Lacagnina & Tse Summary PDF

Distinct hippocampal engrams control extinction and relapse of fear memory (Lacagnina, et al.) Learned fear can relapse after extinction, suggesting that extinction creates a new memory coexisting with the original fear memory Extinction does not permanently erase fear; fear can relapse over...

Distinct hippocampal engrams control extinction and relapse of fear memory (Lacagnina, et al.) Learned fear can relapse after extinction, suggesting that extinction creates a new memory coexisting with the original fear memory Extinction does not permanently erase fear; fear can relapse over time, known as spontaneous recovery. Extinction forms a new memory that suppresses or competes with the original fear memory. Prefrontal cortex (PFC) projections to the amygdala are crucial for extinction memory acquisition. Hippocampal activity is linked to extinction learning and context dependency of retrieval. The dentate gyrus (DG) is essential for contextual fear memory, with fear engram cells mediating fear expression. Design: Transgenics: Cross-bread mice that express either ArcCreERT2::ChR2-eYFP or ArcCreERT2::Halo-eYFP Arc: promoter CreERT2: Estrogen receptor bound by CRE (not active) 4-OHT (tamoxifen): activates recombinase & permanently tags cells Unblocks CRE: CRE bound to Estrogen R (= not active) eYFP: yellow-fluorescent tagging labelling Arc Optogenetics: ChR2-eYFP: blue light to excite/stimulate Activation and reactivation of fear acquisition neurons in DG Halo-eYFP: green light to inhibit Extinction and CFC Procedure 1. Habituation 2. CFC training: conditioning context and alternate context 3. Extinction training Results: Experiment 1: Extinction suppresses reactivation of fear acquisition neurons ArcCreERT2::ChR2-eYFP labelled DG neurons active during contextual fear conditioning (CFC) or extinction.  DG neurons tagged during fear acquisition were less reactivated in EXT and ALT- CTX vs NO-EXT fear and extinction retrieval involve distinct, non-overlapping DG neuronal ensembles despite similar overall DG activation. Experiment 2: Fear retrieval and extinction retrieval reactivate distinct ensembles ArcCreERT2::Halo-eYFP labelled DG neurons active during either fear acquisition or extinction training. Extinction retrieval reactivated neurons tagged during extinction training, while spontaneous recovery reactivated neurons tagged during fear acquisition. fear and extinction memories are represented by distinct DG neuronal populations, activated depending on fear or extinction memory expression. The number of eYFP+ and Arc+ cells did not differ significantly across groups Experiment 3: Silencing extinction-tagged neurons impairs extinction retrieval ArcCreERT2::Halo-eYFP used to test if reactivation of extinction-tagged neurons are needed for extinction expression. Silencing extinction-tagged neurons = increased freezing during initial light exposure Normalized: silencing had no lasting effect on maintenance of extinction. Silencing did not affect behaviour in a neutral context or during spontaneous recovery, suggesting extinction-tagged neurons are crucial only for initial extinction retrieval, not for preventing fear relapse. Experiment 4: Silencing fear acquisition-tagged neurons reduces spontaneous recovery of fear ArcCreERT2::Halo-eYFP used, and fear acquisition neurons were tagged with Halo following CFC training Silencing fear acquisition neurons did not affect freezing during the extinction retrieval test or in ALT CTX Silencing fear acquisition neurons during a spontaneous recovery test 28 days later reduced freezing, indicating their role in fear relapse but not in extinction. Experiment 5: Stimulating fear acquisition-tagged neurons potentiates fear whereas stimulating extinction-tagged neurons suppresses fear ArcCreERT2::ChR2 to tag neurons active during fear acquisition or extinction. Stimulating fear acquisition neurons increased fear expression, confirming their role in fear induction.  Stimulating extinction neurons reduced freezing behavioUr during extinction retrieval, suppressing fear. Activation of extinction neurons blocked spontaneous recovery of fear, with effects persisting even after stimulation ceased. Fear acquisition and extinction are represented by distinct hippocampal neuron ensembles with opposing influences on fear, where extinction neuron activity can effectively suppress fear relapse. Summary Silencing fear neurons = no freezing alterations Not involved during recall Reduced freezing behaviour during spontaneous recovery Activating fear neurons = increase in freezing behaviour Activating fear neurons during extinction = decreased freezing Discussion Extinction training suppressed the reactivation of neurons involved in fear acquisition and activated a different set of neurons, termed extinction neurons. Silencing fear acquisition neurons reduced fear, while silencing extinction neurons increased fear after extinction. Optogenetics stimulation of fear acquisition neurons elevated fear, while stimulation of extinction neurons reduced fear. DG may be important for recovery of fear extinction but once recovered another system may be more important Some neurons in DG are responsible for reactivation of fear CFC Stimulation of CFC neurons = increased fear response in recall Stimulation of Ext neurons = decrease in fear response in spontaneous recovery 2 different engrams: CFC Extinction Schemas and Memory Consolidation (Tse et. al.) Mental schemas are established frameworks of knowledge relevant to story recall, inference, and education, helping us understand and predict the world around us. Schemas are built from prior experiences and knowledge, allowing us to quickly process and integrate new information understand and remember complex information better with a relevant mental schema  Memory encoding happens quickly, but memory consolidation in the neocortex is thought to be gradual. But systems consolidation can occur rapidly if there is an existing associative "schema" Hypotheses: 1. The formation of schemas are an inherent feature of systems consolidation 2. Systems consolidation can happen faster if new information is being added to an already formed schema Experiment #1: Experiments on schema learning impacts of hippocampal lesions before training Design: trained rats to associate different flavours of food with specific sand well locations in a familiar environment (event arena) Rats had to learn flavour-place associations and recall them for a reward, indicating hippocampal involvement Results: hippocampus was crucial for learning: hippocampal lesions showed impaired performance compared to control HPC lesion dug for the same amount of time at all wells Rats used allocentric memory and visual cues to locate rewards, ruling out olfactory guidance Allocentric memory: spatial memory that represents the position of objects relative to one another, rather than relative to the individual’s viewpoint With schema: formed new associations quickly (rapid memory encoding and consolidation) without schema = memory performance declined rapidly. Experiment #2: Time course of memory consolidation Assessing the timeline of consolidation and the involvement of hippocampus during learning of new paired-associates (PA) Design: Rats-retrained and then tested in new layout (context) Is consolidation faster for new or old schema Lesion HPC 24H after training Results: When new PAs were added, they were quickly learned in a single trial, resulting in preferential digging once again at correct cued locations In contrast, animals trained on a similar one-trial task, but with novel PA each day, non-cued, showed consistent forgetting over 90 min both sham-lesioned and HPC-lesioned animals could effectively remember original and new PAs Both groups dug at the sand wells of the original PAs significantly more than chance levels  As for the new PAs post-op, both groups dug equally above chance levels. sham-group learned the new set of PAs Experiment 3: Assessment of hippocampal dependence on memory consolidation during new learning on an established schema Design: Same as experiment 1, but with rats with neurotoxic hippocampal or sham lesions 3 or 48 hours after training on new flavour-place associations Results: rats with hippocampal lesions after 48h could recall new pairs effectively = memory traces transferred to the neocortex within 48h rats with hippocampal lesions after 3h could not recall new pairs effectively = consolidation had not occurred yet Experiment #4: Causal role for schemas in learning Design: Same as experiment 1, but rats were trained in two event arenas: one with a consistent schema and another with an inconsistent schema Results: Performance improved in the consistent but not in the inconsistent context New flavour-place associations were learned faster and retained better in the consistent schema context Mental schemas facilitate encoding and quickly consolidating new information Summary: Experiment 1: Hippocampus is required for learning a spatially based schema of related food locations Experiment 2: Consolidation is rapid, less than 48 hours, when new learning is based on a previously learned schema This rapid learning is hippocampal dependent and not based on the development of a response strategy Experiment 3: Rapid consolidation appears to require a single sleep event Experiment 4: Rapid learning of new food locations (new PAs) is not due to simple familiarity with the context and task but appears to be due to the development of a spatially based schema Discussion New information is faster consolidated in an already established schema Consolidated schema appears to have features of semantic memory (an allocentric representation of the environment)