Hippocampus & Medial Temporal Lobe

Functional Neuroanatomy

PHG

MamillaryBodies

HC

LIMBIC SYSTEM(cingulate gyrus, PHG, hypothalamus, septal area, nucleus acumbens, orbitofrontal ctx, amygdala)

Subcallosal Gyrus

Fornix

Cingulate Gyrus

Ant. Nucleus of Thal

Olfactory bulb

Septal Nuclei

Amygdala

Broca Maclean

The Medial Temporal Lobeand Hippocampus

What is amnesia?• Loss of memory function

• Two types

– Retrograde amnesia• Loss of previously-acquired (”premorbid”) memories

– Anterograde amnesia• Inability to form new (”postmorbid”) memories

Injury

Time

(Corkin, Amaral, Gonzalez, Johnson and Hyman J. Neuro, 1997)(Scoville and Milner, 1957)

Patient H.M. and the Human MTL

• Suffered head injury @age 9– Developed severe epilepsy

• Surgeon surgically removed the medial temporal lobe bilaterally

• HM suffered severe anterograde and temporally graded retrograde amnesia

• Spared skill learning

INTRODUCTIONMedial Temporal Circuitry

Adjacent MTL cortices : Entorhinal (ERC), Perirhinal (PRC) Parahippocampal (PHC)

Hippocampus (HC) proper : Dentate Gyrus (DG), CA3, CA1, and Subiculum (Sub)

PRC

PHC

ERC

Sub

DG CA 3

CA 1

Fornix

Hippocampal Molecular Mechanisms

• Place cells, head direction cells, grid cells

• Long-term potentiation

• Neurogenesis

• Microcircuitry

Hippocampal Place Cells

(O’Keefe & Conway,1978; Wilson & McNaughton, 1993, Ekstrom et al., 2003)

Reproduced from Wilson and McNaughton, 1993, Science

Place Cells, Head Direction Cells, Grid Cells(Hafting et al., 2005; Moser & Moser, 2007)

PRC

PHC

ERC

Sub

DG CA 3

CA 1

Fornix

Hippocampal Molecular Mechanisms

• Place cells, head direction cells, grid cells

• Long-term potentiation

• Neurogenesis

• Microcircuitry

Long-Term Potentiation

(Kandel et al., 2000, Principles of Neural Science(Kandel et al., 2000, Principles of Neural Science)

Long-term potentiation

• Bliss & Lomo (1973) discovered that high-frequency stimulation of neurons in the hippocampus results in lasting increase in synapse strength (known as long-term potentiation, or LTP)

• LTP relies upon a kind of glutamate receptor (NMDA)

• Block LTP – Block Learning

Hippocampal Molecular Mechanisms

• Place cells, head direction cells, grid cells

• Long-term potentiation

• Neurogenesis

• Microcircuitry

Hippocampal Neurogenesis

(Li et al., 2000(Li et al., 2000)

Exercise-induced increases in Dentate Gyrus CBV correlate with Neurogenesis

Pereira A C et al. PNAS 2007

Blocking Neurogenesis produces Learning Deficits

(Clelland et al., Science, 2009)

Taxonomy of Long-term Memory Systems

Squire L, Zola S PNAS 1996;93:13515-13522Adapted from Squire, Knowlton 1994

Episodic Learning & Memory

Personally experienced events within a spatio-temporal Context (Tulving, 1983, 2002)

INTRODUCTIONMedial Temporal Circuitry

Adjacent MTL cortices : Entorhinal (ERC), Perirhinal (PRC) Parahippocampal (PHC)

Hippocampus (HC) proper : Dentate Gyrus (DG), CA3, CA1, and Subiculum (Sub)

PRC

PHC

ERC

Sub

DG CA 3

CA 1

Fornix

Imaging the Human Hippocampus is Challenging

High-Resolution Hippocampal Imaging

HHR Structural (voxel size = .4 x .4 x 3mm)HHR Functional EPI (voxel size = 1.6 x 1.6 x 3 mm)

High-resolution MRI of the MTL

(Zeineh, Engel, Thompson, Bookheimer Neuroimage, 2001)

(Ekstrom, Bazih, Suthana, (Ekstrom, Bazih, Suthana, Al-Hakim, Ogura, Zeineh, Burggren, Bookheimer. Neuroimag, 2009)

Current Research Directions

• Encoding vs. Retrieval

• Match/Mismatch or Updated Encoding– Allocentric Spatial Encoding

• Recollection vs. Familiarity

• Pattern Separation / Pattern Completion

Novelty Encoding Paradigm

Rest

New

Repeat

New

Repeat

New

Rest

Outdoor Indoor

Alternating Blocks of Novel and Repeat Pictures

Time Series for Subregions

Sustained Late Activation No Activation

Parahippocampal

Fusiform

CA 2, 3, DG CA 1

Subiculum Entorhinal

Face-Name Association Zeineh et al, Science, 2003

Learn Face-Name Pair

Covert Name Recall

Distractor

Learn

Recall

Learn

Recall

Learn

Recall

Learn

Recall

D D D DRest Rest

Time 7 minutes

Results

Performance

Used as a regressionmodel for learningand retrieval.

Results

Time Courses

Learn

Recall

Encoding/Retrieval of Spatial Associations

(Suthana, Ekstrom, Moshirvaziri, Knowlton, Bookheimer in preparation)(Suthana, Ekstrom, Moshirvaziri, Knowlton, Bookheimer in preparation)

Recollection versus Familiarity

• (R) Recollection - re-experiencing the encoding event at the time of recall, true episodic memory

• (K) - Know - the feeling of familiarity that you’ve seen something before, but not remembering the exact encoding event– Not implicit because it is conscious

Eldridge et al 2001, 2005: Remember- Know Distinction in HC

R vs. K• Eldridge et al have shown the HC is

selectively involved in R, not with K.

Current Research Directions

• Encoding vs. Retrieval

• Match/Mismatch or Updated Encoding– Allocentric Spatial Encoding

• Recollection vs. Familiarity

• Pattern Separation / Pattern Completion

CA1 region?

• Bilateral CA1 damage results in memory impairments(Zola-Morgan et al., 1986; Sass et al., 1995; Rausch & Babb, 1993)

• Place cells & computational models (McNaughton & Morris 1987; Lee et al. 2004; Levy 1989; Hasselmo & Schnell, 1994; Blum & Abbot,

1996)

PRC

PHC

ERC

Sub

DG CA 3

CA 1

Fornix

CA1 region?

• Bilateral CA1 damage results in memory impairments(Zola-Morgan et al., 1986; Sass et al., 1995; Rausch & Babb, 1993)

• Place cells & computational models (McNaughton & Morris 1987; Lee et al. 2004; Levy 1989; Hasselmo & Schnell, 1994; Blum & Abbot,

1996)

ERC

DG CA 3

CA 1 = comparator(match/mismatch detector)

EGOCENTRIC (SSP): “Learn store locations relative to starting point”

ALLOCENTRIC (MSP): “Learn store locations relative to other stores”

Suthana et al., Journal of Neuroscience, 2009

Learning a Cognitive Map(Allocentric Spatial Encoding)

(Spearman’s ρ = 0.53, p = 0.02, N=18)

Allocentric Egocentric

Suthana et al., Journal of Neuroscience, 2009

Current Research Directions

• Encoding vs. Retrieval

• Match/Mismatch or Updated Encoding– Allocentric Spatial Encoding

• Recollection vs. Familiarity

• Pattern Separation / Pattern Completion

Recollection versus Familiarity

• (R) Recollection - re-experiencing the encoding event at the time of recall, true episodic memory

• (K) - Know - the feeling of familiarity that you’ve seen something before, but not remembering the exact encoding event– Not implicit because it is conscious

R vs. K• Eldridge et al have shown the HC is selectively

involved in R, not with K.

(Eldridge et al., Nature Neuroscience 2000)

Current Research Directions

• Encoding vs. Retrieval

• Match/Mismatch or Updated Encoding– Allocentric Spatial Encoding

• Recollection vs. Familiarity

• Pattern Separation / Completion

– Separation of item/episodic representations

– Orthogonolization of sensory input & reduction of interference(Rolls, 1996; Norman & O’Reilly, 2003)

Pattern separation & the Hippocampus

Felleman & Van Essen (1991)

High-res fMRI of Human CA3/DG (Bakker, Kirwan, Miller, and Stark, Science 2008)

Hippocampal CA3/DG and Pattern Separation

Pattern Separation (CA3/DG)

(Clelland et al., Science, 2009) (Leutgeb et al., Science, 2008)

Conclusions– Proposed Model (Encoding)

PRC

PHC

ERC

DG CA 3

BOLD

Neuronal Firing

Conclusions– Proposed Model (Retrieval)

PRC

PHC

ERC

Sub

DG CA 3

CA 1

Fornix

BOLD

Neuronal Firing

Conclusions– Proposed Model (Allocentric / Mismatch Encoding)

PRC

PHC

ERC

Sub

DG CA 3

CA 1BOLD

Neuronal Firing

HC

Kluver-Bucy SyndromeBilateral Amygdala and Pyriform ctx

(some area 20 and HC)

Subcallosal Gyrus

Fornix

Cingulate Gyrus

MamillaryBodies

Ant. Nucleus

PHGOlfactory bulb

Septal Nuclei

Amygdala

*Emotional Response:Endocrine relase, autonomic discharge, facial posturing, body set

The brain’s response to seeing emotional faces

• Face-specific brain region (fusiform face area)

• Seeing emotional faces (fear, anger) increases activity in the emotional system (amygdala)

• No conscious perception is required

• Frontal lobes can control this response

Single Neuron Recordings in Humans

(Quian Quiroga Reddy, Kreiman, Koch, & Fried. Nature, 2005)

(Waydo, Kraskov, Quian Quiroga, Fried, & Koch. Journal of Neurosci 2006)

Invariant Representations in the Human MTL

Improved Electrode Localization

Improved electrode localization and targeting using high-resolution imaging and cortical unfolding

(Ekstrom, Suthana, Behnke, Bookheimer, and Fried, Journal of Neurosurgery, 2009)(Ekstrom, Suthana, Behnke, Bookheimer, and Fried, Journal of Neurosurgery, 2009)

Target

Lure 1 Lure 2 Lure 3 Lure 4

Pattern Separation in Human CA3/DG

Suthana et al., in preparation