190 To further explore the role of immediate earlygenes in the expression of maternal behavior, anti-sense oligodeoxyribonucleotides (ODNs) have beeninfused into the PVN of periparturient sheep (DaCosta et al., 1999). There is evidence that the releaseof OT from this nucleus at parturition promotesmaternal behavior in this species. The bilateral

infusion of antisense ODNs against c-FOS and c-jun

via microdialysis probes placed in the PVN antago-nized OT release in this region (but not in plasma) andreduced the expression of mRNA to specific peptides(e.g., OT, CRH, and pre-proenkephalin) also in thisnucleus. In addition, this procedure decreased the inci-dence of low-pitch bleats, though only at 10min post-partum. The other components of maternal behaviorwere not significantly modified and rejection beha-viors toward the neonate were not observed.

p0195In summary, the above studies detected discrete(if any) alterations in the maternal performance ofthe knockout mice used, supporting the notion thatthis complex behavior is regulated by a multitude ofhormones and neurotransmitter systems that act inconcert and may compensate for the lack of a partic-ular one. However, this does not rule out the possi-bility that a more primary element is essential for thecoordinated operation of such hormonal/neurotrans-mitter systems and, consequently, that its malfunctionor deletion may preclude the expression of mater-nal behavior. Indeed, work by Brown et al. (1996) pro-vided clear evidence to this effect. Homozygousfemale mice lacking the immediate early gene fosB

show a disruption of maternal behavior, failing toretrieve their pups and crouch over them, despitethe fact that they approach and sniff them. Surpris-ingly, such mothers show no alterations in spatiallearning, and their ability to discriminate betweentwo different odorants is similar to the one observedin wild-type animals. Moreover, pregnancy and par-turition are normal in such knockout mice and noalterations in the reproductive tract or mammaryglands are evident. Furthermore, the serum concen-trations of estradiol and progesterone during preg-nancy are also normal as are the levels of mRNA forOT in the hypothalamus and for PRL in the pituitary.Interestingly, the deleterious effects of the fosB muta-tion on maternal behavior are not overcome by expe-rience: the lack of maternal responsiveness is stillobserved after successive pregnancies and parturi-tions. Additionally, virgin fosB knockouts (males andfemales) are also unable to respond maternally tofoster pups, even after repeated exposure to them.

s01053.4 Epigenetic, IntergenerationalTransmission of Mothering Styles:Its Impact on Offspring Development

p0200Over the last 10 years a large body of research hasinvestigated the intriguing observation that the


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environment surrounding a developing organism canpermanently affect its performance in adulthood.Although this issue has been well recognized sincethe early studies of Levine (1957) and Denenberg(1964), recent studies have revealed the multiplelevels at which the organism’s phenotype is modifiedby early experience (e.g., neuroendocrine reactivity,cognition, social behavior, and sensory gating), theways by which the environment can act on thegenome to modify the brain of the developing indi-vidual (epigenetic), and how the characteristicsacquired in infancy can be transmitted to the nextgeneration (intergenerational). At the core of thisresearch lies the assumption that, even in those spe-cies in which the young are born precocial, the fine-tuning of the circuits mediating complex tasks isunfinished and, therefore, subject to permanent mod-ification by environmental influences. The existenceof critical periods for a variety of traits has beenacknowledged for many years ( Johnson, 2005; Micheland Tyler, 2005), for example, in studies exploringthe role of steroids and tactile stimulation in orient-ing brain sexual differentiation (Beyer and Feder,1987; McCarthy and Konkle, 2005; Moore, 1995) orthe learning by young animals of odors and flavorsthat will determine their mating and food preferencesin adulthood (reviewed in Fleming et al. (2002)).These studies have revealed the existence of timewindows during which the exposure or not of adeveloping individual to specific forms of stimulation(e.g., tactile, olfactory, and hormonal) will determinethe direction and magnitude of a given response inadulthood.

p0205 By contrast, little is known about the mechanismsthat mediate the translation between the perceptionof such varied forms of stimulation and the perma-nent modification of brain function. In the last 7 years,work coming mainly from the laboratory of MichaelMeaney has provided evidence for the operation ofspecific pathways between the tactile stimulationprovided by mother rats to their litter and the adultphenotype of their offspring (see below). The experi-mental strategy used in these studies has been theselection of mother rats according to the frequencywith which they lick the pups’ body. This behavior isa normal component of rat maternal care, and itsmagnitude within the population follows a normaldistribution (Champagne et al., 2003). By choosingthe extremes of the population (i.e., mothers locatedone standard deviation apart from the mean in bothdirections), Meaney’s group has found that mothersproviding high levels of licking (and arched-back

nursing) during the first week of life breed offspringthat, in adulthood, show reduced reactivity of thehypothalamic–pituitary–adrenal (HPA) axis to stress-ful situations, decreased fear responses, a greatercapacity for spatial learning, and a high frequency oflicking toward their own offspring. These behavioralcharacteristics are associated with a higher concen-tration of glucocorticoid receptors (GRs) in the hip-pocampus, decreased hypothalamic CRF expression,larger concentrations of ERa in the MPOA, largernumbers of OT receptors in specific diencephalicregions, and more GABAA-benzodiazepine receptorsin several amygdaloid nuclei than the offspring ofmothers that lick their pups less frequently. Suchdifferences are not due to the genetic characteristicsof the mothers’ offspring as cross-fostering studieshave shown that the adult phenotype correspondsto that of the rearing mother, rather than to thebiological one. Moreover, by studying the maternalbehavior shown as adults by the female offspring ofthe two types of selected rats, the mothering style wasthat of the rearing mother. In other words, an inter-generational transmission of acquired behavioraltraits had occurred.

p0210The way in which alterations in specific receptorsmay relate to differences in behavior has beeninvestigated in relation to the stress response. Thehippocampus of female offspring from high licking/arched-back nursing mothers shows a higher expres-sion of cyclic AMP-response element binding protein(CREB)-binding protein (CBP), a higher acetylationof histones, and a reduced DNA methylation patternof the GR exon 17 promoter in the hippocampus (forcomprehensive reviews, see Champagne et al. (2003),Szyf et al. (2005), and Weaver et al. (2004)). Takentogether, the findings from Meaney’s group haverevealed a specific pathway by which maternal stim-ulation, received at a critical period, can permanentlymodify the expression of particular receptors (GRs)in the brain which, in turn, play a crucial role inthe way adult animals respond to stress. Whethersimilar mechanisms operate in relation to other beha-viors, receptors, or neurotransmitters remains to beinvestigated.

p0215Different experimental strategies have been usedby other investigators to assess the impact of theneonatal environment in determining the adult char-acteristics of the offspring: (1) short (c. 15min day–1;the so-called handling paradigm) versus long mother–young separations; (2) total maternal deprivationaccompanied by artificial rearing; (3) natural altera-tions of maternal behavior provoked by stressful


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surroundings (e.g., as a consequence of social inter-actions); and (4) alterations of the nest environment(e.g., physical materials, and siblings). These studieshave taken into account the biology of the species,that is, the pattern of maternal care, the number anddevelopmental state of the offspring born. The firsttwo strategies have been tried in several strains of ratsand, in general, the handling procedure has beenfound to improve some characteristics of the off-spring when compared with control groups notremoved from their mothers. Thus, as adults, hand-led animals show: reduced emotionality, enhancedlearning, and better maternal responsiveness in adult-hood (Rees and Fleming, 2001). These effects are aconsequence of changes in the mother’s behaviorupon reunion with the litter, such as increased lickingand grooming of the pups, which, in turn, result fromthe increased demands (ultrasonic vocalizations,suckling, and rooting) made by the young (Pereiraand Ferreira, 2006).

p0220 By contrast, long mother–young separations(3–5 h day–1 for at least the first 7 postnatal days)provoke the reverse, that is, increased fear and emo-tional responses, deficient maternal care in adult-hood, and impairments in specific forms of learning(Fleming et al., 1999, 2002; Lovic et al., 2001). Theseresults agree with the findings from Meaney’s groupand emphasize: (1) the importance of specific formsof maternal tactile stimulation for the programmingof certain adult characteristics and (2) the existenceof critical periods during which the plasticity of thecentral nervous system (CNS) is particularly sensi-tive to environmental influences. Indeed, by usingthe maternal separation/artificial rearing strategy,Fleming and colleagues found severe alterations inemotionality (exaggerated responses to stress), sen-sory gating (revealed by a deficiency in prepulsestartle inhibition), and social recognition (evidencedthrough deficits in olfactory memory), in addition tothe expression of behaviors indicative of anxiety(Fleming et al., 1999, 2002; Lovic et al., 2001). Thefinding that intense anogenital stimulation providedwith a brush, exposure to nest odor, or rearing with alittermate can partially or totally reverse some ofthose shortcomings reveals that the plasticity of theCNS during infancy can follow several directions(Melo et al., 2006).

p0225 Altering the immediate environment to the extentthat it creates stress in pregnant or lactating mothersis sometimes the outcome of housing in farm animals(Moberg and Mench, 2001) or of the establishment ofsocial hierarchies in some species (notably, primates).

Sows, ewes, and rhesus macaques have been studiedunder these conditions, in terms of their own mater-nal behavior while under stress and in relation to theconsequences for their offspring. Detrimental effectsof stress during gestation were manifest in sows asincreased cortisol secretion and smaller increasesin body weight across pregnancy. The daughters ofthese sows, when tested as adults, showed abnormalmaternal behavior toward their own piglets, increa-sed cortisol secretion in response to social stress, andan enhanced expression of CRH mRNA in the PVN( Jarvis et al., 2006). Lambs prevented from sucklingtheir mothers (and receiving milk from a bucket) showlarger cortisol secretion, more distress bleats, less timenear their companions, and reduced growth, com-pared with dam-suckled lambs (Napolitano et al.,2003). Deficient contact between ewe and lambin early lactation may have consequences; it is un-known, however, if such early developmental effectsmodify the adult maternal behavior of those femaleoffspring.

p0230The maternal behavior of rhesus macaques kept incolonies under seminatural conditions varies fromabusive to protective; these characteristics are main-tained within individuals across successive parturi-tions. Abusive mothers are characterized by highrates of rejections and contact-breaking from theirinfants. Maestripieri and colleagues found that thispattern of maternal care has a profound impact onoffspring development. Abused infants show higherrates of distress vocalizations and anxiety, later inde-pendence from their mothers, and abnormal playbehavior, compared with infants from nonabusivemothers (McCormack et al., 2006). Moreover, cross-fostered females, tested as adults, resembled theirfoster mothers in the rates of maternal rejectiontoward their own infants but were more like theirbiological mothers in their contact-making behavior(Maestripieri et al., 2007). Abusive mothers also hadlower levels of a serotonin metabolite (5-hydroxy-indole-acetic acid – 5-HIAA) in the cerebrospinalfluid than did the nonabusive ones. In a differentexperimental model the behavior of rhesus monkeysreared with same-aged peers was compared to that ofmonkeys reared by mothers. As adults, peer-rearedfemales were more likely to reject or abuse theirinfants, were more reactive to stress, more aggressivein social interactions, and exhibited lower basal cate-cholamine system activity (for review, see Fleminget al. (1999)).

p0235Unlike most rodents guinea pigs are born preco-cial, that is, covered with body hair, able to regulate


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their body temperature, with their eyes open, andable to urinate and defecate without anogenital stim-ulation from their mother. Despite these character-istics, young guinea pigs depend on their mother forthe regulation of HPA axis reactivity. When placed ina new environment, the mere presence of the motherbuffers this stressful condition; cortisol release is lessand distress vocalizations are fewer (Hennessy, 2003;Wewers et al., 2003) than if the mother is absent. Theimpact of repeated mother–young separation on thebehavior, emotional reactivity, and maternal behaviorof the offspring is unknown.

p0240 Rabbit pups, despite being born altricial, havelittle contact with their mother from parturition andthroughout lactation except for the 3-min dailynursing bout (see Section 3.2). Yet, they remain inclose contact with each other inside the maternalnest, exposed to its rich olfactory environment, andprotected from harsh temperatures and predators.The relevance of this immediate environment,which hardly involves the mother, for the develop-ment of rabbit pups was investigated by isolating theyoung from each other and bringing them togetheronly for nursing. This procedure compromised thedevelopment of thermoregulation, when comparedwith pups that were kept together in a huddle(Bautista et al., 2003).

p0245 The information summarized in this section showsthat in all mammals studied the maternal careprovided to the offspring has a profound impact onthe development of many complex functions, includ-ing emotional reactivity, social interactions, foodselection, spatial learning, mate choice, thermoregu-lation, etc. Moreover, specific studies have revealedthat certain characteristics of maternal behavior itselfare permanently altered in the female offspring, thusoffering a means for the intergenerational transmis-sion of such acquired traits. Yet, when comparing theresults of particular studies that explored the sameissue, discrepancies abound. For instance, the impactof long mother–young separations on maternalbehavior of the adult female offspring varies depend-ing on whether: they were tested as sensitized virginsor lactating mothers; they were exposed to young asjuveniles or not; and the pups given were their own oralien ones (Darnaudery et al., 2004). The test selectedto measure reactivity to a new environment (e.g.,behavior in the elevated plus maze (EPM) vs. cortisolsecretion vs. ambulation in an open field), the sexof the individual studied (more studies have beenperformed in females than in males; Barna et al.,2003), and, of course, the biology of the species

under study all determine the outcome of a particularstudy. Clearly, much more work is needed in thisexciting new field to reveal the extent of maternaleffects on offspring development and the multiplicityof mechanisms that may participate in the trans-mission of specific behavioral and neuroendocrinecharacteristics across generations via an epigeneticroute.

s01103.5 Impact of Maternal Behavior onthe Mother: Effects on Cognition andNeuroplasticity

s01153.5.1 Theoretical Context

p0250The new mother is a study in contrasts. She is thesame female she was before the birth of her offspring;conversely, the transition from nulliparous to parousfemale involves substantial, likely permanent, altera-tions to both brain and behavior. In this section wedetail some of these changes and their ramifications.These questions arise naturally from the simple rec-ognition of the requisite behavioral set for thenew mother, including both behaviors directlyrelated to pup care and maintenance (the so-calledmaternal behavior), and those that are ancillary toor supportive of maternal behavior and require themother to be efficient in her search for resources(Kinsley et al., 1999; Lambert et al., 2005). We discussthe focus of these changes and activities, the off-spring, who represent the culmination of a lifetimeof metabolic investment and the mother’s geneticlegacy.

p0255The mother is confronted with a stark lose–losesituation. She can stay on her nest, safe with heroffspring, and face eventual starvation and the lossof her litter. Or she can leave the nest and her vul-nerable brood in search of food and water, in whichcase she places both herself and those young in dan-ger. We predicted that the mother would benefit frompositive alterations to behaviors that underlie theaforementioned activities. That is, departing the safeconfines of the nest for environments and dangersunknown requires overcoming the fear inherent todoing so, and successfully confronting any risksencountered (predators, rogue males, impassableobstacles, etc.). Then, any foraging costs (increasedtime and effort) could be reduced by enhancementsto spatial and reference memory. These latter chan-ges would ensure a rapid return to the nest andthe defenseless offspring. Therefore, reductionsin fear and anxiety, and improvements to spatial


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pathways and their downstream alteration of neuro-nal structure and function, as suggested by Macbethet al. (2008). Such offspring-enriching effectswere suggested by Kinsley et al. (1999) and reportedby Lambert et al. (2005) and identify an interestingform of symbiosis in which the offspring have ahand/paw in their own survival and bettermentthrough stimulation of their mother’s brain, and herbehavior toward them. Parrish et al. (2007) providean interesting model by which dendritic connec-tions and networks could be created/maintained bysuch rich translation of the environment into neuralcomplexity.

p0295 Reproductive experience does modify the female’sbrain; further, that the brain owes some of its plas-ticity to the hormonal environment has been welldocumented. The MPOA, whose circuitry and in-volvement in maternal behavior has been describedvoluminously, exhibits marked c-fos expression fol-lowing pup interactions and treatments (opiates) thatmodify normal maternal motivation (Numan andInsel, 2003; Stafisso-Sandoz et al., 1998). ObservingGolgi-stained neurons, Keyser-Marcus et al. (2001)have reported that perikarya volume and neuronalcomplexity increased in the MPOA of late-pregnant(day 21), lactating (day 5), and pregnancy hormone-treated (sequential estradiol and progesteroneimplants) females. This increased activity associatedwith the onset of maternity suggests a region of thebrain that is preparing or is ready to display therequisite behaviors toward the pups. The increase insize/volume of the cell body, where a majority ofprotein syntheses are occuring (Miller and Erskine,1995), provides a neurophysiological concomitant,both metaphorically and literally, to the upregulationof activity necessary for successful reproduction.

p0300 In addition to OT, steroid hormones modify boththe structure and function of the hippocampus.Short-term cyclic fluctuations in steroid hormonessuch as estradiol and progesterone can modulate theconcentrations of CA1 hippocampal dendritic spines(Gould et al., 1990; Li et al., 2004; Woolley, 1998;Woolley et al., 1990, 1996; Woolley and McEwen,1992, 1993; Yankova et al., 2001). This researchfocused on nulliparous female rats (although somemales (in this case primates) may show interestingparallels (Kozorovitskiy et al., 2006)).

p0305 As alluded to above, there are likely two primaryroutes by which the altered behavioral capacities ofthe parous female occur, the hormones of pregnancyand the significant stimulation provided by the pups.For example, female rats undergo cyclical and

sizeable hormonal (primarily estradiol and progester-one) alterations during the 4–5-day estrous cycle. Onthe other hand, pregnancy involves substantially ele-vated estrogens and progestins for a significantlylonger duration and with considerably elevated levelscompared to the estrous cycle (e.g., days vs. hours,and higher absolute estrogen levels; during mid–latepregnancy (days 10–22), these levels more than dou-ble their earlier (days 1–10) levels, reaching a peakof approximately 80 pg ml–1 on days 18–22; Bridges,1984).

p0310Enhancing these potent steroid hormones and theiranabolic properties predicts strong and enduringdownstream effects. Therefore, given the markedincreases in these steroid hormones, one might expecteven greater effects on CA1 dendritic spine prolifera-tion as the female experiences the hormonal cocktailthat is pregnancy. Kinsley et al. (2006) found thatspine density was increased in late-pregnant andlactating (day 5) females (which were not differentfrom each other) compared to the other virgingroups, including proestrous females, who had morespines than diestrous and estrous animals (which hasbeen documented previously), and OVX femalestreated with a pregnancy-mimicking (and maternalbehavior-stimulating; Bridges, 1984) sequential estra-diol plus progesteorne hormonal regimen. Such ani-mals had significantly more dendritic spines thanOVX control females (and had numbers that werenot significantly from those of the late-pregnant andlactating females). Pawluski and Galea (2005)reported some lingering effects of parity on hippo-campal neuronal morphology, with the primiparousfemales having significantly greater dendritic arborsafter weaning their litters. The hippocampus, there-fore, appears sensitive and responsive to the hor-mones of pregnancy. The major question is Why?,and it appears to be answered by the behavioraleffects noted above and in Macbeth et al. (2008) inwhich foraging, spatial, and other forms of memoryare enhanced, supporting the display of maternalbehavior. Rasia-Filho et al. (2004) have reported sim-ilar neuronal structural effects in the amygdala ofparous females, suggesting differential neuronalinteractions therein, and consequent alterations ofregulation of fear and emotion – behaviors thatare reliably reported as reduced in parous females(Wartella et al., 2003).

p0315Although the hippocampus may not play a directrole in care of the young (viz., full pup-directed mater-nal behavior; but see also Numan and Insel (2003)),it may maintain ancillary maternal behaviors and


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responses to the environment, other examples ofneuroplasticity that collectively ensure successfulreproduction. For example, there is evidence of estra-diol-induced hippocampal flexibility across species,including increases in synapse-associated proteinimmunoreactivity (Choi et al., 2003; Li et al., 2004);enhancements in long-term potentiation and learning(Warren et al., 1995; Warren and Juraska, 1997); up-regulation of NMDA receptors (Adams et al., 2004);downregulation of reactive astroglia (Garcia-Estradaet al., 1993, 1999); increases in synaptophysin (Fricket al., 2002); and decreases in experimentally inducedapoptosis (Liu et al., 2001). Another interesting fea-ture of hippocampal plasticity is the association ofestrogen status with BDNF mRNA and immuno-reactivity (Solum and Handa, 2002; Scharfman et al.,2003) – data that connect to the Macbeth et al. (2008)observations reported above.

p0320 Recent work from our lab, using reverse transcrip-tase polymerase chain reaction (RT-PCR) (Continoet al., 2007), has implicated a number of hippocampaland prefrontal cortical (PFC) neuroplastic genes inthe expression of the maternal brain. For example, anupregulation of the genes for BDNF, its receptorNTrk2, syntaxin (a presynaptic protein), spinophilin(a dendritic spine regulator), Cox-1 (a mitochondrialprotein); and amyloid precursor protein in the PFCall show interesting differences between parous andnulliparous females. When taken in total, it seemsreasonable to posit that reproduction represents asignificant event in the life of the female. Thechanges are substantial and enduring, and are on apar with other developmental milestones such assexual differentiation and puberty. The data suggestthat the hormones of pregnancy interact with post-partum pup exposure to produce an enriched envi-ronment and thereby improve learning ability (atleast temporarily and possibly permanently), mitigateanxiety and stress responsiveness, and enhance prob-lem solving in a novel context (integration of cogni-tive and stress responses), in the mother. It can beargued that such effects would be selected for, andwould fulfill the criterion of incrementally adaptivechanges favored by natural selection (Kinsley andLambert, 2006).

p0325 Finally, it may be interesting to look at thechanges to a single and singular sense, olfaction, andits potential role in the transition from nulliparous toparous female. Macbeth et al. (2008) made tissuepunches from the olfactory bulb and examinedneurotransmitter dynamics therein. We know thatthe rat is such an olfactory-guided animal, and that

its maternal behavior is substantially regulated byolfactory cues from young (see Fleming andRosenblatt (1974a,b)). Macbeth et al. (2008) reportedincreased concentrations in the olfactory bulb ofdopamine (DA) and its metabolite 3,4-dihydroxy-phenylacetic acid (DOPAC); norepinephrine (NE)and its metabolite 3-methoxy-4-hydroxyphenylglycol(MHPG); and the serotonin (5-HT) metabolite5-HIAA, in multiparous as compared to nulliparousfemales. These data indicate the possibility of altera-tions to upfront olfactory regulation of behavior,with resulting modifications of behavioral responses.Furthermore, turnover ratios, as defined by Macbethet al. (2008) as metabolite-to-monoamine ratios, alsodemonstrated some interesting parity effects, withmultiparous females having significantly higher turn-over ratios of DOPAC:DA and 5-HIAA:5HT com-pared to nulliparous females, but a lower turnoverratioth

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the tonic inhibition exerted by the olfactory systemin species other than rodents); more hormones havebeen added to the cohort that stimulates the onsetand/or maintenance of maternal responsiveness (i.e.,corticosteroids); and our knowledge about the neuro-endocrine control of maternal behavior in farm ani-mals has increased. Still, many key issues surroundingthe complex behavioral and neuroendocrine transi-tion across estrus, pregnancy, parturition, and lacta-tion remain uninvestigated. For instance, althoughall rodents display nest-building, the hormonal con-trol of this activity and the brain regions involvedin its expression are largely unknown. Similarly, thequantitative and qualitative changes in food intakeobserved in many mammals around parturition(including placentophagia) have been little explored,either in terms of their potential biological meaningor the factors that control them. Indeed, the peri-partum stage is increasingly being recognized as acritical period for both mother and young, during

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Further Reading

Gonzalez A, Lovic V, Ward GR, Wainwright PE, and Fleming AS(2001) Intergenerational effects of complete maternaldeprivation and replacement stimulation on maternalbehavior and emotionality in female rats. DevelopmentalPsychobiology 38: 11–32.

Modney BK and Hatton GI (1994) Maternal behaviors: Evidencethat they feed back to alter brain morphology and function.Acta Paediatrica 397(supplement): 29–32.


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Abstract:

We describe and review maternal behavior in mammals (viz., rodents, rabbits, and ungulates), and theparticipation of steroid/peptide hormones in its regulation (e.g., nest-building, nursing, and aggres-sion). We discuss the neurobiology involved in the onset and offset of specific behavioral patterns andthe transmission and interpretation of signals from the young, which facilitate the offspring’s devel-opment. The impact of mothering styles on the psychobiological development of organisms and theiremotional reactivity as adults is addressed, as well as the epigenetic mechanisms participating in theintergenerational transmission of such acquired traits. We also discuss the ancillary and complemen-tary changes that occur to the mother’s brain and behavior, which support the display of care andprotection for young, and which extend to well beyond the peripartum and lactation periods of themother’s life. Such behavioral alterations, among them enhanced cognition and reductions in fear andanxiety, translate into more efficient behavior and a cost:benefit ratio that favors the survival of bothmother and young. We draw attention to topics that merit further investigation (e.g., epigenetictransmission of behavior in mammals other than rodents and mechanisms involved in the facilitationof cognition by motherhood) and to little explored issues (e.g., placentophagia, nest-building, and foodpreferences).

Keywords: Amygdala; Anxiety; BDNF; Epigenetics; Hippocampus; Lactation; Mammals; Medialpreoptic area; Neuroplasticity; Parity; Parturition; Postpartum; Prepartum; Pup sensitization; Spatialmemory; Stress

Author and Co-author Contact Information:

Gabriela Gonzalez-MariscalCINVESTAV – Universidad Autonoma de TlaxcalaApdo Postal 62TlaxcalaTlax [email protected]

Craig Howard KinsleyDepartment of Psychology-Center for NeuroscienceGottwald Science CenterUniversity of Richmond28Westhampton WayRichmondVA [email protected]

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(1979) and a PhD from the State University of New York, University Center at Albany (1985). From 1985 to1989, he was a postdoctoral fellow and research associate in the Laboratory of Human Reproduction and

Reproductive Biology, Department of Anatomy, at Harvard Medical School, and an instructor at HarvardUniversity. He joined the University of Richmond and its Department of Psychology in 1989. He and colleagueKelly Lambert recently published the textbook, Clinical Neuroscience: The Neurobiological Foundations of Mental

Health (1st edition: Worth, 2006; 2nd edition: Oxford University Press, projected, 2009). His research is funded by

the US National Institutes of Health, the National Science Foundation, and by private foundations such as theHoward Hughes Medical Institute, the Keck Foundation, and Arnold O. Beckman Foundation. Among hisachievements since his arrival at Richmond, he is most proud of the 100+ students he has trained who have

matriculated to PhD, MD, and MA programs in neuro-related areas.

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hobb: 00003 - elsevier

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