the hippocampus - university of pittsburghsimonslab.neurobio.pitt.edu/snc/hippocampus 2015.pdf ·...
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The isolated hippocampus vs. seahorse
Hippocampus Seahorse
The hippocampus is located inside the temporal lobe
The Hippocampus: lateral view
The hippocampus inside the temporal lobe
The hippocampus: lateral view
Amygdala
Hippocampus
Fornix
The Hippocampus: frontal view/coronal section
The hippocampus in the rodent brain
10 mm
fim
CA3DG
CA1
mf
pp
sch
comm
The hippocampal formation contains different subregions
1.entorhinal cortex (EC)
2.dentate gyrus (DG)
3.hilus (area CA4)
4.area CA3
5.area CA2
6.area CA1
7.subicular complex:
subiculum
presubiculum
parasubiculum
The entorhinal cortex-hippocampus system
Hippocampus proper: CA (cornus ammonis)1-4) areas
Hippocampal formation: DG + CA (1-4) areas
The hippocampus proper contains diverse cell types
Granule Cells
DGMossy Cells
DG Hilus
Pyramidal cells
(CA)
GABAergic
interneurons
Internal Connectivity
Dentate gyrus:Granule cells (approx. 1,000,000); small soma (≈10 μm)
Unipolar
Innervated by mossy cells (inner 1/3); by entorhinal cortex via medial and lateral perforant path (middle and
outer 1/3); and by dentate and hilar interneurons
Release glutamate
Project ipsilaterally to hilar mossy cells, hilar interneurons, and CA3 pyramidal cells via mossy fibers (1 mossy
fiber contacts approximately 14 CA3 pyramidal cells)
Septo-temporal projection spread: < 400 µm
Dentate gyrus
Hilus (Area CA4):Hilar mossy cells
Multipolar
Innervated by dentate granule cells
Release glutamate
Project ipsi- and contralaterally to granule cells via associational-commissural fibers; and to hilar interneurons
septo-temporal projection spread (as far as 1.1 mm).
Internal Connectivity
Hilus (Area CA4)
Area CA3:Pyramidal cells (approximately 160,000)
Large soma (30 μm)
Bipolar (basal dendrite, apical dendrite)
Innervated by 1) granule cells via mossy fibers (inner segment of apical dendrite); 2) CA3 pyramidal cells via
recurrent collaterals (basal dendrite and middle segment of apical dendrite); 3) entorhinal cortex via the perforant
path (outer segment of apical dendrite); and by CA3 interneurons
Release glutamate
Project ipsi- and contralaterally to CA3 pyramidal cells via associational-commissural fibers; to CA1 pyramidal cells
via Schäffer-collateral fibers; and to CA3 interneurons
Septo-temporal projection spread: can be as far as 7 mm (1 CA3 pyramid may contact up to 30,000 to 60,000 cells
ipsilaterally)
Internal Connectivity
Area CA3
Area CA1:pyramidal cells (approximately 250,000)
Smaller soma (<20 μm)
Bipolar (basal dendrite, apical dendrite)
Innervated by 1) CA3 pyramidal cells via Schäffer-collateral fibers (basal dendrite and middle segment of apical
dendrite; 1 CA1 pyramidal cell may receive input from >5,000 CA3 pyramidal cells); 2) entorhinal cortex via
perforant path (outer segment of apical dendrite); and 3) CA1 interneurons
Release glutamate
Project ipsilaterally to subicular pyramidal cells; to entorhinal cortical pyramidal cells; and to CA1 interneurons
septo-temporal projection spread: narrow (<400 µm?)
Internal Connectivity
Area CA1
Subiculum:
Pyramidal cells
Bipolar (basal dendrite, apical dendrite)
Innervated by CA1 pyramidal cells (basal dendrite), entorhinal cortex via perforant path (middle/outer segment
of apical dendrite), subicular interneurons
Release glutamate
Project ipsi- and contralaterally to 1) entorhinal cortex pyramidal cells; 2) subicular interneurons
Internal Connectivity
Internal Connectivity
Interneurons
Interneurons:Release GABA
Provide feed-forward and feedback inhibition
Contact principal cells as well as interneurons locally
Approximately 5% of the input received by a CA1 pyramidal cell originates from inhibitory interneurons
A single pyramidal cell 100s interneurons; a single interneuron 1000-3000 pyramidal
cells
Fast
Spiking
Non Fast
Spiking
The Hippocampus
Extrinsic Connections
CA3Dentate Gyrus
Associational areas of
cortex
Perirhinal Parahippocampus
Cortex
Entorhinal Cortex
Perforant
path
CA1
Subiculum
Mossy fibers
THE SERIAL AND PARALLEL COMPONENTS OF
THE HIPPOCAMPAL CIRCUITRY
Layers
3&4
Layers
5&6
Extrinsic Connections
cortical afferents
Extrinsic Connections
cortical efferents
Prefrontal cortex
Extrinsic Connections
Subcortical afferents
Dorsomedial
Thalamic nuclei
Anterior
thalamic
nuclei
Thalamus
Entorhinal cortex
Septal nuclei
Amygdala
Extrinsic Connections
Subcortical efferents
Dorsomedial
thalamic
nuclei
Anterior
thalamic
nuclei
Thalamus
Entorhinal cortex
Septal nuclei
Amygdala
Mammillary bodies
Nucleus accumbens
Extrinsic Connections
subcortical afferents
thalamus subiculum
CA1
amygdala subiculum
CA1
septum dentate
hilus
CA3
CA1
interneurons
ACh
GABA
locus coeruleus dentate
hilus
CA3
CA1
NA
raphé nucleus interneurons5HT
ventral tegmentum dentate
CA1
DA
hypothalamic
nuclei
dentate
subcortical efferents
subiculum
thalamus
amygdala
mammillary
bodies
CA3
CA1septum
hypothalamus
Extrinsic Connections
nucleus
accumbens
The Hippocampus
Function
MEMORY PROCESSES
encoding
initial processing of information
applies to short- and long-term memory
consolidation
preparation of information for long-term storage
applies to long-term memory only
storage
preservation of information across extended timeapplies to long-term memory only
retrieval
reactivation of stored informationapplies to long-term memory only
reconsolidation
consolidation after retrieval of previously consolidated
information
applies to long-term memory only
MEMORY SYSTEMS
working or short-term memory
information that guides on-going behavior
transient (sec to min)
capacity-limited (7 + 1 item)
reference or long-term memory
information that has been saved across time
“permanent”
“unlimited”
declarative reference memory (hippocampal dependent)
consolidated with conscious awareness
memory of episodes (episodic memory)
memory of facts (semantic memory)
non-declarative reference memory
consolidated without awareness
memory of procedures and skills (procedural memory)
perceptual-representational memory
UNIQUE PROPERTIES OF EPISODIC MEMORY
It is concerned with conscious recollection of personal experiences of events,
happenings, and situations.
It is oriented towards the past: retrieval in episodic memory means ‘‘mental
time travel’’ to one’s past.
It requires rapid storage of neuronal activity patterns with minimal
interference (reduced overlap) with other activity patterns:
Pattern separation
It is recalled from partial or degraded partial clues to reinstate the content of
the original activity pattern:
Pattern completion
A COMPUTATIONAL MODEL FOR RAPID STORAGE
OF MEMORY REPRESENTATIONS IN THE
HIPPOCAMPUS
Alessandro Treves and Edmund T. Rolls
Dept. of Experimental Psychology,
Oxford, England (1992)
Randall C. O’Reilly and James L. McClelland
Dept. of Psychology, C.M.U., Pittsburgh,
PA (1994)
ASSUMPTIONS OF THE MODEL
Representing cortical activity and minimizing overlap of
cortical representations: Pattern Separation to distinguish
between similar experiences.
Modifying synaptic connections so cortical representations
can later be recalled from partial or noisy version of these
representations: Pattern Completion to allow recall of a full
memory from a subset of cues that were present during the
original experience.
CA3Dentate Gyrus
Associational areas of
cortex
Perirhinal Parahippocampus
Cortex
Entorhinal Cortex
Perforant
path
CA1
Subiculum
Mossy fibers
THE SERIAL AND PARALLEL COMPONENTS OF THE
HIPPOCAMPAL CIRCUITRY
Episodic memory
representations
Perforant path from
entorhinal cortex
(~ 3,750 synapses)
Mossy fibers from
dentate gyrus
(46 boutons or
~ 650 release sites)
Recurrent collaterals
from other CA3 pyramidal
cells (~12,000 synapses)
CA3 pyramidal cell and its synaptic inputs
EC
Overlapped episodic memory
representations
Perforant pathCA3
pyramidal
cells
Diffuse connectivity
Dentate gyrus
The granule cell originates the mossy fiber
CA3
The Mossy Fiber Pathway
4 µm
PC (1)
IN
(~6)
Moss
Three Types of MF synapses: 1) Mossy bouton; 2) en passant
and 3) filipodia
Thorny
excrescences
MF Synapses20 µm
Soma
The CA3 pyramidal cell is the target of mossy fiber input
Basal
dendrites
The mossy fiber input is highly focused
Sparse connectivity of mossy fiber pathway: a key feature
for pattern separation
14 CA3 PC 1 DG GC
DG
CA1
CA1
Sparse connectivity of mossy fibers results in non-
overlapping memory representations
EC Perforant path
Mossy fibersDGCs
CA3
pyramidal
cells
Sparse connectivity
EC
DG
CA3
PC
CA3
DG
MF
GCs
Neurogenesis in the Dentate Gyrus
Modified from Schinder
& Gage, 2004
Adult neurogenesis in the dentate gyrus:
New adult-born dentate gyrus granule cells (young DGCs)
All neuronal cell bodies are immunolabeled
with anti-NeuN antibody (red). New granule
cells (green) were transduced by GFP-
expressing retroviral vectors.
Young granule cells are immunostained with
anti-doublecortin antibody (light blue).
dentate
gyrus
MF bouton from
adult-born DGC
Target
dendrite of
CA3
pyramidal cell
Adult hippocampal neurogenesis:
Old vs. adult-born (young) mossy fiber boutons
Thorny excrescences on
CA3 pyramidal cell
Modified from Deng et al.,
2010
MF bouton from
old DGC
Number of DCGs = 1 x106
Number of adult-born DCGs ~ 5x104
• Relatively weak but diffuse direct perforant path to CA3 to convey the
memory representations from EC.
• Strong but sparse mossy fiber synapses on to CA3 PCs from young
DGCs to select subpopulations of CA3 pyramidal cells and establish
non-overlapping memory representations via the recurrent
collaterals. (Selective ablation with X irradiation of adult-born DGCs
impaired context discrimination; Nakashiba et al. 2012)
The functional integration of adult-born (young) DGCs
into the mnemonic function of area CA3 in Pattern
Separation
Young DGCs provide a low-specificity yet densely sampled
representation of cortical inputs, whereas mature
GCs provide a highly specific yet sparse representation of
an event.
Young DGCs are particularly important for the resolution of
memories of novel events. Therefore, DG will be increasingly
likely to have ‘reserve’ neurons that will be capable of
responding to any novel environment.
The role of mature vs. young DGCs
In contrast, memories consisting of more familiar features
would be expected to rely disproportionately on mature
DGCs, and thus have a particularly high resolution and a
relative insensitivity to the presence of young DGCs.
Mature DGCs are optimally set up to respond to past
experiences whereas young DGCs have the capability to
encode new/unforeseen events.
Pattern Completion and Recall
Perforant path input to CA3 to activate already established
representations stored via the recurrent collaterals of CA3
pyramidal cells
Strong but sparse mossy fibers synapse onto CA3 PCs from
‘mature’ DGCs to select subpopulations of CA3 pyramidal cells
and activate the previously formed CA3 memory engrams
(Blockade of synaptic transmission at MF synapses originating from
old DGCs impaired recall with tetanus toxic expressed in DGCs
blocked until adulthood by doxycyclin (Nakashiba et al. 2012).
anterograde amnesia
No new memories
retrograde amnesia
Lost of old memories
time
Hippocampal injury
amnesia = loss of episodic memory
The Central Role of Hippocampus in Episodic Memory:
Clinical cases
PATIENT HM
At the age of 9 years, HM fell off a bicycle and sustained a laceration of
the left supraorbital region and was unconscious for ~5 minutes. He
experienced his first epileptic seizure (atypicalpetit mal) at 10 years of
age; At the age of 16 he began suffering from severe and debilitating
seizures (grand mal).
1953 - Scoville (et al., 1953) performed a bilateral resection of HM’s
medial temporal lobe, extending posteriorly for a distance of 8 cm from
the midpoint of the tips of the temporal lobes, with the temporal horns
constituting the lateral edges of resection.
(Scoville & Milner, 1997, 16).
At the time of operation, Scoville estimated that the removal consisted
of 8 cm of medial temporal lobe tissue, including: (1) the temporal pole,
(2) amygdaloid complex and (3) approximately two thirds of the
rostrocaudal extent of the intraventricular portion of the hippocampal
formation.
POST-OPERATIVE CLINICAL & PSYLOGICAL
PATIENT H.M.
Post operative symptoms
Extent of seizures minimized. Severe anterograde amnesia. A deficit in recent
memory: Recalled nothing of the day-to-day events of his hospital life.
Could not recognize faces of hospital staff after encountering them, nor find his
way to the bathroom after having been there previously.
Could not remember having previously had lunch, or having previously read a
magazine, or having previously put together a jigsaw puzzle.
Exhibited partial retrograde amnesia: He could not remember death of his favorite
uncle 3 years prior to the operation, nor anything of the time he spent in the
hospital.
Could recall some trivial events that had occurred before admission to hospital.
Could remember events that happened earlier in life up to his early twenties.
(Ribot’s law).
No sensory-motor deficits.
No impairment of procedural memory.
No impairment of personality or intelligence.
H.M. controlPatient H.M.:
Bilateral
temporal lobectomy
to relieve severe
epileptic seizures
Henry Gustav Molaison
born 26 Feb 1926
died 2 Dec 2008
MRI imaging
Ventral Surface
Normal Brain H.M.’s Brain.
1 cm
Coronal thionin-stained histological section at the level of the lateral geniculate
nuclei. The ablation of the tip of the temporal lobe, the uncus and the amygdala
were made with a scalpel. The more posterior temporal lobe tissue was
removed by suction.
CCFX
Th
RN
DGDG
1 cm.
Postmortem examination of patient H.M.’s brain
THE SIGNIFICANCE OF CASE H.M.
H.M. is interesting to neuroscientists because he was:
1. The first unambiguous case of amnesia
produced by a circumscribed lesion of the
brain.
2. The first case to demonstrate that the structures
in the MTL participate in memory (and not in
emotion).
3. The first case to show that the
declarative/procedural division of memory has a
biological substrate.
4. The starting point for the development of animal
models of amnesia in the nonhuman primate.
Patient H.M.:
No procedural memory deficit
Mirror drawing test
Patient R.B.Selective cell loss in area CA1 after a brief ischemic episode
Patient R.B.:
Declarative memory deficit: anterograde amnesia
copy:
10-20 min
retention interval:
Patient R.B.:
Declarative Memory Deficit: Anterograde Amnesia
Rey-Osterrieth Complex Figure Test
Patient R.B.:
No retrograde
amnesia
episodic memory
Patient E.P.Radical memory loss following a bout of viral encephalitis
Healthy
brain
E.P.
Patient R.B., H.M., or E.P.:
Declarative but no procedural memory deficit
Weather prediction task: A probability learning task
Patient R.B., H.M., or E.P.:
Declarative but no procedural memory deficit
Patients H.M., R.B. or E.P.
Declarative but no procedural memory deficit
Parkinson’s disease (PD) affects procedural memory
Weather prediction test: procedural Description of the test: declarative
Patient E.P.:
massive
damage to the
hippocampus,
amygdala, and
ento- and peri-
rhinal cortex
E.P. control
Patient E.P.
Declarative memory deficit:
retrograde and anterograde amnesia
Episodic Memory
Personal semantic (PS) memory is factual knowledge about a person's
own past. It has features of both episodic and semantic memory
Recognition for public events,
famous faces, and famous names
came into the news after 1950.
sample test test
comp_____ after a 5 min delay
e.g.:
computer
comparison
Compassion
Patient E.P.:
Non-declarative (procedural) memory intact
1. Highly organized and complex internal network
2. Highly interconnected with cortical and subcortical structures
3. Central player in the consolidation and temporary storage
of episodic memory
4. Exhibit neurogenesis, a form of cellular plasticity involved in
episodic memory formation (pattern separation).
The Hippocampus
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