the hippocampus - university of pittsburghsimonslab.neurobio.pitt.edu/snc/hippocampus 2015.pdf ·...

The Hippocampus

Germán Barrionuevo

[email protected]

mailto:[email protected]

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).


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)


Area CA3

Area CA1:pyramidal cells (approximately 250,000)

Smaller soma (<20 μm)


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?)


Area CA1

Subiculum:

Pyramidal cells


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



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


cortical afferents


cortical efferents

Prefrontal cortex


Subcortical afferents

Dorsomedial

Thalamic nuclei

Anterior

thalamic

nuclei

Thalamus

Entorhinal cortex

Septal nuclei

Amygdala


Subcortical efferents

Dorsomedial

thalamic

nuclei

Anterior

thalamic

nuclei

Thalamus

Entorhinal cortex

Septal nuclei

Amygdala

Mammillary bodies

Nucleus accumbens


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


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.:


Patients H.M., R.B. or E.P.


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

the hippocampus - university of pittsburghsimonslab.neurobio.pitt.edu/snc/hippocampus 2015.pdf ·...

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