Hippocampal-prefrontal input supports spatial encoding in working memory

Hippocampal-prefrontal input supports spatial encoding in working memory Spellman Rigotti Ahmari Fusi Gogos Gordon

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Hippocampal-prefrontal input supports spatial encoding in working memory 2015 Nature 10.1038/nature14445 Spellman2015-hippocampal-prefrontal-input-supports-spatia Spellman2015-hippocampal-prefrontal-input-supports-spatia.txt, the project's staged copy 56d6e9f7665eab7489d0606d536efed435acb25e 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 the direct ventral hippocampus to medial prefrontal cortex projection during spatial working memory Quotation withheld because this record is not cleared for redistribution. which phase of spatial working memory requires this pathway, what it carries, and by what anatomical route Quotation withheld because this record is not cleared for redistribution. shows the pathway is needed for encoding but not maintenance or retrieval, both behaviourally and in the prefrontal representation, with gamma synchrony as the carrier Quotation withheld because this record is not cleared for redistribution. mechanism Quotation withheld because this record is not cleared for redistribution. spatial working memory Quotation withheld because this record is not cleared for redistribution. electrophysiology electrophysiology Quotation withheld because this record is not cleared for redistribution. mechanisms Gamma-frequency synchronization between vHPC and mPFC carries the spatial cue across the direct projection, so that entrainment of mPFC spikes to vHPC gamma is what enables successful encoding. Quotation withheld because this record is not cleared for redistribution. mechanisms vHPC gamma oscillations entrain vHPC output in phase, which then influences mPFC spike timing at monosynaptic delays, making spike entrainment the physical signature of the signal being propagated. Quotation withheld because this record is not cleared for redistribution. mechanisms The vHPC input acts excitatorily on mPFC units, driving the location-selective elevation of firing rate that constitutes the cue representation. Quotation withheld because this record is not cleared for redistribution. vHPC input drives a selective firing-rate elevation in each unit's preferred goal, without changing baseline rates Quotation withheld because this record is not cleared for redistribution. the same goal selectivity persists during choice runs and no longer needs vHPC input, so physiology mirrors the behavioural dissociation Quotation withheld because this record is not cleared for redistribution. vHPC gamma leads mPFC spiking at lags consistent with monosynaptic transmission, and terminal inhibition reduces that phase-locking Quotation withheld because this record is not cleared for redistribution. the directionality is specific to gamma: in theta the mPFC leads, and theta synchrony survives terminal inhibition Quotation withheld because this record is not cleared for redistribution. terminal illumination suppresses transmission without silencing the source cells, which is what makes the manipulation projection-specific Quotation withheld because this record is not cleared for redistribution. a four-goal maze prevents the animal from forming a spatially directed plan until the choice phase, which is what separates encoding from retrieval Quotation withheld because this record is not cleared for redistribution. The authors cannot definitively exclude an effect of terminal inhibition during the choice (retrieval) phase; the null result there was underpowered. what this limits: the encoding claim as against the choice phase: ALTHOUGH WE CANNOT CONCLUSIVELY RULE OUT AN EFFECT OF TERMINAL INHIBITION DURING CHOICE, THESE EXPERIMENTS INDICATE THAT INPUT FROM THE vHPC TO THE mPFC IS CRITICAL FOR ENCODING Quotation withheld because this record is not cleared for redistribution. Retrospective location coding might exist in mPFC in a form their decoding analysis could not detect (e.g. synaptic weights or very brief reactivation). what this limits: the absence of retrospective coding, which is scoped to the ANALYSIS: IT IS NOT DETECTABLE USING THE ANALYTIC TECHNIQUES PRESENTED HERE, SUCH AS in synaptic weights or in reactivation too brief for the bins Quotation withheld because this record is not cleared for redistribution. The pseudo-population decoding approach assumes comparable spike statistics across animals and sessions and discards correlated variability. what this limits: every population-decoding result: THIS APPROACH ASSUMES EQUIVALENT SPIKE STATISTICS ACROSS ANIMALS AND RECORDING SESSIONS, AND IGNORES POTENTIAL CONTRIBUTIONS TO POPULATION CODING FROM CORRELATED SPIKE VARIABILITY Quotation withheld because this record is not cleared for redistribution. The gamma phase-locking effect is small: under 10% of mPFC units were significantly phase-locked even at the best lag. what this limits: the gamma phase-locking claim, with its size: AT THE LAG WITH THE GREATEST PHASE-LOCKING, FEWER THAN 10% OF mPFC UNITS WERE SIGNIFICANTLY PHASE-LOCKED TO vHPC GAMMA Quotation withheld because this record is not cleared for redistribution. the choice-phase null is not conclusive; an n of 37 per group would have been needed to detect the observed effect size what this limits: the choice-phase null, with what it would have taken to see the effect: A SLIGHT TREND TOWARD IMPAIRMENT DID NOT REACH SIGNIFICANCE, AND POST-HOC POWER ANALYSIS REVEALED THAT AN n OF 37 PER GROUP would have been required Quotation withheld because this record is not cleared for redistribution. the authors state plainly that they cannot conclusively rule out an effect during choice duplicate of: limitations[0] · what this limits: the same scope as limitations[0] - an effect during choice is not conclusively excluded Quotation withheld because this record is not cleared for redistribution. the absence of retrospective coding is scoped to the analysis: it could be held in synaptic weights or in reactivation too brief to decode from binned histograms what this limits: the same scope as limitations[1] - the null on retrospective coding is a null of the method Quotation withheld because this record is not cleared for redistribution. the gamma effect is subtle - fewer than 10% of mPFC units were significantly phase-locked at the best lag duplicate of: limitations[3] · what this limits: the same scope as limitations[3] - under 10% of units, at the best lag Quotation withheld because this record is not cleared for redistribution. the promoter was changed between the two behavioural experiments, so they are not methodologically identical what this limits: any comparison BETWEEN the two behavioural experiments: THE hSYNAPSIN PROMOTER WAS CHOSEN FOR THE 4-GOAL EXPERIMENT TO ACCOUNT FOR POSSIBLE LONG-RANGE GABAERGIC vHPC-mPFC PROJECTIONS AND TO AVOID POTENTIAL TOXICITY EFFECTS - so they differ in more than the goal count Quotation withheld because this record is not cleared for redistribution. male mice only what this limits: any sex-general reading: MALE C57BL/6 MICE (JACKSON LABS) WERE USED FOR ALL EXPERIMENTS Quotation withheld because this record is not cleared for redistribution. the theta result ran counter to the authors' initial hypotheses and is reported as such what this limits: the theta result specifically: THE FINDING THAT mPFC THETA ACTIVITY LEADS vHPC THETA, AND THAT THETA SYNCHRONY BETWEEN THE TWO STRUCTURES DID NOT APPEAR TO DEPEND UPON vHPC-mPFC AFFERENTS, RAN COUNTER TO OUR INITIAL HYPOTHESES Quotation withheld because this record is not cleared for redistribution. delay-period persistent firing as the expected mechanism, imported and then not found in the rodent homologue Quotation withheld because this record is not cleared for redistribution. a maximum margin linear classifier with cross-validation, used to read location from distributed population rates Quotation withheld because this record is not cleared for redistribution. a CamKIIα-mCherry virus carrying no opsin, run in the acute stimulation/silencing and 2-goal t-maze experiments eliminates: the light delivery and the viral infection themselves as the cause of the behavioural effect - the exclusion is carried by the term OPSIN-NEGATIVE CONTROL rather than spelled out · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. the researcher who trained and ran the mice was blinded to viral group by a second lab member, who did the assignment eliminates: the experimenter's knowledge of which animals carried the opsin influencing training or scoring · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. encoding, maintenance and retrieval are defined by TRIAL PHASE and made separable by a maze redesign - the distinction is built into the apparatus, not read off the behaviour Quotation withheld because this record is not cleared for redistribution. projection-specific means the terminals are silenced where they arrive, not the cells that send them - validated by showing vHPC firing is untouched by mPFC illumination Quotation withheld because this record is not cleared for redistribution. no evidence of retrospective coding is scoped explicitly to the analytic technique, naming two forms it could take and still be missed Quotation withheld because this record is not cleared for redistribution. functionally analogous but anatomically distinct - the stated relation between primate dorsolateral PFC and rodent prelimbic cortex, which licenses comparing them cautiously Quotation withheld because this record is not cleared for redistribution. method: projection-specific optogenetic terminal inhibition with archaerhodopsin, timed to single trial phases, combined with prefrontal single-unit recording and population decoding a second reading DIFFERING from the recorded value. Recorded: electrophysiology — 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: phase-specific long-range routing of spatial information during working memory a second reading DIFFERING from the recorded value. Recorded: spatial working memory — 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. builds-on → Wang et al., 2006 (adaptive intra-trial delay procedure for the T-maze task) Quotation withheld because this record is not cleared for redistribution. qualifies → prior reports of retrospective and prospective location coding in rodent mPFC during delays Quotation withheld because this record is not cleared for redistribution. reinterprets → the earlier finding that vHPC silencing reduces dHPC-mPFC theta synchrony, proposing it was an indirect effect on dHPC Quotation withheld because this record is not cleared for redistribution. extends → work implicating vHPC and mPFC in contextual learning, by moving it to a seconds timescale Quotation withheld because this record is not cleared for redistribution. contradicts → persistent prefrontal firing as the mechanism maintaining the cue between encoding and retrieval Quotation withheld because this record is not cleared for redistribution. encoding —contrasted-with→ retrieval encoding retrieval differs in: THE AXIS IS WHICH PHASE OF THE MEMORY THE PATHWAY IS NEEDED FOR, AND THREE PHASES ARE NAMED. 'Quotation withheld.' The same anatomy is necessary at one moment of a trial and dispensable at the others - so a lesion or inactivation that spans the whole trial cannot produce this result, and studies that do span it will report the pathway as generally required. · strength of the relation: 1 Quotation withheld because this record is not cleared for redistribution. gamma —contrasted-with→ theta gamma theta differs in: THE AXIS IS FREQUENCY BAND, AND THE DIRECTION OF FLOW REVERSES WITH IT. 'Quotation withheld.' The same two structures lead each other in opposite directions depending on the band - so a connectivity claim without the band is not merely imprecise, it is ambiguous between two opposite claims. · strength of the relation: 1 · note: opposite directionality between the same two structures, and only gamma depends on the direct pathway Quotation withheld because this record is not cleared for redistribution. gamma —operationalised-as→ pairwise phase consistency gamma pairwise phase consistency strength of the relation: 0.95 Audit 2026-09-28: DOUBTFUL - read against its span and kept, but long-range gamma synchrony was quantified with pairwise phase consistency; operationalised-as is loose. Quotation withheld because this record is not cleared for redistribution. ANOVA ANOVA Quotation withheld because this record is not cleared for redistribution. repeated-measures ANOVA repeated-measures ANOVA Quotation withheld because this record is not cleared for redistribution. paired t-test paired t-test Quotation withheld because this record is not cleared for redistribution. Bonferroni correction for multiple comparisons Bonferroni correction for multiple comparisons Quotation withheld because this record is not cleared for redistribution. significance threshold (alpha) significance threshold (alpha) Quotation withheld because this record is not cleared for redistribution. Rayleigh test of circular uniformity Rayleigh test of circular uniformity Quotation withheld because this record is not cleared for redistribution. pairwise phase consistency (spike-field phase-locking measure) pairwise phase consistency (spike-field phase-locking measure) Quotation withheld because this record is not cleared for redistribution. linear classifier / population decoding linear classifier / population decoding Quotation withheld because this record is not cleared for redistribution. cross-validation cross-validation Quotation withheld because this record is not cleared for redistribution. resampling with replacement (bootstrap) resampling with replacement (bootstrap) Quotation withheld because this record is not cleared for redistribution. statistical power analysis / effect size statistical power analysis / effect size Quotation withheld because this record is not cleared for redistribution. maximum margin linear classifier, cross-validated maximum margin linear classifier, cross-validated Quotation withheld because this record is not cleared for redistribution. pairwise phase consistency pairwise phase consistency Quotation withheld because this record is not cleared for redistribution. Rayleigh's test Rayleigh's test Quotation withheld because this record is not cleared for redistribution. post-hoc power analysis post-hoc power analysis Quotation withheld because this record is not cleared for redistribution. Optogenetically silencing vHPC-to-mPFC terminals during the sample run impairs delayed non-match-to-place performance in opsin-expressing mice, while the same silencing during the entire trial also impairs it and silencing during choice does not reach significance. Quotation withheld because this record is not cleared for redistribution. Sample-phase silencing again impaired performance, confirming the pathway is required during encoding. Quotation withheld because this record is not cleared for redistribution. Silencing the pathway during the memory delay produced no significant behavioural impairment. Quotation withheld because this record is not cleared for redistribution. Population decoding of the sample goal from mPFC units was abolished (reduced to chance) by terminal illumination in Arch-expressing mice but was unchanged in Arch-negative controls. Quotation withheld because this record is not cleared for redistribution. Sample-phase terminal inhibition removed the firing-rate increase that goal-selective mPFC units show at their preferred goal, while leaving their baseline rates intact. Quotation withheld because this record is not cleared for redistribution. During choice runs the same goal-selective firing-rate elevation persisted despite terminal inhibition, so mPFC location coding at retrieval does not need the direct vHPC input. Quotation withheld because this record is not cleared for redistribution. Terminal inhibition did not change overall mPFC firing rates, either pooled or split into putative pyramidal cells and interneurons. Quotation withheld because this record is not cleared for redistribution. A decoder trained on no-light trials was unaffected when tested on sample-light trials, suggesting terminal inhibition does not generally interfere with encoding of task-relevant information. Quotation withheld because this record is not cleared for redistribution. A subset of mPFC units phase-locked to vHPC gamma, and phase-locking was strongest at lags where vHPC gamma preceded mPFC spiking, indicating vHPC leads mPFC in the gamma band. Quotation withheld because this record is not cleared for redistribution. Inhibiting the vHPC-mPFC terminals weakened gamma phase-locking, showing the long-range gamma synchrony depends on the direct anatomical projection. Quotation withheld because this record is not cleared for redistribution. In the theta band the directionality reversed - mPFC led vHPC - and theta synchrony was not affected by silencing the pathway. Quotation withheld because this record is not cleared for redistribution. Gamma phase-locking was stronger during sample runs than choice runs, associating it with the encoding phase. Quotation withheld because this record is not cleared for redistribution. Additionally, gamma phase-locking during sample runs distinguished correct from incorrect trials. Quotation withheld because this record is not cleared for redistribution. The mPFC showed no retrospective coding of the previously visited location. Quotation withheld because this record is not cleared for redistribution. inhibiting the direct pathway during the delay produced no significant impairment Quotation withheld because this record is not cleared for redistribution. sample goal is decoded from prefrontal population activity at 96% on arrival at the goal Quotation withheld because this record is not cleared for redistribution. inhibiting the pathway during encoding drops that decoding to chance in opsin-expressing animals only Quotation withheld because this record is not cleared for redistribution. the same manipulation leaves task-phase decoding unaffected, so it does not generally impair encoding Quotation withheld because this record is not cleared for redistribution. overall mPFC firing rates are unchanged by terminal illumination Quotation withheld because this record is not cleared for redistribution. goal selectivity during choice runs survives the same inhibition, mirroring the behaviour Quotation withheld because this record is not cleared for redistribution. a subset of mPFC units phase-lock to vHPC gamma, most at lags where vHPC gamma precedes mPFC spiking Quotation withheld because this record is not cleared for redistribution. in theta the direction reverses and synchrony is unaffected by the same manipulation Quotation withheld because this record is not cleared for redistribution. gamma phase-locking is stronger on sample than choice runs, and stronger on correct than incorrect trials Quotation withheld because this record is not cleared for redistribution. no retrospective location coding was found in mPFC during the delay Quotation withheld because this record is not cleared for redistribution. spatial working memory spatial working memory Quotation withheld because this record is not cleared for redistribution. vHPC vHPC Quotation withheld because this record is not cleared for redistribution. sample phase sample phase Quotation withheld because this record is not cleared for redistribution. delay phase delay phase Quotation withheld because this record is not cleared for redistribution. preferred goal preferred goal Quotation withheld because this record is not cleared for redistribution. spatial working memory spatial working memory Quotation withheld because this record is not cleared for redistribution. lag analysis lag analysis Quotation withheld because this record is not cleared for redistribution. opsin-negative control opsin-negative control Quotation withheld because this record is not cleared for redistribution. intra-trial delay intra-trial delay Quotation withheld because this record is not cleared for redistribution. firing rate firing rate Quotation withheld because this record is not cleared for redistribution. gamma phase-locking gamma phase-locking Quotation withheld because this record is not cleared for redistribution. 4-goal T-maze 4-goal T-maze Quotation withheld because this record is not cleared for redistribution. sample goal identity sample goal identity Quotation withheld because this record is not cleared for redistribution. 792 — well-isolated mPFC single units recorded, from 9 mice Quotation withheld because this record is not cleared for redistribution. 44% — share of mPFC single units showing selectivity for a spatial dimension distinguishing the goal arms Quotation withheld because this record is not cleared for redistribution. 96% — peak accuracy of decoding the sample goal from the mPFC population, at arrival at the reward port Quotation withheld because this record is not cleared for redistribution. 0.98 — accuracy of decoding task phase (sample vs choice) at the moment the start-box doors opened Quotation withheld because this record is not cleared for redistribution. ~40% — reduction of the vHPC-evoked postsynaptic multiunit response in mPFC by terminal illumination in Arch+ mice Quotation withheld because this record is not cleared for redistribution. ~50% — reduction of spontaneous multiunit activity when light was delivered to vHPC cell bodies (versus no effect on vHPC when only terminals were illuminated) Quotation withheld because this record is not cleared for redistribution. 1.48 — effect size for the behavioural impairment in Arch+ mice in the 4-goal experiment, with 90% power at N of 7 Quotation withheld because this record is not cleared for redistribution. n of 37 animals/group — sample size a post-hoc power analysis says would be needed to detect the choice-phase effect Quotation withheld because this record is not cleared for redistribution. fewer than 10% — proportion of mPFC units significantly phase-locked to vHPC gamma at the best lag Quotation withheld because this record is not cleared for redistribution. t=−3.91, p=0.001 — test of the performance difference between trials where sample and choice goals matched in the left/right dimension (0.65) and where they differed (0.71) about this quote: FLATTENED EXPONENT IN THIS QUOTE - THE NUMBER IS WRONG BY ORDERS OF MAGNITUDE AS IT STANDS. The staged text reads '4.0 × 10 3', where the paper writes 10 to the power 3. The superscript was pushed onto the line by the PDF extractor. The quote is verbatim to the staged text and its anchor is sound; the STAGED TEXT is what is damaged. NOT repaired - repair means re-staging the body and re-anchoring the record. Quotation withheld because this record is not cleared for redistribution. 792 well-isolated single units from 9 mice, 44% spatially selective — the recorded sample Quotation withheld because this record is not cleared for redistribution. about 40% reduction in evoked response, about 50% reduction in local activity at the source — validation of the terminal inhibition Quotation withheld because this record is not cleared for redistribution. 96% — peak decoding accuracy for sample goal Quotation withheld because this record is not cleared for redistribution. 0.98 — task-phase decoding accuracy, the specificity control Quotation withheld because this record is not cleared for redistribution. n of 37 animals per group — what would have been needed to detect the choice-phase effect - the null is quantified rather than asserted Quotation withheld because this record is not cleared for redistribution. effect size 1.48, power 90% at N=7 and 83% at N=6 — the power behind the positive result Quotation withheld because this record is not cleared for redistribution. fewer than 10% of mPFC units — how many were significantly phase-locked at the best lag Quotation withheld because this record is not cleared for redistribution.

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