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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 SIMPLE CLASSICAL NONASSOCIATIVE LEARNING CONDITIONING Semantic memory (Tulving, 1972, 2002) EMOTIONAL SKELETAL HABITUATION MemoryRESPONSES RESPONSES knowledge of for facts, general SENSITIZATION 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. 28. 29. 30. 31. 32. full-length PS1 with 39 FLAG epitope sequence was generated as described for PS2 (9). To establish the inducible PS1 cells, we sequenced the resulting constructs and stably transfected them into the H4 human neuroglioma founder cell line as described for the PS2inducible cells (9). M. Seeger et al., Proc. Natl. Acad. Sci. U.S.A. 94, 5090 (1997); J. Walter et al., ibid., p. 5349. E. Levy-Lahad et al., Science 269, 973 (1995). Values (mean 6 SD, n 5 30; *P , 0.05) representing the ratios of alternative:normal CTF in multiple wildtype and FAD mutant (N141I) PS2 clonal lines induced for 24 hours were determined (13, 36). Data from three independent experiments with five different wild-type and mutant PS2 clonal lines paired according to expression level were used. D. M. Kovacs, T.-W. Kim, R. E. Tanzi, unpublished data. D. Scheuner et al., Nature Med. 2, 864 (1996); T. Tomita et al., Proc. Natl. Acad. Sci. U.S.A. 94, 2025 (1997); 33. 34. 35. 36. 37. D. R. Borchelt et al., Neuron 17, 1005 (1996); M. Citron et al., Nature Med. 3, 67 (1997); K. Duff et al., Nature 383, 710 (1996); W. Xia et al., J Biol. Chem. 272, 7977 (1997). G. Forloni et al., Neuroreport 4, 523 (1993); D. Loo et al., Proc. Natl. Acad. Sci. U.S.A. 90, 7951 (1993); F. M. LaFerla et al., Nature Genet. 9, 21 (1995). E. Paradis et al., J. Neurosci. 16, 7533 (1996). A. I. Bush et al., Ann. Neurol. 32, 57 (1992). J. Perez-Tur et al., Neuroreport 7, 297 (1995). We thank G. Thinakaran and S. Sisodia for antibodies and J. Henderson for technical assistance. Supported by grants from the National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Metropolitan Life Foundation. R.E.T. is a Pew Scholar, D.M.K. is a French Foundation Fellow, and T.-W. K. is a recipient of a National Research Service Award. 14 May 1997; accepted 17 June 1997 Differential Effects of Early Hippocampal Pathology on Episodic and Semantic Memory NEURAL BASIS OF EPISODIC MEMORY IN HUMANS FIRST CLEAR EVIDENCE OF A DISSOCIATION Differential Effects of Early Hippocampal Pathology on Episodic and Semantic Memory Downloaded from www.sciencemag.org on March 18, 2007 produces a severe loss of episodic memory but leaves general cognitive development, based mainly on semantic memory functions, relatively intact. F. Vargha-Khadem,* D. G. Gadian, K. E. Watkins, A. Connelly, The first of our three patients (6), Beth, now aged 14, was born after a difficult W. Van Paesschen, M. Mishkin delivery, and she remained without a heart20. Y. A. Lazebnik et al., Proc. Natl.amnesia is U.S.A. Acad. Sci. described full-length PS1 with 39 FLAG epitope sequence was for to D. R. Borchelt et al., Neuron 17, 1005 (1996); M. Citron 8 min before being Global patients with brain injuries that ocPositive: N.anterogradealat J. Immunol. 154, by in three and in the third at age 9.(9Magnetic beatShe 7alsoetsustained injury 3, resuscitat- K. Duff et al., Nature al., Nature Med. to 67 (1997); 92, 9042 (1995); in one case ., birth, in another generated as described for PS2 ). To establish the ed. the right curred Neamati et age 4, 383 710 hours after et al., J Biol. 1693 (1994). inducible PS1 cells, resonance techniques revealed bilateral hippocampal pathologywe all three cases. Re- brachial plexus. ,Two (1996); W. Xiaresuscita- Chem. 272, 7977 in sequenced the resulting constructs 21. In addition markably, despite their pronounced amnesia for the and stably transfected them into the H4 human she had(1997). to H4 human neuroglioma cells, all finda generalized seizure, and such episodes of everyday life, all three tion, Negative: attended SK-N-SC neuroblas- and attained levels of speechas described for the PS2- recurredForloni et al., Neuroreportdays523 (1993); D. Loo et neuroglioma founder cell line ings were confirmed in native 33. G. 4, sporadically for 2 to 3 patients mainstream schools and language attacks inducible cells (9). toma cells (14). al., Proc. (interviewed Endel Tulving) Natl. Acad. Sci. U.S.A. 90, 7951 (1993); competence, literacy, and factual knowledge that are within the low average to averageby despite treatment with anticonvulsant med- . 9, 21 (1995). F. M. LaFerla et al., Nature Genet 28. M. Seeger et al., Proc. Natl. Acad. Sci. U.S.A. 94, 22. M. S. Brown and J. L. Goldstein, Cell 89, 331 (1997). 2 weeks, al., J. Neurosci. 16 range. The findings provide support for the view that the episodic and ., ibid., p. 5349. semantic com- ication. WithinParadis ethowever, Beth had , 7533 (1996). 34. E. 5090 (1997); J. Walter et al 23. X. Wang et al., EMBO J. 15, 1012 (1996). recovery, although the brachiponents of cognitive memory are partly dissociable, with only the episodic component made a good A. I. Bush et al., Ann. Neurol. 32, 57 (1992). 35. 24. J.-T. Pai, M. S. Brown, J. L. Goldstein, Proc. Natl. 29. E. Levy-Lahad et al., Science 269, 973 (1995). al plexus injury resulted et al., Neuroreport- 7, 297 (1995). in permanent im being fully dependent on the hippocampus. Acad. Sci. U.S.A. 93, 5437 (1996). 36. J. Perez-Tur 30. Values (mean 6 SD, n 5 30; *P , 0.05) representing pairment of the right arm and hand due to 25. X. Wang et al., J. Biol. Chem. 270, 18044 (1995). the ratios of alternative:normal CTF in multiple wild37. We thank G. Thinakaran and S. Sisodia for antibodies partial type and FAD mutant (N141I) PS2 clonal lines in- loss of the nerve function deriving and J. Henderson for technical assistance. Supported 26. Alternative endoproteolysis sites for PS2 are localized from duced for 24 hours were determined (13, 36). Data the fifth grants from the National nerve on Aging, National by and sixth cervical Institute within the domain after predicted transmembrane doOne influential view of memory organiza- view (three independent experiments with3five differ- No other neurological problems were and Stroke, and the from 2), which still has its adherents ( ), roots. Institute of Neurological Disorders main 5, encoded by exon 11 (formerly exon 10) (36). she reached age 5 when memtion (1 the potential cognitive or declara ent wild-type and mutant core defect in evident untilMetropolitan Life Foundation. R.E.T. is a Pew Scholar, 27. The point mutations)inpictures the aspartate cleavage - proposed instead that the PS2 clonal lines paired according to amnesia is a loss of used. D.M.K. is a French Foundation Fellow, and T.-W. K. is a sites of PS2tive form, comprising both fact and event temporal-lobeexpression level were context- ory difficulties were first noted on her en(D326A and D329A) and control aspartate memory, as into a PS2 process that is depen recipient of a National Research D. M. Kovacs, T.-W. Kim, R. E. Tanzi, unpublished trance (D308A) were introduced a unitary open reading frame -31. rich episodic memory, in that in some am- data. into a mainstream school. The secService Award. dent on the hippocampal system, a set D. Scheuner et al., Nature Med. 2, 864 (1996); T. ond by site-directed mutagenesis with Muta-Gene phage- of32. nesic cases, semantic memory, which is free Tomita patient, Jon, now aged 19, was delivheavily inducible construct encoding the et al., Proc. Natl. Acad. Sci. been 94, 2025 ered mid kit (Bio-Rad). Theinterconnected medial temporal- of context, appears to have U.S.A.relatively (1997); prematurely at 1997; accepted 17 June 1997 14 May 26 weeks of gestation. lobe structures consisting of the hippocam- preserved. An opportunity to assess these Weighing just under 1 kg and suffering from pus and underlying entorhinal, perirhinal, different views has been provided by our breathing problems, he was kept in an inand parahippocampal cortices. According study of patients with amnesia due to hip- cubator for 2 months, during which time he produces a severe ventilator. to this notion, both fact (or semantic) pocampal pathology sustained, in two of our was tube-fed and placed on a loss of episodic memory but improved steadily and develmemory and event (or episodic) memory patients, very early in life, before they had Thereafter, heleaves general cognitive development, are impaired together in a graded manner acquired the knowledge base that charac- oped normally. At the age on4, semantic memory funcbased mainly of he suffered depending on the extent of damage to the terizes semantic memory. The results sug- two, protracted relativelyhours), afebrile tions, (1.5 to 2 intact. hippocampal system as D. G. An earlier gest a E. Watkins, A. of the two convulsions. His memory impairment was a whole. Gadian, K. possible reconciliation Connelly, F. Vargha-Khadem,* The first of our year and a views, namely that episodic memory de- first noted by his parents about athree patients (6), Beth, F. Vargha-Khadem and K. E. Watkins, Cognitive NeuroW. Van Paesschen, M.primarily on the hippocampal com- half afternow two long-14, was born after a difficult the aged lasting attacks. The pends Mishkin science Unit, Institute of Child Health, University College delivery, now aged 22, was an ponent of the larger system, whereas seman- third patient, Kate,and she remained without a heartLondon Medical School, Wolfson Centre, Mecklenburgh Square, London WC1N 2AP, is tic patients with brain on the that ocbeat for 7 to age of 9, when she Global anterograde amnesia UK. described in threememory depends primarilyinjuries un- average student until the 8 min before being resuscitatD. G. Gadian and A. Connelly, Radiology and Physics accidentally She also sustained injury curred in one case of Child Health,in another by age derlying cortices. third at age 9. Magnetic ed. received a toxic dose (400 mg to the right 4, and in the Unit, Institute at birth, University College London Previously, in the absence of any report- for 3 days) of theophylline, a drug with Medical School, 30 Guilford Street, London WC1N 1EH, resonance techniques revealed bilateral hippocampal of amnesia due to very earlycases. Re- she was being treated for asthma. An after resuscitaed cases pathology in all three bilat- which brachial plexus. Two hours UK. W. Van Paesschen, pronounced amnesia markably, despite their Radiology and Physics Unit, Institute for the episodes of everyday lobe (4), three episode of seizures,aunconsciousness, eral injury to the medial temporal life, all acute tion, she had generalized seizure, and such of Child Health, University College London Medical it had seemed that such early damage language attacks recurred sporadically patients attended Guilford Street, Londonschools UK, and attained levels of speech andmight and respiratory arrest ensued, from which for 2 to 3 days School, 30 mainstream WC1N 1EH, and so impede cognitive development that average Institute of Neurology, factual knowledge despite treatment with anticonvulsant medcompetence, literacy, andQueen Square, London WC1N that are within the low average to the she showed good physical recovery but 3BG, UK. resulting syndrome would take the form, which left her profoundly amnesic. Subserange. The findings provide support for theIn- not of amnesia, but of severe mental retar- com- ication. Within 2 weeks, however, Beth had M. Mishkin, Laboratory of Neuropsychology, National view that the episodic and semantic quently, at age 17, she developed temporal stitutes of Mental Health, 49 Convent Drive, Bethesda, made a good recovery, conponents of cognitive memory are partly dissociable, with only findings described here lobe epilepsy, which has been wellalthough the brachidation (5). The the episodic component MD 20892– 4415, USA. al anticonvulsant resulted being fully dependent on the hippocampus. show instead that early bilateral pathology trolled withplexus injury medication.in permanent im* To whom correspondence should be addressed. E-mail: Neuropsychological examination arm and hand due to that is limited largely to the hippocampus fkhadem@ich.ucl.ac.uk pairment of the right showed partial loss of the nerve function deriving from the fifth and sixth cervical nerve One influential view of memory organiza- view (2), which still has its adherents (3), roots. No other neurological problems were Positive: tion (1) pictures the cognitive or declara- proposed instead that the core defect in evident until she reached age 5 when memtive form, comprising both fact and event temporal-lobe amnesia is a loss of context- ory difficulties were first noted on her enmemory, as a Negative: unitary process that is depen- rich episodic memory, in that in some am- trance into a mainstream school. The secdent on the hippocampal system, a set of nesic cases, semantic memory, which is free ond patient, Jon, now aged 19, was delivheavily interconnected medial temporal- of context, appears to have been relatively ered prematurely at 26 weeks of gestation. lobe structures consisting of the hippocam- preserved. An opportunity to assess these Weighing just under 1 kg and suffering from pus and underlying entorhinal, perirhinal, different views has been provided by our breathing problems, he was kept in an inand parahippocampal cortices. According study of patients with amnesia due to hip- cubator for 2 months, during which time he to this notion, both fact (or semantic) pocampal pathology sustained, in two of our was tube-fed and placed on a ventilator. memory and event (or episodic) memory patients, very early in life, before they had Thereafter, he improved steadily and develare impaired together in a graded manner acquired the knowledge base that charac- oped normally. At the age of 4, he suffered depending on the extent of damage to the terizes semantic memory. The results sug- two, protracted (1.5 to 2 hours), afebrile hippocampal system as a whole. An earlier gest a possible reconciliation of the two convulsions. His memory impairment was by a year IT REMAINS A HEATED DEBATE views, namely that episodic memory de- first notedthe his parents aboutattacks.and a F. Vargha-Khadem and K. E. Watkins, Cognitive Neurotwo long-lasting The pends primarily on the hippocampal com- half after science Unit, Institute of Child Health, University College ponent of the larger system, whereas seman- third patient, Kate, now aged 22, was an London Medical School, Wolfson Centre, Mecklenburgh Square, London WC1N 2AP, UK. tic memory depends primarily on the un- average student until the age of 9, when she ❖ We now know that the hippocampus, the parahippocampal D. G. Gadian and A. Connelly, Radiology and Physics accidentally received a toxic dose (400 mg derlying cortices. Unit, Institute of Child Health, University College London absence of Medical School, 30 Guilford Street, London WC1N 1EH, region (i.e., entorhinal, perirhinal ed Previously, in thedue to very any report- for 3 days) ofbeing treated foraasthma.with and parahippocampal cortex) she was theophylline, drug An which cases of amnesia early bilat UK. Radiology and Physics and W. Van Paesschen,University cortex Unit, Institute eral injuryfor episodic memory acute episode of seizures, unconsciousness, the prefrontal College London Medical are important to the medial temporal lobe (4), of Child Health, it had seemed that such early damage might and respiratory arrest ensued, from which School, 30 Guilford Street, London WC1N 1EH, UK, and so impede cognitive development that the she showed good physical recovery but Institute of Neurology, Queen Square, London WC1N ❖ However, the specific role of each structure remains unknown. 3BG, UK. resulting syndrome would take the form, which left her profoundly amnesic. SubseM. Mishkin, Laboratory of Neuropsychology, National Innot of amnesia, but of severe mental retar- quently, at age 17, she developed temporal stitutes of Mental Health, 49 Convent Drive, Bethesda, dation (5). The findings described here lobe epilepsy, which has been well conMD 20892– 4415, USA. ❖ We know even less about the fundamental neuronal pathology trolled with anticonvulsant medication. show instead that early bilateral * To whom correspondence should be addressed. E-mail: that is those regions supporting Neuropsychological examination showed fkhadem@ich.ucl.ac.uk mechanisms (i.e., how are neurons inlimited largely to the hippocampus 376 SCIENCE z VOL. 277 z 18 JULY 1997 z www.sciencemag.org NEURAL BASIS OF EPISODIC MEMORY IN HUMANS 376 episodic memory?) ❖ z VOL. 277 z 18 JULY 1997 z www.sciencemag.org The main problem: ❖ ❖ SCIENCE Techniques used in humans do not have the sufficient spatial and temporal resolution The solution: ❖ Use animal studies in convergence with human studies Downloaded from www.sciencemag.org on March 18, 2007 20. Y. A. Lazebnik et al., Proc. Natl. Acad. Sci. U.S.A. 92, 9042 (1995); N. Neamati et al., J. Immunol. 154, 1693 (1994). 21. In addition to H4 human neuroglioma cells, all findings were confirmed in native SK-N-SC neuroblastoma cells (14). 22. M. S. Brown and J. L. Goldstein, Cell 89, 331 (1997). 23. X. Wang et al., EMBO J. 15, 1012 (1996). 24. J.-T. Pai, M. S. Brown, J. L. Goldstein, Proc. Natl. Acad. Sci. U.S.A. 93, 5437 (1996). 25. X. Wang et al., J. Biol. Chem. 270, 18044 (1995). 26. Alternative endoproteolysis sites for PS2 are localized within the domain after predicted transmembrane domain 5, encoded by exon 11 (formerly exon 10) (36). 27. The point mutations in the potential aspartate cleavage sites of PS2 (D326A and D329A) and control aspartate (D308A) were introduced into a PS2 open reading frame by site-directed mutagenesis with Muta-Gene phagemid kit (Bio-Rad). The inducible construct encoding the 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 items ent presented Sequwereial order One of the following: A+ vs E - A + vs D - A + vs C B + vs E - B + vs D - C + vs E - Sequenc of a es of tatio Presentation e prlist enitems n 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 lRe(e.g.,nition ist cog 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 opy Author's personal c CORTEX Author's personal copy Hippocampal damage impairs order memory, but not item memory Fortin, Agster and Eichenbaum, 2002 Sequential order Memory for the order in which the items ent Sequential r presented SequwereiOne of thedeorder al or following: A+ vs C– B+ vvsE– B+ vvsD–– C+ vs E– A+ s E– A+ s D - A+ vs C– A+ vs E - A + vs D - A + vodor cup appearing– Select + vs E– B+ vs s C C+ vs E – B D Sequence presentation Sequence through E Odors A presentation + v in the sequence B + vs E - B + vs D - Cearlierodor -cup appearing Selects E Sequenc of a esenitems n Presentation e prlist OdorstA through E of atio earlier in the sequence Select odor cup appearing earlier +n Dhe sequence i t– Odor sequence: Odors A through E Odor sequence: 2.5-min 2.5-min A 2.5-min B A B A (b) 100 One A+ following: A+ vs E– of thevs D– One of the following: 2.5-min B C 2.5-min 2.5-min C For 2.5-min each 5-min 2. sample cup:5-min 2. C D For each sample cup: 2.5-min D 2.5-min 2.5-min D B E – B E B +D +D - E Recognition Approach Dig for reward Dig for reward + One B the U Memory A– vs H+ itemsfollowing: C– vs T+ for the of – vson the Wait 2.5 minutes Wait 2.5 minutes – + – + c vs + g DNMS) lRe(e.g.,nitionvs U+s KC– vs T+ ist A–oD Hvs SB– E v – + Select – cup + odor not D lowin E vs K One of the folvs Sg: presented in the sequence Approach Dig for reward Wait 2.5 minutes 100 90 90 80 80 70 Sequential order performance Controls Sequential Hippocampus Controls Hippocampus * * * A - vs H + B - vs U + C - vs T + D - vs S + E - v– T+ + sK Select odor cup not presented in the sequence C Select – dT+ cup not o or C presented in the sequence order performance * * * * * * * * * 70 60 60 50 Probe: A vs C 50 Probe: A vs C B vs D Lag 1 D B vs C vs E A vs D 100 (c) 100 90 B vs E A vs E A vs Lag 2 B vs E D Lag 3 E A vs Lag 2 C vs E Lag 3 Lag 1 (c) One of the following: Recognition For each sample cup: Approach Percent correct Percent correct (%) (%) (a) Percent correct Percent correct (%) (%) (a) Odor sequence: (b) Recognition performance Controls Hippocampus Recognition Controls Hippocampus performance 90 80 80 70 70 60 60 50 Probe: A vs X 50 Probe: A vs X B vs X B vs X C vs X D vs X C vs X E vs X D vs X E vs X Figure 8 Sequential order and recognition tasks. (a) On each trial the animal was presented with a series of five odors (e.g., odors A through E). The animal was then either - T+ C probed for its memory of the order of the items in the series (top) or its memory of the items presented (bottom). þ, rewarded odor, À, nonrewarded odor. (b) Hippocampal Figure 8 Sequential order and recognition tasks. (a) On each trial the animal was presented with a series of five odors (e.g., odors A through E). The animal was then either animals were impaired on all sequential order probes. Performances on different probes are grouped according to the lag (number of intervening elements). (c) Hippocampal probed for its memory of the order of the items in the series (top) or its memory of the items presented (bottom). þ, rewarded odor, À, nonrewarded odor. (b) Hippocampal animals performed as well as controls on the recognition probes. ‘X’ designates a randomly selected odor that was not presented in the series and used as the alternative choice. Ã animals were impaired on all sequential order probes. Performances on different probes are grouped according to the lag (number of intervening elements). (c) Hippocampal , 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, with animals performed as well as controls on the recognition probes. ‘X’ designates a randomly selected odor that was not presented in the series and used as the alternative choice. permission from Macmillan Publishers Ltd. Ã , 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, with 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 Isolated neurons on a single tetrode Neurons are from PFC neurons No need for driveable tetrodes in cortex Ultra-compact, Ultra-light Stable for months MEMORY FOR WHEN EVENTS OCCUR CODING OF HIPPOCAMPAL AND PREFRONTAL NEURONS HC neurons will show odor-specific activity during odor presentation Ensemble analyses Example of cell differentially firing to odors “In Seq” vs “Out of Seq” Activity vectors of all simulatenously recorded neurons differentiate between odors In Seq” and “Out of Seq” (see statistics) 8 4 0 Odor delivery -2.0 -1.0 0 Time (s) 1.0 D * C B Odor identification HC coding: * Average firing rate for each trial type ± SEM 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 16 4 1.0 -2.0 4 0 0 Odor delivery 2.0 8 5 Odor delivery 0 Time (s) -1.0 0 Time (s) 1.0 Odor delivery Odor delivery 2.0 -2.0 Correct Incorrect 12 10 0 0 PFC neurons will show reward-related activity (e.g., firing when no reward) Correct Incorrect 15 2 1 4 time Reward-relate d activity 20 4 3 8 (in ~4sec) Response production (pull-out) PFC neurons activity will show response selection and planning (e.g., pull out) Ordinal position 8 * Firing rate of Cell #1 2.0 ...Odor C PFC neurons will show ordinal coding (e.g., 2nd item in seq) near odor presentation Odor A: Odor B: Odor C: Odor D: 12 * “In Seq” 1000ms Selection of correct action Ordinal position PFC neurons will show odor-specific activity before odor presentation “Out of Seq” Response correct or incorrect? 0ms Prospective activity PFC coding: -1.0 20 Odor B (~4sec earlier) Firing rate (Hz) * Firing rate of Cell #1 2.0 Odor A... -2.0 30 * A Firing rate of Cell #2 Odor A: Odor B: Odor C: Odor D: Odor E: 12 Firing rate of Cell #2 Firing rate (Hz) Single-cell analyses Activity vectors of all simulatenously recorded neurons are different for each odor presentation (see statistics) Average firing rate for each odor type ± SEM 16 HC neurons will distinguish odors “In Sequence” vs “Out of Sequence” Ensemble analyses Firing rate (Hz) Single-cell analyses Example of cell selective for Odor B -1.0 0 Pull-out time (s) 1.0 MEMORY FOR WHEN EVENTS OCCUR OUR WORKING MODEL Flow of information between the structures 2.0 -2.0 -1.0 0 Pull-out time (s) 1.0 2.0 ...
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This note was uploaded on 12/13/2011 for the course BIOSCI 93 taught by Professor Staff during the Fall '11 term at UC Irvine.

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