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Hippocampus & Medial Temporal Lobe
Functional Neuroanatomy November 12, 2009
Nanthia Suthana, Ph.D.Cognitive Neurophysiology Laboratory
Department of Neurosurgery
Felleman & Van Essen (1991)
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
Hippocampal Circuits
Fornix
bran
ch
(Postcomm
isuralB
ranch)
Fornix
(Pre
com
mis
sura
l)(septal-hippocampal pathway) Affects - Theta rhythm (4-8Hz)
(Hippocampal commissure)
(Perforant & alvear path)
AfferentsEfferents
HIPPOCAMPUS(Cortico-entorhinal projections)
ERC/Sub(PHG)
Cortex
Septal nuclei
Mammillary Body
ContralateralHippocampus
1. & 2.
3. 4.
The Hippocampus Dentate Complex(HC-DG)
Afferent Pathways
Pyramidal cell(CA1,2)
PHG (ERC, Sub)
1. Perforant Pathway: PHG (ERC) --> DG Also ….2. Alvear Pathway: PHG --> CA1 3. Septo-hippocampal path (via fornix): Septal nuclei --> DG4. Hippocampal commissure (connects bilateral hippocampi)
Dentate gyrus (granule cells)
(mossy fibers)
Pyramidal cell(CA3)
(schaffer collaterals)
1. (perforant path)
(Also note: this efferent path closes the HC circuit loop!)
2. (alvear path)
Septal nuclei3. (septo-hippocampal path - thru fornix)
The HippocampusCA fields
A) Lateral Ventricle, B) ependymal glia (ventricular surface), C) Alvear Layer, (pyramidal axons)
3 layers of hippocampus (archicortex): 1. Polymorph Layer (pyramidal axons & basket cells (-))2. Hippocampal pyramidal layer (pyramidal cell bodies)
3. Molecular Layer (pyramidal dendrites)
A) Lateral ventricleB) Ependymal glia
C) Alvear layer
1. Polymorph Layer
2. Pyramidal Layer
3. Molecular Layer(pyramidal dendrite)
(pyramidal axon)
(pyramidal cell body)
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
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
Encoding/Retrieval of Spatial Associations
(Suthana, Ekstrom, Moshirvaziri, Knowlton, Bookheimer in preparation)(Suthana, Ekstrom, Moshirvaziri, Knowlton, Bookheimer in preparation)
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