Engram Lecture 1: Episodic Memory Formation 2021-2022

23-9-2021 Mechanisms of Long-Term Memory Consolidation 1 2 Different Kinds of Memory * What about semantic learning? 3 4 Patient HM: Summary Episodic Memory: Patient HM Background -epilepsy patient (documented by Brenda Milner, Sue Corkin, and others) -bilateral removal of medial temporal l...

23-9-2021 Mechanisms of Long-Term Memory Consolidation 1 2 Different Kinds of Memory * What about semantic learning? 3 4 Patient HM: Summary Episodic Memory: Patient HM Background -epilepsy patient (documented by Brenda Milner, Sue Corkin, and others) -bilateral removal of medial temporal lobe (1953), including amygdala and most of hippocampus, by William Scoville -symptoms after surgery epilepsy was alleviated but: memory impairment 5 6 1 23-9-2021 Removal hippocampus leads to deficits in EVENT memory -No recall of events more than a few minutes ago. Examples: What is the date? No recognition of doctor. Forgetting the question… -Impossibility to memorize new events, and deficit to recall events that had occurred up to three years before surgery. -Thus: - complete anterograde episodic memory deficit - graded retrograde deficit 7 8 Some long-term memories are spared: Skill learning Was this memory deficit for events a total surprise? Epilepsy attack is often preceded by -olfactory sensation -mood change -motoric phase -grand mal or petit mal -gross motor movements, or complicated motor behaviors Execution of complicated behavioral patterns indicates retrieval from memory No new memories (of events during epileptic episode) are formed 9 Skill learning does not depend on hippocampous, instead, skill representations include changes in topography in sensory areas 10 Lots of types of memory formation are spared -FACTS memory (semantic) & distant EVENT memory (autobiographical/epsiodic) -ability to learn new facts (facts regarding a person, new vocabularly) -ability to learn new skills (e.g. a perceptual discrimination) -normal intelligence -normal reasoning abilities -short-term memory Long-term memory formation is not a monolithic ability! 11 Nudo et al., 1996 12 2 23-9-2021 Who was Patient HM ? Some anatomy Episodic memory requires binding of disparate foci of cortical activity. Because of the extensive connectivity of amygdala and hippocampus with all cortex, both structures could play a central role in the encoding of episodic memories 13 14 Hippocampal-cortical interactions through circuit of Papez Hippocampal-cortical interactions 15 16 Hippocampus in humans Hippocampal-cortical interactions through Entorhinal cortex Mossy Fiber Pathway Schaffer Collateral Pathway 17 18 3 23-9-2021 Hippocampus is an evolutionary old structure, which is comparable across different species Hippocampus, sea horse 19 Roughly the same anatomical divisions in rat, monkey, and man 20 Information Flow In In Out 21 22 Hippocampus and amygdala are both connected to whole brain and thus welll suited to play a central role in memory I. Amygdala: -a mass of grey matter next to the hippocampus. -afferents and efferents: -cortex -hippocampus -hypothalamus -olfactory bulb *efferents to ventral striatum II. Hippocampus: -primitive cortex at the fringe of medial temporal lobe -afferents:-cortex (predominantly entorhinal) -amygdala, hypothalamus Amygdala-cortical interactions -unidrectional flow through the hippocampus: -dentate gyrus  CA3  CA1  Subiculum 23 -efferents: -subiculum to entorhinal cortex -CA3 to cingular cortex (through fornix & anter thal nucl) -amygdala 24 -hypothalamus 4 23-9-2021 Standard model of episodic memory consolidation (Larry Squire) The ‘standard’ theory of episodic memory consolidation 1) Initially, hippocampal linking of neocortical storage sites 2) Through a slow consolidation process (years), neo-cortical storage becomes ‘stand alone’. 3) The more remote a memory, the less hippocampus is needed ( graded retrograde amnesia). 4) Hippocampus always needed for new episodic memories ( anterograde amnesia). 25 26 Testing predictions from the standard theory of episodic memory formation Brain regions activated during event Which structures in temporal lobe produce the deficit? An animal model of amnesia Time… Time… Hippocampus 27 28 Concurrent Object Discrimination Testing retrograde, graded amnesia 29 Stuart Zola-Morgan, Science, 1989 30 5 23-9-2021 Delayed Non-Match to Sample Testing anterograde amnesia 31 Amygdala and Hippocampus contribute equally to memory formation 32 Findings: 1) Retrograde, graded amnesia 2) Anterograde amnesia 3) Amygdala and Hippocampus both contribute Conclusion:  Standard theory has been confirmed Do you believe this conclusion?? 33 34 Saunders et al., 1984 Could effects be due to damage to surrounding parahippocampal and rhinal cortex?? Anything suspicious here? More effective Less effective And that’s the reason 35 36 6 23-9-2021 A rhinal lesion alone Meunier et al., 1993 37 Meunier et al. (1993) found that Rhinal lesions produce the deficit which was thought to be caused by A+H lesions. They also suggest that perirhinal cortex explains most of the deficit caused by rhinal lesions. 38 Thus, hippocampus and amygdala do not produce the anterograde memory deficit on DNMS task. To confirm, selectively lesion the hippocampus and the amygdala. R. Hampton, Hippocampus, 2004 39 40 Murray & Mishkin, J Neurosci., 1999 41 Murray & Mishkin, 1998 42 7 23-9-2021 What is episodic memory and did the tests used tap this ability? Do the results from this animal model indicate that the hippocampus is not important for episodic memory formation ? Typical of episodic memory is that the learning is incidental and fast Learn discrimination AB in context X Learn discrimination CD in context Y Retention of AB is better in context X than in context Y Retention of CD is better in context Y than in context X Retention in familiar context is better (even though the learning was incidental) Interference by unfamiliar context In a rat lesion study (Honey et al.), this context effect disappears after hippocampus lesions In the monkey studies, memory formation required training. Tests tapped skill learning / object recognition 43 And what is context? It certainly includes spatial information! 44 Let’s have a look at studies of spatial processing in rats Spatial information is the glue for event-memory… 45 Place cells 46 Wilson & McNaughton (1993): A hippocampal ensemble code for space. Nadel & O’Keefe, 1978 Experiment: ensemble recording in CA1 during explorative behavior Main findings: 1. Pyramidal cells in CA1 show place fields 2. Sparse coding: -In any location, few cells are active Some of those have overlapping place fields -Exploration of the total environment is covered by a small subset of neurons in the recorded population 3. Population states (within recruited population) are correlated with the animal's spatial location in a particular environment 4. Accurate prediction of the animal's location is possible purely on the basis of population state. This confirms the role of the hippocampus for spatial encoding. "... opens the possibility of the interpretation of neuronal activity in the absence of explicit behavior, such as during periods of sleep..." 47 48 8 23-9-2021 Recording from 80 hippocampal cells at once… So, hippocampus codes for space Relevance for episodic memory? Hippocampal units get converging, multimodal neocortical input and thus can be a link between distributed cortical ensembles that are co-active. During hippocampal bursting activity (while sleeping), neo-cortical neurons linked to hippocampal units form cortical links (Hebbian learning, consolidation). As a result of consolidation, a hippocampal-cortical network is formed: Hippocampal units represent a location or a spatial context, to which a rich set of experiences/events/episodes/landmarks is linked. Relevant for episodic memory formation, and contradicts classical theory of episodic memory consolidation! Wilson & McNaughton, Science, 1993 49 50 Again: Classical Consolidation Theory of Episodic Memory Neurons become linked sleep (consolidation) Neurons activated during event Odor info Odor info Visual info Visual info Stand alone memory trace Odor info Visual info Alternative: The multiple trace theory of episodic memory consolidation (Nadel) Time… Time… Iterative process of feedback and cortical input Hippocampus Neurons Spatial info 51 52 Multiple TraceTheory of Episodic Memory General Principles Neurons become linked sleep (consolidation) Neurons activated during event Final memory trace 1) Hippocampal codes (which represent spatial information) provide necessary, independent indexes for different memories 2) Hippocampus is necessary for retrieval of even the oldest memories Odor info Odor info Visual info Time… Visual info Odor info Visual info Time… 4) Retrieved memories are also re-stored Iterative process of feedback and cortical input Spatial info 3) Retrograde amnesia should not be ‘graded’ after complete hippocampal damage 5) If hippocampus is part of a hippocampal-cortical ensemble that stores episodic memories, then hippocampus activity might in part reflect local cues, landmarks, object properties, in addition to spatial information Hippocampus Neurons 53 54 9 23-9-2021 Testing predictions from the multiple trace theory of memory formation Molecular evidence for independent codes, making use of time course of IEGs Arc 55 56 57 58 59 60 Molecular evidence for independent codes Guzowski et al., Nature Neuroscience, 1999 Hippocampus remains necessary for retrieval of even the oldest episodic (autobiographical) memories Ryan et al., Hippocampus, 2000 10 23-9-2021 Reactivation and reconsolidation: Multiple Traces for an episodic memory? After complete hippocampal lesions, retrograde (autobiographical) memory deficit is ‘flat’, not graded TRAINING / EVENT RECALL Training in a task Controls Training in a task Amnesics Training in a task Ok performance Reminder (the type of reinforcement, a conditional stimulus, or a cue or context, on a single trial) Reminder (the type of reinforcement, a conditional stimulus, or a cue or context, on a single trial) Better performance Amnesia ECS, hypothermia, protein synthesis blockers Training in a task Ok performance ECS, hypothermia, protein synthesis blockers 61 Nadel et al., 2000 62 SJ Sara et al., 2000 Some evidence from molecular biology for re-consolidation Some evidence from molecular biology for re-consolidation A role for LGs Using the anti-sense technique BDNF, ZIF-268 Anti-sense RNA 63 64 3h 24h Consolidation You will read about this… Bottom line: different genes for consolidation and reconsolidation Paradigm: Less time freezing = forgetting 65 JLC Lee et al., Science, 2004 66 11 23-9-2021 Hippocampus codes not only spatial information… but also landmark/object information Re-consolidation is affected by pairing with Zif268 antisense, but not by pairing with BDNF antisense 24h 48h 24h 48h Landmark information: Recording in different recording boxes placed in same room Separate LGs for consolidation and re-consolidation: Strong evidence for multiple trace theory 67 68 Leutgeb et al., Science, 2005 Conclusions All Predictions from multiple-trace theory are supported 1) Hippocampal codes (which represent spatial information) provide necessary, independent indexes for different memories 2) Hippocampus is necessary for retrieval of even the oldest memories 3) Retrograde amnesia should not be ‘graded’ after complete hippocampal damage 4) Retrieved memories are also re-stored 5) If hippocampus is part of a hippocampal-cortical ensemble that stores episodic memories, then hippocampus activity might in part reflect local cues, landmarks, object properties, in addition to spatial information 1) Hippocampus is part of a cortico-hippocampal ensemble that represents episodic memories 2) The hippocampus shows fast plasticity (thus, one-trial learning), which allows it to guide slower cortical consolidation 3) The hippocampus orchestrates cortical binding and indexing, hippocampal-cortical networks representing memories, according to principles of multiple-trace theory 4) Even similar activity patterns in cortex representing episodic memories can be distinguished by independent sparse codes in hippocampus 69 Note: Amygdala 70 And some extra thoughts The amygdala is recruited into the memory trace when there is an emotional component (e.g., fear) (so still plays an important role in memory) 71 1) In case of procedural memory storage (skills, semantic material) other subcortical structures interact with cortex during consolidation. 2) These ‘guiding’ structures (e.g., basal ganglia), as well as cortex, lack fast plasticity (simplifying…) 3) Therefore, practice is needed. 4) Cortical skill memory traces that use same population of neurons, instead of forming indexed, differentiated memory traces, compete and interfere with each other. 5) The distinction between neocortex and hippocampus may be related to the differences in ease with which LTP can be induced (easier in hippocampus) 72 12 23-9-2021 Additional issues and topics The end 73 74 Structural Plasticity in the Hippocampus Long-Term Potentiation: A model for hippocampal and cortical learning? 75 77 76 EA Maguire Papers 78 13 23-9-2021 A shrinking anterior hippocampus, and a growing posterior hippocampus in taxi drivers? 79 80 The effect of aging on spatial / episodic memory Clinical relevance of hippocampus research The hippocampus and episodic memory in Alzheimer’s disease Maze Learning Children born without hippocampus, show normal language development, i.e. Normal semantic memory (Vargha-Kadem et al., 1997) 81 Gallagher et al., 1995 82 Instability of hippocampal representations in old rats Performance of old vs young rats in Morris Water Test First visit 83 Second visit 84 14 23-9-2021 Conclusions 1) Hippocampus is part of cortico-hippocampal ensemble that represents episodic memories 2) The hippocampus shows fast plasticity (thus, one-trial learning), which allows it to guide slower cortical consolidation 3) The hippocampus orchestrates cortical binding and indexing, according to principles of multipletrace theory 4) In case of procedural memory storage (skills, semantic material) other structures are involved to guide binding and consolidation. 5) These ‘guiding’ structures (e.g., basal ganglia), as well as cortex, lack fast plasticity (simplifying…) 6) Therefore, practice is needed. 85 86 Wilson and McNaughton (1994): Reactivation of hippocampal ensemble memories during sleep. Experiment: Ensemble recording in CA1: - During pre-exploration sleep (PRE) - During explorative behavior period (RUN) - During post-exploration sleep (POST) 87 - Wilson & McNaughton, Science, 1994 88 Wilson and McNaughton (1994). Reactivation of hippocampal ensemble memories during sleep. Experiment: Ensemble recording in CA1: - During pre-exploration sleep (PRE) - During explorative behavior period (RUN) - During post-exploration sleep (POST) Main findings: PRE: not many high correlations RUN: increased number of high correlation in the firing of neurons with overlapping place fields. POST: re-activation of the correlation pattern observed during RUN-phase. --> Expression of some type of memory 89 90 15 23-9-2021 Hoffman &McNaughton, Science, 2002: Correlation between cortical ensembles during sleep (i.e. during hippocampal ensemble reactivation)? Relevance for episodic memory CA1 units get converging, multimodal neocortical input and thus can be a link between distributed cortical ensembles that are co-active. A test in the monkey During hippocampal bursting activity (while sleeping), neo-cortical neurons linked to CA1 units form cortical links (Hebbian learning, consolidation). As a result of consolidation, a hippocampal-cortical network is formed: CA1 units represent a location or a spatial context, to which a rich set of experiences/events/episodes/landmarks is linked. Crucial support for this hypothesis: during consolidation CA1 activity of neurons with overlapping place fields becomes correlated - Correlation is not due to within-hippocampus processing of spatial information. - Why? CA1 units show no lateral connections. - Therefore, correlation between two CA1 units with overlapping place fields must reflect correlation among cortical inputs. 91 92 93 94 95 96 16 23-9-2021 97 Relevance for Episodic Memory Odor info Odor info General Background Neurons become linked sleep (consolidation) Neurons activated during event 98 The hippocampus contributes to the formation of fast incidental conjunctions between very different stimulus representations (episodic memory). Cortex contributes to the slow, incremental formation of conjunctions between more similar stimuli in learning tasks (semantic and skill learning). Visual info Visual info Time… Iterative process of feedback and cortical input Spatial info Hippocampus Neurons Iterative process of feedback, cortical input, feedback 99 100 Independent codes for different memories (O’Reilly and Rudy, 1999): Requirements: - Hippocampal activation pattern should not be a direct reflection of the stimulus input. - Hippocampal code must be capable of re-activating stored representations in a precise way. CA3: generates random codes because of diffuse cortical projections  this allows random codes to be associated with a cortical input pattern  (it does not allow re-activation of that input pattern, because of the diffuse back projections) CA1: Receives random code from CA3, and gets very precise (topographical) cortical input  CA1 code becomes linked to cortical input pattern  it is CA1 that is instrumental for memory retrieval 101 102 O’Reilly 17 23-9-2021 Odor info Odor info The major hippocampal pathways Neurons become linked sleep (consolidation) Neurons activated during event Visual info Time… Iterative process of feedback and cortical input Hippocampus Neurons in CA1 CA1 population activity In a location is a random code generated in CA3 Visual info Time… Iterative process of feedback, cortical input, feedback Correlations not due to within-hippocampus ‘lateral’ connections! 103 104 The setup: Stimulation of commisure and Mossy fiber pathway The rest is up to you  105 106 18