Early remodeling of the neocortex upon episodic memory encoding

Early remodeling of the neocortex upon episodic memory encoding Bero Meng Cho Shen Canter Ericsson Tsai

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Early remodeling of the neocortex upon episodic memory encoding 2014 Proceedings of the National Academy of Sciences 10.1073/pnas.1408378111 Bero2014-early-remodeling-of-the-neocortex-upon-episo Bero2014-early-remodeling-of-the-neocortex-upon-episo.txt, the project's staged copy 37e3e02ffe1ef7f5023547ccfc8b52d28e6089a7 not-redistributable neuroscience

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0 spans located by searching the stored text for the quote's exact words, allowing any whitespace between them whether the neocortex remodels early during memory encoding, rather than only weeks later during consolidation, and whether prefrontal activity is required for hippocampal engagement Quotation withheld because this record is not cleared for redistribution. how does the prefrontal cortex contribute to long-term memory encoding, a role established correlationally but not mechanistically Quotation withheld because this record is not cleared for redistribution. shows encoding triggers transcriptional, structural and functional remodeling of medial prefrontal cortex within an hour, and that silencing those neurons during encoding blocks hippocampal activation and long-term memory Quotation withheld because this record is not cleared for redistribution. existence Quotation withheld because this record is not cleared for redistribution. neocortical remodeling during episodic memory encoding Quotation withheld because this record is not cleared for redistribution. experiment experiment Quotation withheld because this record is not cleared for redistribution. mechanisms Excitatory mPFC neurons fire during encoding and drive activation of the entorhinal–hippocampal circuit, which in turn permits long-term memory to form Quotation withheld because this record is not cleared for redistribution. mechanisms Encoding rapidly reprograms mPFC gene expression, and this transcriptional shift primes the local circuit for the structural and functional synaptic plasticity that follows Quotation withheld because this record is not cleared for redistribution. an epoch is isolated rather than a region: excitatory prefrontal neurons are silenced only during the conditioning session, and memory is measured a day and a month afterwards Quotation withheld because this record is not cleared for redistribution. the apparent contradiction with the standard model is resolved by indexing both claims to a stage rather than choosing between them Quotation withheld because this record is not cleared for redistribution. five measurements at five levels of description are stacked on one claim - transcript, ultrastructure, spine morphology, synaptic current, and causal necessity Quotation withheld because this record is not cleared for redistribution. the control condition is selected by measurement: context exposure produced more immediate-early gene expression than foot shock alone, so it becomes the conservative comparison throughout Quotation withheld because this record is not cleared for redistribution. unchanged total synapse density is what licenses the claim that existing circuitry was remodeled rather than new synapses added Quotation withheld because this record is not cleared for redistribution. the optogenetic manipulation is verified to have worked before its behavioural consequence is interpreted, by measuring the activity marker it was meant to suppress Quotation withheld because this record is not cleared for redistribution. the causal chain is traced outward one structure at a time - prefrontal, then entorhinal, then CA1 - rather than asserted from the endpoints Quotation withheld because this record is not cleared for redistribution. behavioural specificity is checked against the two obvious confounds, locomotion and shock sensitivity, both of which are unaffected Quotation withheld because this record is not cleared for redistribution. the transcriptional result is read as a direction rather than a list: plasticity-promoting genes up, plasticity-suppressing genes down Quotation withheld because this record is not cleared for redistribution. sequencing results are confirmed on independent samples by a second assay before being built on Quotation withheld because this record is not cleared for redistribution. the encoding signature is compared with a disease signature and found to be its inverse, which converts a description into a prediction about pathology Quotation withheld because this record is not cleared for redistribution. The study does not establish the relative contributions of other nodes of the distributed neocortical network to hippocampal-dependent memory formation. what this limits: the specificity of the mPFC result: FUTURE STUDIES DELINEATING THE RELATIVE CONTRIBUTIONS OF VARIOUS NODES OF THE NEOCORTICAL NETWORK ... WILL LIKELY PROVIDE CRITICAL INSIGHT Quotation withheld because this record is not cleared for redistribution. which neocortical inputs drive hippocampal activation at encoding was unknown, and this paper identifies one without excluding others what this limits: the state of the question this paper answers: THE NEOCORTICAL INPUTS THAT DRIVE HIPPOCAMPAL ACTIVATION DURING MEMORY ENCODING ... REMAIN UNCLEAR Quotation withheld because this record is not cleared for redistribution. encoding engages widely distributed circuits, so the relative contribution of each node remains to be apportioned what this limits: the same scope as limitations[0] - encoding ELICITS THE COORDINATED ACTIVITY OF WIDELY DISTRIBUTED NEURAL CIRCUITS, and the apportionment is not made here Quotation withheld because this record is not cleared for redistribution. the mechanisms by which prefrontal pathology impairs memory in disease are still unclear, and the account offered is a possibility rather than a result what this limits: the disease reading: THE mPFC IS AMONG THE FIRST BRAIN REGIONS TO DEVELOP AMYLOID-BETA PLAQUE DEPOSITION - an association offered, with the mechanism unestablished Quotation withheld because this record is not cleared for redistribution. prior mechanistic work concentrated on consolidation and retrieval, so the encoding literature it is being compared against is thin what this limits: the comparison with the prefrontal memory literature: MECHANISTIC INVESTIGATION OF THE ROLE OF THE PREFRONTAL CORTEX IN MEMORY PROCESSING HAS LARGELY FOCUSED ON ITS ROLE IN MEMORY CONSOLIDATION AND RETRIEVAL, not encoding Quotation withheld because this record is not cleared for redistribution. genome-wide sequencing and gene-ontology network analysis, imported to turn a memory manipulation into a direction of transcriptional change rather than a candidate-gene test Quotation withheld because this record is not cleared for redistribution. a light-driven chloride pump under a cell-type-specific promoter, which converts a regional correlation into an epoch-specific causal test Quotation withheld because this record is not cleared for redistribution. context-exposed mice as the control group in the subsequent experiments, chosen over foot-shock-only animals because immediate early gene expression in mPFC was significantly greater in the context-exposed controls eliminates: that the mPFC activation reflects the context or the foot shock on its own rather than the association between them - and the control is chosen to be the HARDER comparison of the two · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. memory encoding memory encoding Quotation withheld because this record is not cleared for redistribution. active zone active zone Quotation withheld because this record is not cleared for redistribution. neocortical remodeling - as a late consolidation process occurring weeks to months after encoding versus as an early process within the hour; the paper shows both exist and indexes them by stage Quotation withheld because this record is not cleared for redistribution. the direction of hippocampal-neocortical influence - neocortex driving hippocampus at encoding, hippocampus driving neocortex at consolidation; the same pair of structures with the arrow reversed by stage Quotation withheld because this record is not cleared for redistribution. dendritic spine - thin and plastic versus mushroom and stable; a morphological continuum read as two functional kinds Quotation withheld because this record is not cleared for redistribution. synaptic change - as more synapses versus as remodeling of existing ones; unchanged total density decides it here Quotation withheld because this record is not cleared for redistribution. mEPSC frequency versus amplitude - presynaptic against postsynaptic locus, and only the first moved Quotation withheld because this record is not cleared for redistribution. recent versus remote long-term memory - 1 day against 30 days, tested separately because the standard model predicts prefrontal involvement only in the second Quotation withheld because this record is not cleared for redistribution. claim_type: mechanism a second reading DIFFERING from the recorded value. Recorded: existence — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. method: single-trial contextual fear conditioning in mice, assayed by genome-wide RNA-seq, transmission electron microscopy, Golgi-Cox spine morphology and whole-cell recording, with optogenetic silencing of excitatory mPFC neurons during encoding a second reading DIFFERING from the recorded value. Recorded: experiment — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. phenomenon: long-term episodic memory encoding and the early plasticity that accompanies it a second reading DIFFERING from the recorded value. Recorded: neocortical remodeling during episodic memory encoding — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. contradicts → the prevailing view that neocortical reorganization is limited to late stages of memory processing differs in: THE AXIS IS WHEN THE NEOCORTEX IS INVOLVED. The span states the view being contradicted in full: 'long-term memory encoding requires early and rapid plasticity within the hippocampus, Quotation withheld'. The disagreement is about TIMING - early against late - and not about whether the neocortex reorganises. Quotation withheld because this record is not cleared for redistribution. extends → Marr's theoretical modeling work and the standard model of systems-level memory consolidation Quotation withheld because this record is not cleared for redistribution. builds-on → recent reports that prefrontal neurons are 'tagged' during encoding and are required for incorporating new information into existing schemas Quotation withheld because this record is not cleared for redistribution. contradicts → the prevailing view that neocortical reorganization is limited to the late stages of memory processing differs in: SAME SPAN AS [0], SAME AXIS: the timing of neocortical involvement, early against late. Two claim relations off one sentence, both contradicting the same prevailing view, and neither carried the parameter until now. Quotation withheld because this record is not cleared for redistribution. extends → neuroimaging work reporting hippocampal-prefrontal coactivation at encoding, which had identified the anomaly without a mechanism Quotation withheld because this record is not cleared for redistribution. critiques → the concentration of mechanistic prefrontal work on consolidation and retrieval rather than encoding Quotation withheld because this record is not cleared for redistribution. supports → reports that prefrontal neurons are tagged at encoding and required for incorporating new information into existing schemas Quotation withheld because this record is not cleared for redistribution. builds-on → the Marr-derived standard model in which the hippocampus integrates distributed neocortical input into a contextualised trace Quotation withheld because this record is not cleared for redistribution. supports → the proposal that prefrontal metabolic properties suit it to learning-induced biosynthetic demand Quotation withheld because this record is not cleared for redistribution. memory encoding —causes→ transcriptome memory encoding transcriptome strength of the relation: 0.95 Audit 2026-09-28: DOUBTFUL - read against its span and kept, but the span says the transcriptome is reprogrammed during encoding; causes is loose. Quotation withheld because this record is not cleared for redistribution. memory encoding —causes→ active zone memory encoding active zone direction on the measure: increases · strength of the relation: 0.95 Quotation withheld because this record is not cleared for redistribution. thin spines —contrasted-with→ mushroom spines thin spines mushroom spines strength of the relation: 1 Quotation withheld because this record is not cleared for redistribution. medial prefrontal cortex —operationalised-as→ immediate early gene medial prefrontal cortex immediate early gene strength of the relation: 0.9 Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but reduced Zif268 (immediate early gene) expression CONFIRMED that mPFC activation was prevented; operationalised-as is loose. Quotation withheld because this record is not cleared for redistribution. synaptic efficacy —operationalised-as→ miniature excitatory postsynaptic currents synaptic efficacy miniature excitatory postsynaptic currents strength of the relation: 0.95 Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but the span writes 'the efficacy of excitatory presynaptic transmission', not 'synaptic efficacy'. Quotation withheld because this record is not cleared for redistribution. episodic memory —operationalised-as→ contextual fear conditioning episodic memory contextual fear conditioning strength of the relation: 0.95 Quotation withheld because this record is not cleared for redistribution. correlation correlation Quotation withheld because this record is not cleared for redistribution. p-value p-value Quotation withheld because this record is not cleared for redistribution. standard error of the mean standard error of the mean Quotation withheld because this record is not cleared for redistribution. genome-wide RNA sequencing genome-wide RNA sequencing Quotation withheld because this record is not cleared for redistribution. Ingenuity Gene Network Analyses Ingenuity Gene Network Analyses Quotation withheld because this record is not cleared for redistribution. quantitative RT-PCR quantitative RT-PCR Quotation withheld because this record is not cleared for redistribution. Pearson r Pearson r Quotation withheld because this record is not cleared for redistribution. One hour after contextual fear conditioning, 342 genes were differentially expressed in the medial prefrontal cortex relative to controls. Quotation withheld because this record is not cleared for redistribution. Memory encoding rapidly enlarged the active zone and postsynaptic density and increased docked vesicle number at individual mPFC synapses. Quotation withheld because this record is not cleared for redistribution. The ratio of thin to mushroom dendritic spines on mPFC pyramidal neurons rose within an hour of fear conditioning. Quotation withheld because this record is not cleared for redistribution. Miniature excitatory postsynaptic current frequency, but not amplitude, increased at mPFC synapses after encoding, indicating a presynaptic change. Quotation withheld because this record is not cleared for redistribution. Optogenetic silencing of excitatory mPFC neurons during encoding suppressed activity markers in hippocampal area CA1. Quotation withheld because this record is not cleared for redistribution. Silencing excitatory mPFC neurons only during encoding impaired both recent (1 day) and remote (30 day) fear memory. Quotation withheld because this record is not cleared for redistribution. Despite the structural and functional changes, the total number of mPFC synapses did not change, so the remodeling occurred in existing circuitry. Quotation withheld because this record is not cleared for redistribution. 342 genes were differentially expressed in mPFC an hour after fear conditioning, 121 up and 221 down Quotation withheld because this record is not cleared for redistribution. up-regulated genes formed a network for cAMP synthesis, neuritogenesis, long-term potentiation and axon guidance Quotation withheld because this record is not cleared for redistribution. down-regulated genes were implicated in microglial proliferation, phagocyte activation and apoptosis Quotation withheld because this record is not cleared for redistribution. an hour after conditioning the active zone and postsynaptic density had expanded and docked vesicle number had risen Quotation withheld because this record is not cleared for redistribution. the three ultrastructural indices were highly correlated at individual synapses Quotation withheld because this record is not cleared for redistribution. the ratio of thin to mushroom spines rose an hour after conditioning Quotation withheld because this record is not cleared for redistribution. mEPSC frequency rose but amplitude did not, placing the change presynaptically Quotation withheld because this record is not cleared for redistribution. total synapse density was unchanged, so existing circuitry was remodeled rather than expanded Quotation withheld because this record is not cleared for redistribution. silencing mPFC during encoding cut Zif268 and synaptophysin in hippocampal CA1 Quotation withheld because this record is not cleared for redistribution. and in entorhinal cortex, the gateway between the two Quotation withheld because this record is not cleared for redistribution. mice silenced during encoding froze less at both 1 day and 30 days Quotation withheld because this record is not cleared for redistribution. neither locomotion nor shock sensitivity differed between groups Quotation withheld because this record is not cleared for redistribution. context exposure alone raised mPFC immediate-early gene expression more than foot shock alone Quotation withheld because this record is not cleared for redistribution. the encoding expression profile is the inverse of the Alzheimer profile - plasticity genes up and immune genes down, against immune up and plasticity down Quotation withheld because this record is not cleared for redistribution. contextual fear conditioning contextual fear conditioning Quotation withheld because this record is not cleared for redistribution. stage-dependent directionality model of memory-relevant information flow stage-dependent directionality model of memory-relevant information flow Quotation withheld because this record is not cleared for redistribution. contextual fear conditioning contextual fear conditioning Quotation withheld because this record is not cleared for redistribution. Dendritic spines Dendritic spines Quotation withheld because this record is not cleared for redistribution. stage-dependent directionality model stage-dependent directionality model Quotation withheld because this record is not cleared for redistribution. thin spines thin spines Quotation withheld because this record is not cleared for redistribution. mushroom spines mushroom spines Quotation withheld because this record is not cleared for redistribution. mPFC transcriptome mPFC transcriptome Quotation withheld because this record is not cleared for redistribution. immediate early gene expression immediate early gene expression Quotation withheld because this record is not cleared for redistribution. active zone and postsynaptic density length active zone and postsynaptic density length Quotation withheld because this record is not cleared for redistribution. ratio of thin spines to mushroom spines ratio of thin spines to mushroom spines Quotation withheld because this record is not cleared for redistribution. mEPSC frequency mEPSC frequency Quotation withheld because this record is not cleared for redistribution. Zif268 expression Zif268 expression Quotation withheld because this record is not cleared for redistribution. freezing freezing Quotation withheld because this record is not cleared for redistribution. basal locomotor activity basal locomotor activity Quotation withheld because this record is not cleared for redistribution. sensitivity to foot shock sensitivity to foot shock Quotation withheld because this record is not cleared for redistribution. 342 genes (121 up-regulated, 221 down-regulated) — Number of genes differentially expressed in mPFC one hour after fear conditioning versus control Quotation withheld because this record is not cleared for redistribution. Pearson r = 0.7991; P ≤ 0.0001 — Strength of the correlation between active zone length and docked synaptic vesicle number across individual synapses Quotation withheld because this record is not cleared for redistribution. n = 77–92 — Number of individual synapses measured per group for active zone and postsynaptic density length by electron microscopy Quotation withheld because this record is not cleared for redistribution. 1 d and 30 d — Delays after training at which recent and remote long-term memory were tested Quotation withheld because this record is not cleared for redistribution. 342 genes — differentially expressed in mPFC one hour after conditioning, 121 up and 221 down Quotation withheld because this record is not cleared for redistribution. 1 h — the interval after conditioning at which every molecular and structural measure was taken value source note: THE VALUE DRAWS ON THE PAPER BEYOND THIS QUOTE: part of it is printed elsewhere in the paper, not in this quote ('sequencing (RNA-seq) of mouse mPFC 1 h following contextual…'). Quotation withheld because this record is not cleared for redistribution. 1 d and 30 d — recent and remote memory test points Quotation withheld because this record is not cleared for redistribution. 2.5 ± 0.5 mo — age of the wild-type male mice Quotation withheld because this record is not cleared for redistribution. GSE58510 — the GEO accession for the deposited sequencing data Quotation withheld because this record is not cleared for redistribution.

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