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Unformatted text preview: THE NEURAL BASIS OF EPISODIC MEMORY NORBERT FORTIN, PHD N112A: Neuroscience Fundamentals November 9, 2011 OVERVIEW ❖ The multiple memory systems of the brain ❖ Declarative, episodic and semantic memory ❖ Neural basis of episodic memory: evidence from human studies ❖ Neural basis of episodic memory: evidence from animal studies THE MULTIPLE MEMORY SYSTEMS OF THE BRAIN DIFFERENT BRAIN SYSTEMS FOR DIFFERENT TYPES OF MEMORIES MEMORY NONDECLARATIVE DECLARATIVE SEMANTIC EPISODIC FACTS EVENTS MEDIAL TEMPORAL LOBES Hippocampus and Parahippocampal region SKILLS & HABITS PRIMING & PERCEPTUAL LEARNING MOTOR COGNITIVE SHIFTS IN JUDGMENTS AND PREFERENCE STRIATUM CORTEX SIMPLE CLASSICAL CONDITIONING EMOTIONAL RESPONSES SKELETAL RESPONSES AMYGDALA CEREBELLUM NONASSOCIATIVE LEARNING HABITUATION SENSITIZATION REFLEX PATHWAYS Adapted from Squire (1992) OVERVIEW ❖ The multiple memory systems of the brain ❖ Declarative, episodic and semantic memory ❖ Neural basis of episodic memory: evidence from human studies ❖ Neural basis of episodic memory: evidence from animal studies DECLARATIVE, EPISODIC, AND SEMANTIC MEMORY DEFINITIONS AND IMPORTANT FEATURES Declarative memory (Cohen & Squire, 1980; Eichenbaum & Cohen, 2001) MEMORY MEMORY DECLARATIVE SEMANTIC Episodic memory (Tulving, 1972, 2002) EPISODIC FACTS Memory that can be “declared”, that is “explicit” NONDECLARATIVE Flexible expression EVENTS MEDIAL TEMPORAL LOBES Hippocampus and Parahippocampal region Memory for events, personal experiences Memory of the event is tied to the spatial and temporal context in which it occurs SKILLS & HABITS PRIMING & PERCEPTUAL LEARNING MOTOR COGNITIVE SHIFTS IN JUDGMENTS AND PREFERENCE NONASSOCIATIVE SIMPLE LEARNING CLASSICAL CONDITIONING (Tulving, 1972, 2002) Semantic memory EMOTIONAL RESPONSES SKELETAL RESPONSES HABITUATION SENSITIZATION Memory for facts, general knowledge of the world Context-independent OVERVIEW ❖ The multiple memory systems of the brain ❖ Declarative, episodic and semantic memory ❖ Neural basis of episodic memory: evidence from human studies ❖ Neural basis of episodic memory: evidence from animal studies NEURAL BASIS OF EPISODIC MEMORY IN HUMANS PATIENT K.C. Positive: Negative: (interviewed by Endel Tulving) type and FAD mutant (N141I) PS2 clonal lines inand J. Hende 26. Alternative endoproteolysis sites for PS2 are localized pairment of the right arm duced for 24 hours were determined (13, 36). partial loss of the nerve Data by grants from within the domain after predicted transmembrane dofrom three independent experiments with five differ- the fifth and ofsix Institute Ne main 5, encoded by exon 11 (formerly exon 10) (36). from ent (2), which still has its adherents lines roots. Metropolitan 27. The point mutations in the potential aspartate cleavage - view wild-type and mutant PS2 clonal (3), paired No other neurolog One influential view of memory organiza according to expression level were used. in evident untilD.M.K. is a Fr sites of PS2tion (1)and D329A) and control aspartate - proposed instead that the core defect (D326A pictures the cognitive or declara she reached recipient of a D. M. Kovacs, amnesia R. loss of context- data. (D308A) were introduced into a PS2 open reading frame tive form, comprising both fact and event31. temporal-lobe T.-W. Kim,is aE. Tanzi, unpublished ory difficulties were first D. Scheuner memory, in that , 864 (1996); T. trance by site-directed mutagenesis with Muta-Gene phage- -32. rich episodicet al., Nature Med. 2in some am- Tomita into a mainstream memory, as a unitary process that is depen et al cases, Natl. Acad. Sci. U.S.A. 94, free ond mid kit (Bio-Rad). The the hippocampal encodingathe of nesic., Proc.semantic memory, which is 2025 (1997);patient, 14 May 1997 Jon, now a dent on inducible construct system, set NEURAL BASIS OF EPISODIC MEMORY IN HUMANS FIRST CLEAR EVIDENCE OF A DISSOCIATION of context, appears to have been relatively ered prematurely at 26 w preserved. An opportunity to assess these Weighing just under 1 kg different views has been provided by our breathing problems, he w produces a se study of patients with amnesia due to hip- cubator for 2 months, dur but and placed pocampal pathology sustained, in two of our was tube-fed leaves ge patients, very early in life, before they had Thereafter, he improved based mainly acquired the knowledge base that charac- oped normally. At the ag tions, relative terizes semantic memory. The results sug- two, protracted (1.5 to His first o gest a possible reconciliation of the two convulsions. The memor views, namely that episodic memory de- first noted by his parents now aged 14 F. Vargha-Khadem and K. E. Watkins, Cognitive Neuropends primarily on the hippocampal com- half after the two long-la delivery, and science Unit, Institute of Child Health, University College ponent of the larger system, whereas seman- third patient, Kate, now London Medical School, Wolfson Centre, Mecklenburgh beat until to Global anterograde amnesia UK. described in threememory depends primarilyinjuries un- average studentfor 7 the is Square, London WC1N 2AP, tic patients with brain on the that ocD. Gadian and A. Connelly, another Physics curred in oneG.case at birth, in Radiology and by age derlying cortices. third at age 9. Magnetic ed. received a to 4, and in the accidentally She also Unit, Institute of Child Health, University College London Previously, in the absence of any cases. Rebrachial plex resonance techniques revealed bilateral hippocampal pathology in all three report- for 3 days) of theophyl Medical School, 30 Guilford Street, London WC1N 1EH, ed cases of amnesiaof everyday life, all three she was beinghad due to very early bilat- which tion, she treat UK. markably, despite their Radiology and Physics Unit, Institute for the episodes pronounced amnesia W. Van Paesschen, eral injury to the medial temporal lobe (4), acute episode of seizures of Child patients attendedHealth, University College London Medical attained levels of speech andmight and respiratory arrest en mainstream schools and it had seemed that such early damage language attacks recurr School, 30 Guilford Street, London WC1N 1EH, UK, and despite treatm competence, literacy, andQueen Square, London WC1N that impede cognitive low average tothe she showed good phys so are within the development that average Institute of Neurology, factual knowledge 3BG, UK. range. The findings provide support for theIn- resulting the episodic and semantic com- left her profoundl view that syndrome would take the form, which ication. With M. Mishkin, Laboratory of Neuropsychology, National at age amnesia, but of severe mental stitutes of Mental Health, 49 are partly dissociable, a she d ponents of cognitive memory Convent Drive, Bethesda, not of with The findings described retar- quently, made which ha only the episodic component epilepsy, 17,good lobe dation (5). here MD 20892– 4415, USA. al anticonvulsa being fully dependent on the hippocampus. show instead that early bilateral pathology trolled with plexus inju * To whom correspondence should be addressed. E-mail: Neuropsychological ex that is limited largely to the hippocampus fkhadem@ich.ucl.ac.uk pairment of t heavily interconnected medial temporallobe structures consisting of the hippocampus and underlying entorhinal, perirhinal, and parahippocampal cortices. According to this notion, both fact (or semantic) memory and event (or episodic) memory are impaired together in a graded manner depending on the extent of damage to the hippocampal system as a whole. An earlier Differential Effects of Early Hippocampal Pathology on Episodic and Semantic Memory F. Vargha-Khadem,* D. G. Gadian, K. E. Watkins, A. Connelly, W. Van Paesschen, M. Mishkin 376 SCIENCE One influential view of memory organiza- Positive: tion (1) pictures the cognitive or declarative form, comprising both fact and event memory, as a Negative: unitary process that is dependent on the hippocampal system, a set of heavily interconnected medial temporallobe structures consisting of the hippocampus and underlying entorhinal, perirhinal, z VOL. 277 z 18 JULY 1997 z www.sciencemag.org view (2), which still has its adherents (3), proposed instead that the core defect in temporal-lobe amnesia is a loss of contextrich episodic memory, in that in some amnesic cases, semantic memory, which is free of context, appears to have been relatively preserved. An opportunity to assess these different views has been provided by our partial loss o from the fif roots. No oth evident until ory difficultie trance into a ond patient, ered prematu Weighing jus breathing pro NEURAL BASIS OF EPISODIC MEMORY IN HUMANS IT REMAINS A HEATED DEBATE ❖ We now know that the hippocampus, the parahippocampal region (i.e., entorhinal, perirhinal and parahippocampal cortex) and the prefrontal cortex are important for episodic memory ❖ However, the specific role of each structure remains unknown. ❖ We know even less about the fundamental neuronal mechanisms (i.e., how are neurons in those regions supporting episodic memory?) ❖ The main problem: ❖ ❖ Techniques used in humans do not have the sufficient spatial and temporal resolution The solution: ❖ Use animal studies in convergence with human studies OVERVIEW ❖ The multiple memory systems of the brain ❖ Declarative, episodic and semantic memory ❖ Neural basis of episodic memory: evidence from human studies ❖ Neural basis of episodic memory: evidence from animal studies NEURAL BASIS OF EPISODIC MEMORY IN ANIMALS HOW TO TEST EPISODIC MEMORY IN ANIMALS? Remember Tulving’s (1972) original definition of episodic memory: ❖ Memory for events, or personal experiences ❖ Memory for events is intrinsically tied to the context in which they occur, especially the spatial and temporal context Thus, you can show that an animal has episodic memory (or at least episodic-like memory) if it can remember detailed info about the context in which an event occurred. NEURAL BASIS OF EPISODIC MEMORY IN ANIMALS EPISODIC MEMORY AS THE MEMORY FOR EVENTS WITH THE SPATIAL AND TEMPORAL CONTEXTS IN WHICH THEY OCCURRED “Where did I leave my iPhone?” Event #1 Event #2 Event #3 NEURAL BASIS OF EPISODIC MEMORY IN ANIMALS EPISODIC MEMORY AS THE MEMORY FOR EVENTS WITH THE SPATIAL AND TEMPORAL CONTEXTS IN WHICH THEY OCCURRED “Where did I leave my iPhone?” Event #1 Event #2 Event #3 More general A B C Context of A Context of B Context of C Event #1 Event #2 Event #3 NEURAL BASIS OF EPISODIC MEMORY IN ANIMALS HIPPOCAMPUS, PARAHIPPOCAMPAL REGION, AND PREFRONTAL CORTEX Critical network of structures (3-D view of rat brain) Prefrontal cortex Hippocampus Perirhinal cortex Postrhinal cortex Entorhinal cortex ant left right post NEURAL BASIS OF EPISODIC MEMORY IN ANIMALS HIPPOCAMPUS, PARAHIPPOCAMPAL REGION, AND PREFRONTAL CORTEX Sequence of events (items) in their contexts A B C Context of A Context of B Context of C Predominant model Item info Spatial context info Perirhinal Postrhinal Entorhinal (lateral) Critical network of structures (3-D view of rat brain) Entorhinal (medial) Item-in-context Hippocampus Temporal relationships? Hippocampus Prefrontal cortex left post ant right (Model based on Manns & Eichenbaum, 2006; Eichenbaum & Lipton, 2008; Ranganath, 2010; Lee & Kim 2010; Kesner, 2010) OVERVIEW ❖ The multiple memory systems of the brain ❖ Declarative, episodic and semantic memory ❖ Neural basis of episodic memory: evidence from human studies ❖ Neural basis of episodic memory: evidence from animal studies ❖ How do we remember when events occur? MEMORY FOR WHEN EVENTS OCCUR HOW DO WE STUDY THIS IN RATS? Memory for items (events) and of the order in which they occurred Memory for the order in which the iSequential order tems were presented One of the following: A+ vs E - A + vs D - A + vs C B + vs E - B + vs D - C + vs E - Sequencof a ese items Presentation e prlist ofntation Select odor cup appearing earlier in the sequence Odors A through E Odor sequence: A 2.5-min B 2.5-min C 2.5-min D 2.5-min B +D - E Memory for the items on the lRecognition ist (e.g., DNMS) For each sample cup: One of the following: Approach Dig for reward Wait 2.5 minutes A - vs H + B - vs U + C - vs T + D - vs S + E - vs K + Select odor cup not presented in the sequence C - + T Fortin, Agster and Eichenbaum, 2002 MEMORY FOR WHEN EVENTS OCCUR HOW DO WE STUDY THIS IN RATS? Fortin, Agster and Eichenbaum, 2002 MEMORY FOR WHEN EVENTS OCCUR ROLE OF THE HIPPOCAMPUS AND PREFRONTAL CORTEX Author's personal copy Author's personal copy Hippocampal damage impairs order memory, but not item memory Fortin, Agster and Eichenbaum, 2002 A vs E A vs D A vs C– B vs E B + vs D – C+ vs E– vE v D - A+ vs C– + vs E - A+ + s s – - AA +s odor cup appearing A A v– Select s C v + vs E D B+ vs D–the sequence – + earlier + vs E - B + vs D - C + vsinE - C vs E B B Select odor cup appearing One of the One wing: following: follo of the + + – – Sequence presentation Odors A presentation Sequence through E Sequencof prlist of items Presentation e sequence: ntation a ese A through E Odor Odors Odors A through E Odor sequence: 2.5-min 2.5-min Odor sequence: A B A A 2.5-min B 2.5-min B C 2.5-min C 2.5-min C D 2.5-min D 2.5-min 2.5-miFor each.5-min n 2 sample cup:.5-min 2 For each sample cup: earlier in the sequence Select odor cup appearing earlier+inDhe sequence t– D 2.5-min B E B E +D – +D Approach Dig for reward Dig for reward Recognition One of the following: – + B– – + U+ Wait 2.5 minutes Memory A vs HOne of thevfollowing: C vs T for the itemsson the Wait 2.5 minutes + D– v + E– list A– vs H+s SB– vs U+ s KC– vs T+ (e.g., DNMS) v Select– odor cup+ not D– v o S+ One of the follswing: E vs K Recognition presented in the sequence Approach Dig for reward Wait 2.5 minutes Controls Hippocampus * 90 80 order performance * * * * * * 80 70 * * * * * 70 60 60 50 Probe: A vs C B vs D C vs E A vs D B vs E A vs E Lag 1 B vs D C vs E Lag 2 A vs D B vs E Lag 3 A vs E Lag 2 Lag 3 - Recognition For each sample cup: Approach 100 90 Sequential order performance Controls Hippocampus Sequential 50 Probe: A vs C B E (b)100 Select odor cup not A - vs H + B - vs U + C - vs T + sequence presented in the D - vs S + E - C–s TK + v+ Select–odor cup not + T presentCd in the sequence e Lag 1 (c) 100 (c) Percent correct Percent correct (%) (%) (a) (b) Percent correct Percent correct (%) (%) Sequential order Memory for the order in which the One the following: iSequ+ ntial oforder– + tems wereSequential order presented e–+ (a) 100 90 Recognition performance Controls HippocampusRecognition Controls Hippocampus performance 90 80 80 70 70 60 60 50 Probe: A vs X 50 Probe: A vs X B vs X C vs X D vs X E vs X B vs X D vs X E vs Figure 8 Sequential order and recognition tasks. (a) On each trial the animal was presented with a series of five odors (e.g.,vs X odors ACthrough E). The animalXwas then eithe - T+ probed for its memory of the order of the items in the series (top) or itsCmemory of the items presented (bottom). þ, rewarded odor, À, nonrewarded odor. (b) Hippocampal Figure 8 Sequential order and recognition probes. On each trial on different probes are grouped according to the lag (number of intervening The animal was then eithe animals were impaired on all sequential order tasks. (a)Performancesthe animal was presented with a series of five odors (e.g., odors A through E).elements). (c) Hippocampa probed for its memory of as order of the items in the series (top) or its memory of the items presented that was not presented in the , nonrewarded as the alternative choic animals performed as well thecontrols on the recognition probes. ‘X’ designates a randomly selected odor(bottom). þ, rewarded odor, Àseries and usedodor. (b) Hippocampal Ãanimals were impaired on all sequential order probes. Performances on different probes are grouped according to the lag (number of intervening elements). (c) Hippocampa , p < .05. (a–c) Adapted from Fortin NJ, Agster KL, and Eichenbaum H (2002) Critical role of the hippocampus in memory for sequences of events. Nat. Neurosci. 5: 458–462, w animals performed as well Publishers Ltd. permission from Macmillanas controls on the recognition probes. ‘X’ designates a randomly selected odor that was not presented in the series and used as the alternative choic à , p < .05. (a–c) Adapted from Fortin NJ, Agster KL, and Eichenbaum H (2002) Critical role of the hippocampus in memory for sequences of events. Nat. Neurosci. 5: 458–462, w permission from Macmillan Publishers Ltd. Similar findings with prefrontal damage (DeVito and Eichenbaum, 2010) MEMORY FOR WHEN EVENTS OCCUR RECORDING FROM HIPPOCAMPAL AND PREFRONTAL NEURONS Order task had to be adapted for electrophysiological recordings MEMORY FOR WHEN EVENTS OCCUR RECORDING FROM HIPPOCAMPAL NEURONS High-density recording headstage Tetrode recordings Pic of tetrode :p Tetrode wire 1 2 Neuron #1: Neuron #2: Isolated neurons on a single tetrode Control 24 tetrodes independently Ultra-compact, ultra-light Stable for months Neurons are from CA1 cell layer Tet #1 Tet #2 Tet #3 Tet #4 Tet #5 Tet #6 Tet #7 Tet #8 3 4 MEMORY FOR WHEN EVENTS OCCUR RECORDING FROM PREFRONTAL NEURONS High-density recording headstage No need for driveable tetrodes in cortex Ultra-compact, Ultra-light Stable for months Isolated neurons on a single tetrode Neurons are from PFC neurons MEMORY FOR WHEN EVENTS OCCUR CODING OF HIPPOCAMPAL AND PREFRONTAL NEURONS HC neurons will show odor-specific activity during odor presentation Ensemble analyses 8 Activity vectors of all simulatenously recorded neurons differentiate between odors “In Seq” and “Out of Seq” (see statistics) Odor A: Odor B: Odor C: Odor D: Odor E: 4 0 Odor delivery -2.0 -1.0 0 Time (s) 1.0 * A D * C B 2.0 Odor identification Odor A... In Sequence: Out of Sequence: 10 * 0 Odor delivery -2.0 Odor “In-Seq” or “Out-of-Seq”? -1.0 0 Time (s) 1.0 Prospective activity 16 12 Selection of correct action 4 1.0 -2.0 Correct Incorrect 8 0 -1.0 0 Time (s) 1.0 0 Odor delivery Odor delivery 2.0 Correct Incorrect 12 4 Odor delivery 2.0 PFC neurons will show reward-related activity (e.g., firing when no reward) 5 Odor delivery 0 Time (s) time Reward-relate d activity 10 2 0 0 Response production (pull-out) 15 1 4 (in ~4sec) 20 4 3 8 * Firing rate of Cell #1 2.0 PFC neurons activity will show response selection and planning (e.g., pull out) Ordinal position 8 “In Seq” 1000ms PFC neurons will show ordinal coding (e.g., 2nd item in seq) near odor presentation Odor A: Odor B: Odor C: Odor D: * ...Odor C Ordinal position PFC neurons will show odor-specific activity before odor presentation “Out of Seq” Response correct or incorrect? 0ms PFC coding: -1.0 Average firing rate for each trial type ± SEM Odor B (~4sec earlier) Firing rate (Hz) * 20 Firing rate of Cell #1 HC coding: -2.0 30 Firing rate of Cell #2 12 Average firing rate for each odor type ± SEM Example of cell differentially firing to odors “In Seq” vs “Out of Seq” Firing rate of Cell #2 Firing rate (Hz) 16 Ensemble analyses Activity vectors of all simulatenously recorded neurons are different for each odor presentation (see statistics) Example of cell selective for Odor B Single-cell analyses Firing rate (Hz) Single-cell analyses HC neurons will distinguish odors “In Sequence” vs “Out of Sequence” -2.0 -1.0 0 Pull-out time (s) 1.0 2.0 -2.0 -1.0 0 Pull-out time (s) 1.0 2.0 MEMORY FOR WHEN EVENTS OCCUR OUR WORKING MODEL Flow of information between the structures ...
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