Hippocampal mechanisms of memory and cognition. Matthew Wilson Departments of Brain and Cognitive Sciences and Biology MIT

Hippocampal mechanisms of memory and cognition Matthew Wilson Departments of Brain and Cognitive Sciences and Biology MIT 1

Courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission. Source: Amaral, David G., and M. P. Witter. "The three-dimensional organization of the hippocampal formation: A review of anatomical data." Neuroscience 31, no. 3 (1989): 571-591. From Amaral and Witter, 1989 2

Hippocampus in spatial and episodic memory The hippocampus is involved in the formation of episodic memory as well as spatial memory used in navigation. Navigation - linkage of spatial locations Episodic memory - linkage of events Both may depend critically on temporal sequence encoding 3

Neural recording device 4-channel microwire electrode Source Unknown. All rights reserved. This content is excluded from our Creative Commons license. For more information, see https://ocw.mit.edu/help/faq-fair-use/. Multiple electrode microdrive array 4

Spike amplitude clustering 5

Example of a Simple Spatial Environment 6

Ensemble Activity in Area CA1 During Spatial Exploration AAAS. All rights reserved. This content is excluded from our Creative Commons license. For more information, see https://ocw.mit.edu/help/faq-fair-use/. Source: Wilson, M. A., and B. L. McNaughton. "Dynamics of the Hippocampal Ensemble Code for Space (Vol 261, Pg 1055, 1993)." Science 264, no. 5155 (1994): 16. Wilson and McNaughton, Science, 1993 7

Place Fields on Linear Tracks 8

Hippocampal Place Cells 9

Hippocampal Ensemble Decoding 10

Decoding Sleep Reactivation 11

Hippocampus online and offline Two-Stage Memory Model Theta rhythm Sharp wave/ripples Buzsaki 1989 Courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission. Source: Buzsáki, György. "Two-stage model of memory trace formation: A role for noisy brain states." Neuroscience 31, no. 3 (1989): 551-570. Buzsaki, 1989 Buzsaki 1989 Buzsaki, 1989 12

Source Unknown. All rights reserved. This content is excluded from our Creative Commons license. For more information, see https://ocw.mit.edu/help/faq-fair-use/. 13

Interaction of asymmetric excitation with oscillatory variation in inhibition can translate one linear dimension (space) into another (time). Hippocampal phase precession may be a demonstration of that process. Direction of movement Direction of movement Place cell 1 14

Overlapping asymmetric place fields with oscillatory variation in excitability translate behavioral time relationships to biophysical timescales with preserved temporal order Biophysical timescale Direction of movement Place cell 1 Place cell 2 Behavioral timescale 15

Hippocampal theta sequences Wiley. All rights reserved. This content is excluded from our Creative Commons license. For more information, see https://ocw.mit.edu/help/faq-fair-use/. Source: Foster, David J., and Matthew A. Wilson. "Hippocampal theta sequences. "Hippocampus 17, no. 11 (2007): 1093-1099. Foster and Wilson, 2007 16

Hippocampal spatial representations are encoded as sequences during behavior Courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission. Source: Davidson, Thomas J., Fabian Kloosterman, and Matthew A. Wilson. "Hippocampal replay of extended experience." Neuron 63, no. 4 (2009): 497-507. Davidson, Kloosterman, and Wilson, Neuron, 2009 17

HPC-PFC: functionally connected Prefrontal cortex PFC Hippocampus HPC 18

HPC-PFC: functionally connected Prefrontal cortex PFC X Hippocampus HPC X Spatial navigation & memory deficits in rodents Episodic memory deficits in humans Working memory deficits in rodents and humans Loss of executive control The hippocampus: encoding and recognising spatial context The prefrontal cortex: integrating the cues of current context (held on-line in working memory) to control appropriate behaviour 19

HPC-PFC: functionally connected during spatial working memory tasks T-maze 20

HPC-PFC: individual electrophysiologies Place cells : neurons with spatial receptive fields ( place fields ) Rodents, primates, humans Working memory cells in primates from Niki (1974) Brain Res. 70, 346-349 Courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission. Source: Niki, Hiroaki. "Differential activity of prefrontal units during right and left delayed response trials." Brain research 70, no. 2 (1974): 346-349. 21

Multiple units from multiple electrodes in multiple sites 22

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Data Behaviour & Position Extracellular Action Potentials (spikes) Local Field Potentials (LFP) choice HPC forced PFC 24

Interactions: spikes vs. Interactions: LFP Spikes vs. LFP PFC spike times HPC spike times 300 250 Theta peak times HPC LFP -200 4.041 4.0412 4.0414 4.0416 4.0418 4.042 x 10 7 0 1000 Time (ms) 25

Enhanced theta-phase locking during correct choice Jones, Matthew W., and Matthew A. Wilson. "Theta rhythms coordinate hippocampal prefrontal interactions in a spatial memory task." PLoS biol 3, no. 12 (2005): e402. https://doi.org/10.1371/journal.pbio.0030402. License CC BY. Jones and Wilson, PLoS Biol., 2005 26

LFP vs. LFP: Coherence Coherence Frequency (Hz) Jones, Matthew W., and Matthew A. Wilson. "Theta rhythms coordinate hippocampal prefrontal interactions in a spatial memory task." PLoS biol 3, no. 12 (2005): e402. https://doi.org/10.1371/journal.pbio.0030402. License CC BY. Jones, M. et al. PLoS 2005 27

Optogenetic manipulation of hippocampal inhibitory cells Courtesy of elife. License CC BY 4.0. Source: Siegle, Joshua H., and Matthew A. Wilson. "Enhancement of encoding and retrieval functions through theta phase-specific manipulation of hippocampus." Elife 3 (2014): e03061 28

Courtesy of elife. License CC BY 4.0. Source: Siegle, Joshua H., and Matthew A. Wilson. "Enhancement of encoding and retrieval functions through theta phase-specific manipulation of hippocampus." Elife 3 (2014): e03061 Siegle and Wilson, elife, 2014 29

Role of Sleep in Memory Sleep allows examination of memory independent of behavior. The formation of lasting memories may involve the communication of information between brain areas during sleep. Broadly identify two stages of non-rem sleep (NREM) and rapid eye movement sleep (REM). 30

Experimental design SLEEP RUN SLEEP 1-2 hrs 1-2 hrs 15 min slow-wave sleep REM sleep awake behavior Courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission. Source: Miller, Earl K., and Matthew A. Wilson. "All my circuits: using multiple electrodes to understand functioning neural networks." Neuron 60, no. 3 (2008): 483-488. 31

Compressed Run sequences are expressed in hippocampus during nrem sleep 4 sec Run 150 msec Sleep Courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission. Source: Miller, Earl K., and Matthew A. Wilson. "All my circuits: using multiple electrodes to understand functioning neural networks." Neuron 60, no. 3 (2008): 483-488. Lee and Wilson, Neuron, 2002 32

Sequences are re-expressed during CA1 ripple events Duration of low probability sequences Correlation of low probability sequences and ripples Example of a low probability sequence and a ripple event Courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission. Source: Lee, Albert K., and Matthew A. Wilson. "Memory of sequential experience in the hippocampus during slow wave sleep." Neuron 36, no. 6 (2002): 1183-1194. 33

Overlapping asymmetric place fields with oscillatory variation in excitability translate behavioral time relationships to biophysical timescales with preserved temporal order Direction of movement Place cell 1 Place cell 2 Behavioral timescale 34

Are there signatures of memory reactivation in the neocortex during hippocampal reactivation Simultaneously record in the hippocampus and primary and secondary visual cortex during spatial behavior. Look for reactivation in both structures during sleep. 35

Experimental Design: C CA1 Visual 1. Intra-maze local cues, no prominent distal cues 2. Well trained animals: alternation task 3. Recording sites: visual cortex (Occ1, Occ2) and CA1 4. Sleep states (SWS, REM, Wake, Int) classified using EMG and hippocampal EEG 1mm Nature. All rights reserved. This content is excluded from our Creative Commons license. For more information, see https://ocw.mit.edu/help/faq-fair-use/. Source: i, Daoyun, and Matthew A. Wilson. "Coordinated memory replay in the visual cortex and hippocampus during sleep." Nature neuroscience 10, no. 1 (2007): 100-107. 36

Sequence memory reactivation in hippocampus and visual cortex A CTX 30 HP 50 L R 20cm 20 0 L R 20cm 25 0 B Lap RUN C Lap RUN Avg 01234567 1s Avg 012345 1s Frame 1s Frame 1s Seq POST 0.5s 0132567 POST Seq 01235 0.2s Nature. All rights reserved. This content is excluded from our Creative Commons license. For more information, see https://ocw.mit.edu/help/faq-fair-use/. Source: i, Daoyun, and Matthew A. Wilson. "Coordinated memory replay in the visual cortex and hippocampus during sleep." Nature neuroscience 10, no. 1 (2007): 100-107. Ji and Wilson, Nature Neuroscience, 2007 37

Reactivation occurs during activity frames correlated with the slow oscillation A L5 CTX HP Ripple 0.5s B Count 100 50 CTX frame Count 1000 500 CTX silent Count 140 70 HP frame Count 600 300 HP silent 0 1 2 3 Duration (s) 0 0.5 Duration (s) 1 0 1 2 3 Duration (s) 0 0.5 Duration (s) 1 C Correlation (x 0.001) 10 5 0 10 5 0-0.2 0 0.2 Start 10 Correlatio n (x 0.001) 5 0 10 5 0-0.2 0 0.2 End -1-0.5 0 0.5 1 Time (s) -1-0.5 0 0.5 1 Time (s) Nature. All rights reserved. This content is excluded from our Creative Commons license. For more information, see https://ocw.mit.edu/help/faq-fair-use/. Source: i, Daoyun, and Matthew A. Wilson. "Coordinated memory replay in the visual cortex and hippocampus during sleep." Nature neuroscience 10, no. 1 (2007): 100-107. 38

Can we influence memory reactivation Sound L downward frequency sweep during sleep? speaker Sound R upward frequency sweep frequency frequency time nosepoke time reward site reward site Sleep box (away from track) speaker For 2-2.5 hours Sound L Sound R control sounds Nature. All rights reserved. This content is excluded from our CreativeCommons license. For more information, see https://ocw.mit.edu/help/faq-fair-use/. Source: L Bendor, Daniel, and Matthew A. Wilson. "Biasing the content of Hippocampal replay during sleep." Nature neuroscience 15, no. 10 (2012): 14391444 39

Behavioral task design Nature. All rights reserved. This content is excluded from our CreativeCommons license. For more information, see https://ocw.mit.edu/help/faq-fair-use/. Source: L Bendor, Daniel, and Matthew A. Wilson. "Biasing the content of Hippocampal replay during sleep." Nature neuroscience 15, no. 10 (2012): 14391444 40

Do task-related sounds bias the content of future replay? Hypothesis: Sound R- place cells with rightsided place fields are more active during replay Sound L- place cells with left-sided place fields are more active during replay Nature. All rights reserved. This content is excluded from our CreativeCommons license. For more information, see https://ocw.mit.edu/help/faq-fair-use/. Source: L Bendor, Daniel, and Matthew A. Wilson. "Biasing the content of Hippocampal replay during sleep." Nature neuroscience 15, no. 10 (2012): 14391444 41

Bias observed in individual place cell responses Nature. All rights reserved. This content is excluded from our CreativeCommons license. For more information, see https://ocw.mit.edu/help/faq-fair-use/. Source: L Bendor, Daniel, and Matthew A. Wilson. "Biasing the content of Hippocampal replay during sleep." Nature neuroscience 15, no. 10 (2012): 14391444 Bendor and Wilson, Nature Neuroscience, 2012 42

Rasch et al. 2007 Rudoy et al. 2009 stimulation Cortex Determines Bias pre-replay pre-replay brain brain state state Hippocampus Reactivation event (transfer of memory) Bias which memories are transferred Science. All rights reserved. This content is excluded from our Creative Commons license. For more information, see https://ocw.mit.edu/help/faq-fair-use/. Source: Rasch, Björn, Christian Büchel, Steffen Gais, and Jan Born. "Odor cues during slow-wave sleep prompt declarative memory consolidation." Science 315, no. 5817 (2007): 1426-1429. 43

Hippocampal activity during quiet wakefulness During awake behavior, there are periods of quiet wakefulness that have EEG that is similar to NREM consisting of brief bursts of activity modulated by high frequency ripple oscillations. Is there structure to the patterns of multiple single neuron activity during this state? 44

Does sequence reactivation occur during quiet wakefulness? a RUNNING b STOPPED AFTER RUNNING 45

Memory of recent experience replayed in reverse-time order Running Stopping a Position Position vs. time b Cell 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 RUN 560 570 580 590 600 610 620 Time (s) Hippocampal place-cell activity vs. time c 1 2 3 4 5 6 10 987 11 12 13 14 15 16 17 18 19 592.2 592.4 592.6 592.8 593 593.2 593.4 593.6 Reverse-time sequence replay during hippocampal ripples Reprinted by permission from Macmillan Publishers Ltd: Nature. Source: Foster, David J., and Matthew A. Wilson. "Reverse replay of behavioural sequences in hippocampal place cells during the awake state." Nature 440, no. 7084 (2006): 680-683.. 2006. Foster and Wilson, Nature, 2006 46

Learning sequences of actions Temporal credit assignment Dopamine unit activity could differentially weight the content of hippocampal sequences, propagating value information from the rewarded location backwards along the incoming trajectory. Foster and Wilson, Nature 440: 680-683, 2006 47

Hippocampal place-cell sequences depict future paths to remembered goals Brad E. Pfeiffer & David J. Foster Nature, 2013 Courtesy of Nature. Used with permission. Source: Pfeiffer, Brad E., and David J. Foster. "Hippocampal place-cell sequences depict future paths to remembered goals." Nature 497, no. 7447 (2013): 74-79. 48

Long behavioral sequences on a 10m track Courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission. Source: Davidson, Thomas J., Fabian Kloosterman, and Matthew A. Wilson. "Hippocampal replay of extended experience." Neuron 63, no. 4 (2009): 497-507. Davidson, Kloosterman and Wilson, Neuron, 2009 49

Reconstruction of extended sequence replay during quiet wakefulness Davidson, Kloosterman and Wilson, Neuron, 2009 50

Deciphering the code Forward replay 3 2 4 Building blocks of memory? 1 2 3 4 1 51

Deciphering the code Forward replay 3 2 4 Building blocks of memory? 1 2 3 4 1 52

Extended replay spans multiple ripple events Elsevier, Inc., http://www.sciencedirect.com. All rights reserved. This content is excluded from our Creative Commons license. For more information, see https://ocw.mit.edu/help/faq-fair-use/. Source: Davidson, Thomas J., Fabian Kloosterman, and Matthew A. Wilson. "Hippocampal replay of extended experience." Neuron 63, no. 4 (2009): 497-507. https://doi.org/10.1016/j.neuron.2009.07.027. Davidson, Kloosterman and Wilson, Neuron, 2009 53

Extended replay has a characteristic speed Courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission. Source: Davidson, Thomas J., Fabian Kloosterman, and Matthew A. Wilson. "Hippocampal replay of extended experience." Neuron 63, no. 4 (2009): 497-507. Davidson, Kloosterman and Wilson, Neuron, 2009 54

Single ripple sequences are at same scale as theta sequences Courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission. Source: Davidson, Thomas J., Fabian Kloosterman, and Matthew A. Wilson. "Hippocampal replay of extended experience." Neuron 63, no. 4 (2009): 497-507. Davidson, Kloosterman, and Wilson, Neuron, 2009 55

Overall summary Sequence memory can be encoded in the hippocampus during active behavior. Sequence memory is subsequently replayed during sleep in both the hippocampus and neocortex. The content of reactivated memory during sleep can be biased by external manipulation. Sequence memory replayed during quiet wakefulness is associated reward information and may serve a different role in learning than replay during sleep. 56

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