Local generation of multineuronal spike sequences in the hippocampal CA1 region

Local generation of multineuronal spike sequences in the hippocampal CA1 region Stark Roux Eichler Buzsáki

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Local generation of multineuronal spike sequences in the hippocampal CA1 region 2015 Proceedings of the National Academy of Sciences of the United States of America 10.1073/pnas.1508785112 Stark2015-local-generation-of-multineuronal-spike-sequ Stark2015-local-generation-of-multineuronal-spike-sequ.txt, the project's staged copy 5db78ec8b132373b792c330bc02fef0710aa9963 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 ordered firing of CA1 neurons during ripples is imported from CA3 or assembled locally Quotation withheld because this record is not cleared for redistribution. whether sequences survive when the usual upstream driver is bypassed and the same neurons are activated directly by light Quotation withheld because this record is not cleared for redistribution. shows that sequence order is partly preserved across theta, spontaneous ripples and optically induced ripples, and that interneuron spiking is what carries the consistency Quotation withheld because this record is not cleared for redistribution. mechanism Quotation withheld because this record is not cleared for redistribution. multineuronal spike sequences in hippocampal CA1 Quotation withheld because this record is not cleared for redistribution. electrophysiology electrophysiology Quotation withheld because this record is not cleared for redistribution. mechanisms Three sources intersect to produce the sequences: patterned drive from CA3, a wide spread of intrinsic cellular excitability, and heterogeneous local connectivity, the last two making neurons respond unequally to the same extrinsic input status: the paper's own words: We hypothesize that Quotation withheld because this record is not cleared for redistribution. mechanisms Biophysical heterogeneity across pyramidal cells converts even an identical input ramp into diverse spike patterns and hence into a reproducible sequential order Quotation withheld because this record is not cleared for redistribution. mechanisms Each interneuron is driven by a limited set of pyramidal assemblies and silences the competing assemblies, which places it at a fixed point in the sequence and gives pyramidal spiking a temporal scaffold Quotation withheld because this record is not cleared for redistribution. even if every neuron received an identical ramp of input current, diverse and sequential spiking would still follow from intrinsic neuronal and circuit heterogeneity Quotation withheld because this record is not cleared for redistribution. interneurons are each controlled by a few pyramidal assemblies and suppress the rest, which is why they appear in orderly positions Quotation withheld because this record is not cleared for redistribution. the proposal is a three-way intersection: sequential drive from CA3, spread of intrinsic cellular properties, and differences in local connectivity Quotation withheld because this record is not cleared for redistribution. the preexisting order may itself be the residue of earlier experience or of development, which the design cannot separate Quotation withheld because this record is not cleared for redistribution. Only a limited number of pyramidal cells could be monitored with silicon probes; larger ensemble recordings are needed to test the hypothesis. what this limits: the completeness of every sequence reported: MANY MORE PYRAMIDAL NEURONS TOOK PART IN THE SEQUENTIAL PATTERNING OF ACTIVITY THAN THOSE MONITORED HERE BY THE SILICON PROBES Quotation withheld because this record is not cleared for redistribution. The theta/ripple correlation results on their own cannot separate a CA3 from a CA1 origin of the sequences. what this limits: the local-generation claim: SEQUENCES MAY BE GENERATED BY THE UPSTREAM CA3 REGION OR LOCALLY IN CA1 BUT THESE RESULTS ALONE CANNOT DISAMBIGUATE THE CONTRIBUTIONS OF THE TWO REGIONS Quotation withheld because this record is not cleared for redistribution. The measured sequence consistency is loose - rank correlations were widely spread and rarely above 0.5. what this limits: how tightly the sequences repeat: RANK CORRELATIONS WERE WIDELY DISTRIBUTED AND RARELY EXCEEDED VALUES OF 0.5 ... INDICATING RELATIVELY LOOSE SELF- AND CROSS-CLASS CONSISTENCY Quotation withheld because this record is not cleared for redistribution. the theta-ripple correlation alone cannot disambiguate the contributions of CA3 and of CA1 duplicate of: limitations[1] · what this limits: the same scope as limitations[1] - CA3 and CA1 origins are not separated by these correlations Quotation withheld because this record is not cleared for redistribution. far more pyramidal cells probably participate than the probes could record, and larger ensembles are needed duplicate of: limitations[0] · what this limits: the same scope as limitations[0] - larger ensemble recordings are needed to test the hypothesis Quotation withheld because this record is not cleared for redistribution. with pyramidal cells alone the cross-class correlation is not significant - though the paper notes the same holds within a single condition what this limits: the pyramidal-only analysis: THE CORRELATION BETWEEN SPONTANEOUS AND INDUCED OSCILLATIONS WAS NOT SIGNIFICANT. HOWEVER, THIS WAS ALSO THE CASE WHEN SEQUENCE PATTERNS WERE CORRELATED WITHIN THE SAME CONDITIONS Quotation withheld because this record is not cleared for redistribution. whether the preexisting order reflects experience or development is not addressed what this limits: the origin of the preexisting order: THE PREEXISTING SEQUENCES MAY THEMSELVES REFLECT THE LOCAL CIRCUIT CONFIGURATIONS SHAPED BY PREVIOUS EXPERIENCES, BY THE DEVELOPMENTAL GENETIC PROGRAM, OR ANY COMBINATION THEREOF Quotation withheld because this record is not cleared for redistribution. rank-order templates with permutation-based significance, used so that sequence order can be tested without assuming timing distributions Quotation withheld because this record is not cleared for redistribution. direct local activation used specifically to bypass the upstream input whose contribution is in question Quotation withheld because this record is not cleared for redistribution. short events under 15 ms discarded and adjacent events with gaps under 15 ms merged, before the sequence analysis eliminates: one event being counted as two, or noise being counted as an event, in a measure built on counting events · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. CA3 → CA1 THE TWO CANNOT BE SEPARATED IN THIS STUDY - the DESIGN form of the negative relation / No edge type can express it: all eight assert that a relation HOLDS. A confounding statement bounds what the paper's own results can mean, and it lives where nothing downstream will find it. THE SAME PAIR DRIEU2019 WAS MIS-READ AS CONTRASTING. 'Quotation withheld' One paper cannot separate them; another paper's glossary was read as distinguishing them. The corpus now holds the inability next to the mistake. Quotation withheld because this record is not cleared for redistribution. synthetic ripple is the same construct Stark2014 named iHFO and Wu2015 reused - an optically induced high-frequency oscillation, kept terminologically apart from the spontaneous ripple throughout Quotation withheld because this record is not cleared for redistribution. sequence consistency here is a RANK correlation between the firing order in one event and a template built from other events, so it measures order and not timing Quotation withheld because this record is not cleared for redistribution. self-consistency (order repeats within a class of events) and cross-class consistency (order carries between classes) are different measures, and the paper's claim rests on the second Quotation withheld because this record is not cleared for redistribution. spike gain is the same within-unit ratio used in Wu2015 - rate during the event over baseline rate - so the two records are comparable on this measure Quotation withheld because this record is not cleared for redistribution. PYR and INT are assigned by a Gaussian mixture model over waveform features, the same classification route as Wu2015 Quotation withheld because this record is not cleared for redistribution. claim_type: mechanism a second reading reaching the same value. Recorded: mechanism — note: a second reading reaching the same value from a different sentence. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. method: simultaneous multi-site recording with per-shank light delivery in freely moving and anaesthetised mice, with rank-order sequence templates and permutation tests 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: recurring order of firing across a population of CA1 neurons within an oscillatory event a second reading DIFFERING from the recorded value. Recorded: multineuronal spike sequences in hippocampal CA1 — 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 → The authors' own earlier demonstration (ref. 26) that local optogenetic stimulation of CA1 pyramidal cells induces fast LFP oscillations resembling spontaneous ripples Quotation withheld because this record is not cleared for redistribution. contradicts → The prevailing assumption (refs 4, 12, 16, 21, 23) that CA1 sequential firing during ripples and theta is generated in CA3 recurrent networks and inherited synaptically by CA1 status: the paper's own words: has not been shown Quotation withheld because this record is not cleared for redistribution. replicates → A previous study (ref. 34) of the stability of sequential activation of pyramidal cells and interneurons during neocortical slow oscillations Quotation withheld because this record is not cleared for redistribution. contradicts → the tacit assumption that CA1 ripple sequences are synaptically inherited from CA3 assemblies Quotation withheld because this record is not cleared for redistribution. extends → Stark et al. 2014, which showed local optogenetic activation is sufficient to induce ripple-like oscillations Quotation withheld because this record is not cleared for redistribution. critiques → the inference from waking-sleep correlation to experience-induced synaptic plasticity Quotation withheld because this record is not cleared for redistribution. supports → preplay reports of correlations present before a novel experience Quotation withheld because this record is not cleared for redistribution. confirms → neocortical work finding stable pyramidal-interneuron sequences during slow oscillations Quotation withheld because this record is not cleared for redistribution. EVIDENCE CORRECTED (RE-GROUNDED) · INT —causes→ consistency INT consistency EVIDENCE CORRECTED: RE-GROUNDED. The old span attested 'INT' only inside 'interneurons'. The paper defines INT as its label for interneurons and uses it 46 times; this sentence writes it as a word and states the effect on consistency with its size. — strength of the relation: 1 · note: 12% of the units carry the sequence; dropping them sends cross-class consistency to chance Audit 2026-09-28: DOUBTFUL - read against its span and kept, but interneurons made a large contribution to sequence consistency; causes is loose. Quotation withheld because this record is not cleared for redistribution. EVIDENCE CORRECTED (RE-GROUNDED) · consistency —operationalised-as→ permutation test consistency permutation test EVIDENCE CORRECTED: RE-GROUNDED. The old span described the ranking procedure. This sentence names both and states the test outright - '…CONSISTENCY was determined BY A PERMUTATION TEST, randomly…'. — strength of the relation: 1 · note: significance comes from shuffling unit labels, so the null is order-specific rather than rate-specific Audit 2026-09-28: DOUBTFUL - read against its span and kept, but sequence consistency was tested with a permutation test; operationalised-as is loose. Quotation withheld because this record is not cleared for redistribution. EVIDENCE CORRECTED (RE-GROUNDED FROM AN INFERENCE TO THE INTERVENTION IT RESTS ON) · CA1 —causes→ spike sequences CA1 spike sequences EVIDENCE CORRECTED: RE-GROUNDED FROM AN INFERENCE TO THE INTERVENTION IT RESTS ON. The old span reports a conclusion - 'These results INDICATE…' that mechanisms in CA1 contribute to ripple- and theta-associated sequences - which names one endpoint and hedges the mechanism (mechanisms confined to CA1). The replacement is the experiment: 'We show that OPTOGENETIC ACTIVATION…' of a small group of CA1 pyramidal cells yields consistent spike sequences. A manipulation and its result, both endpoints named. For a 'causes' edge an intervention is better evidence than an inference drawn from one. — strength of the relation: 0.9 · note: the paper's own claim: local mechanisms contribute, not that CA3 does not Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but the span writes 'neuronal sequences' / 'sequential spiking patterns', not 'spike sequences'. Quotation withheld because this record is not cleared for redistribution. replay —contrasted-with→ preplay replay preplay strength of the relation: 0.9 · note: the warning this paper leaves the field: a correlation read as learning may predate the learning Audit 2026-09-28: DOUBTFUL - read against its span and kept, but the span is cut before the replay-preplay contrast. Quotation withheld because this record is not cleared for redistribution. PYR —contrasted-with→ INT PYR INT strength of the relation: 1 · note: the 4.7-fold against 1.8-fold rate rise is the evidence that light drove PYR directly and INT through the circuit Quotation withheld because this record is not cleared for redistribution. EVIDENCE CORRECTED (RE-GROUNDED) · theta —contrasted-with→ spontaneous ripples theta spontaneous ripples EVIDENCE CORRECTED: RE-GROUNDED. The old span set up a comparison without naming its terms. This sentence names them as the study's own design - '…during THETA oscillations, SPONTANEOUS RIPPLES, and focal…' - so the contrast is the experiment rather than an observation about it. — strength of the relation: 1 · note: two states with different drivers whose sequences nonetheless match, which is what motivates the local-circuit hypothesis Audit 2026-09-28: DOUBTFUL - read against its span and kept, but the span compares ripple sequences with theta cycles; contrasted-with is loose. Quotation withheld because this record is not cleared for redistribution. INT —causes→ consistency INT consistency strength of the relation: 1 · note: RE-GROUNDS another row of this record:, the endpoint was attested mid-word. Audit 2026-09-28: DOUBTFUL - read against its span and kept, but including interneurons doubles cross-class consistency; causes is loose. Quotation withheld because this record is not cleared for redistribution. consistency —operationalised-as→ permutation test consistency permutation test strength of the relation: 1 · note: RE-GROUNDS another row of this record: the old span named ONE endpoint. Audit 2026-09-28: DOUBTFUL - read against its span and kept, but significance of consistency was determined by permutation; operationalised-as is loose. Quotation withheld because this record is not cleared for redistribution. theta —contrasted-with→ spontaneous ripples theta spontaneous ripples strength of the relation: 1 · note: RE-GROUNDS another row of this record: the old span named ONE endpoint. Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but the span lists the three conditions the study compared; contrasted-with is loose. Quotation withheld because this record is not cleared for redistribution. CA1 —causes→ spike sequences CA1 spike sequences the relation itself is separately evidenced · strength of the relation: 0.9 Quotation withheld because this record is not cleared for redistribution. rank correlation rank correlation Quotation withheld because this record is not cleared for redistribution. permutation test permutation test Quotation withheld because this record is not cleared for redistribution. Wilcoxon signed-rank test Wilcoxon signed-rank test Quotation withheld because this record is not cleared for redistribution. binomial test binomial test Quotation withheld because this record is not cleared for redistribution. Mann-Whitney U test Mann-Whitney U test Quotation withheld because this record is not cleared for redistribution. Kruskal-Wallis test Kruskal-Wallis test Quotation withheld because this record is not cleared for redistribution. circular correlation circular correlation Quotation withheld because this record is not cleared for redistribution. chi-squared test chi-squared test Quotation withheld because this record is not cleared for redistribution. cross-validation cross-validation Quotation withheld because this record is not cleared for redistribution. Gaussian mixture model Gaussian mixture model Quotation withheld because this record is not cleared for redistribution. principal component analysis principal component analysis Quotation withheld because this record is not cleared for redistribution. significance level significance level Quotation withheld because this record is not cleared for redistribution. permutation test permutation test Quotation withheld because this record is not cleared for redistribution. rank correlation rank correlation Quotation withheld because this record is not cleared for redistribution. Wilcoxon Wilcoxon Quotation withheld because this record is not cleared for redistribution. exact Binomial test exact Binomial test Quotation withheld because this record is not cleared for redistribution. Rayleigh test Rayleigh test Quotation withheld because this record is not cleared for redistribution. Mann-Whitney U test Mann-Whitney U test Quotation withheld because this record is not cleared for redistribution. Individual neurons' firing rates, their rate modulation, and the order in which pyramidal cells and interneurons fired were all correlated across three different network states: theta oscillations, spontaneous ripples, and optogenetically induced ripples. Quotation withheld because this record is not cleared for redistribution. Because sequences recur during locally induced ripples that receive no CA3 or entorhinal patterning, the sequential order of CA1 spiking cannot be purely inherited from upstream regions and must partly arise from CA1's own circuitry and single-cell biophysics. Quotation withheld because this record is not cleared for redistribution. Half of the optogenetically induced spike sequences matched the spontaneous ripple sequence recorded at the same site, with a median rank correlation of 0.13. Quotation withheld because this record is not cleared for redistribution. Interneurons made up only 12% of the participating units and were only indirectly driven by the light, yet they contributed importantly to sequence consistency in both spontaneous and induced ripples. Quotation withheld because this record is not cleared for redistribution. With pyramidal cells alone the correlation between theta-cycle and ripple sequence order dropped to chance, so the shared ordering across states depends on including interneurons. Quotation withheld because this record is not cleared for redistribution. The preferred firing phase of each unit within the ripple cycle was the same for spontaneous and light-induced ripples, so cycle-level spike timing is conserved between the two. Quotation withheld because this record is not cleared for redistribution. Sequence consistency was real but weak: rank correlations were broadly spread and seldom above 0.5, and the same conclusions followed whether a template or a pairwise comparison method was used. Quotation withheld because this record is not cleared for redistribution. Under anaesthesia, spontaneous and induced sequences were not consistent with each other. Quotation withheld because this record is not cleared for redistribution. firing rates during theta and during ripples were correlated neuron by neuron Quotation withheld because this record is not cleared for redistribution. sequences recorded during ripples matched those during theta cycles in 10 of 11 sessions Quotation withheld because this record is not cleared for redistribution. spike phase within the cycle was preserved between spontaneous and induced ripples Quotation withheld because this record is not cleared for redistribution. pyramidal cells fired about 1.8 ms before interneurons on each ripple cycle Quotation withheld because this record is not cleared for redistribution. sequences repeated across spontaneous ripple events at 23 of 27 recording sites Quotation withheld because this record is not cleared for redistribution. half the induced sequences matched their own site's spontaneous sequences Quotation withheld because this record is not cleared for redistribution. theta sequences and induced-ripple sequences also matched, at 10 of 25 sites Quotation withheld because this record is not cleared for redistribution. with interneurons alone, sequences stayed consistent across classes Quotation withheld because this record is not cleared for redistribution. interneurons are 12% of the units and carry the consistency Quotation withheld because this record is not cleared for redistribution. in the pyramidal-only session analysis three sessions were consistent and three were REVERSED, so the group mean describes neither Quotation withheld because this record is not cleared for redistribution. CONTROL NULL: illumination of an opsin-free mouse produced no spikes, no oscillations and no artefact Quotation withheld because this record is not cleared for redistribution. CONTROL: induced-ripple rates track spontaneous rates, so the induced pattern is not set by opsin level or distance from the light Quotation withheld because this record is not cleared for redistribution. spontaneous and induced ripples occurred predominantly in the same brain state Quotation withheld because this record is not cleared for redistribution. SCOPE TO CHECK: the main text reports similar results under anaesthesia, and the supplementary caption it cites states cross-class sequences are NOT consistent there Quotation withheld because this record is not cleared for redistribution. SCOPE TO CHECK, second half: the supplementary figure caption states plainly that spontaneous and induced sequences are not consistent under anaesthesia Quotation withheld because this record is not cleared for redistribution. synthetic ripples synthetic ripples Quotation withheld because this record is not cleared for redistribution. gain gain Quotation withheld because this record is not cleared for redistribution. cross-class consistency cross-class consistency Quotation withheld because this record is not cleared for redistribution. threshold intensity threshold intensity Quotation withheld because this record is not cleared for redistribution. spike gain spike gain Quotation withheld because this record is not cleared for redistribution. consistency consistency Quotation withheld because this record is not cleared for redistribution. synthetic ripples synthetic ripples Quotation withheld because this record is not cleared for redistribution. preplay preplay Quotation withheld because this record is not cleared for redistribution. light stimulation light stimulation Quotation withheld because this record is not cleared for redistribution. rank correlation rank correlation Quotation withheld because this record is not cleared for redistribution. light intensity light intensity Quotation withheld because this record is not cleared for redistribution. consistency consistency Quotation withheld because this record is not cleared for redistribution. spike gain spike gain Quotation withheld because this record is not cleared for redistribution. phase phase Quotation withheld because this record is not cleared for redistribution. 5.1-fold — increase in pyramidal cell firing rate during spontaneous ripples, versus 4.1-fold for interneurons Quotation withheld because this record is not cleared for redistribution. 582 — total well-isolated CA1 cells recorded across freely moving and anaesthetized mice Quotation withheld because this record is not cleared for redistribution. 56 — recording sites that met the criteria for sequence analysis, across 16 sessions Quotation withheld because this record is not cleared for redistribution. 0.28 — median rank correlation quantifying self-consistency of multineuronal sequences during spontaneous ripples (85% of sites significant) Quotation withheld because this record is not cleared for redistribution. 3.4 times — factor by which cross-class rank correlations dropped when interneurons were excluded and only pyramidal cells were used Quotation withheld because this record is not cleared for redistribution. 156 ± 1.7°, 254 ± 6.7° — mean preferred ripple-cycle phases of pyramidal cells and interneurons, a 1.8 ms lag Quotation withheld because this record is not cleared for redistribution. 13 of 26 (50%) — induced-ripple sequences that were consistent with the spontaneous ripple sequence at the same site Quotation withheld because this record is not cleared for redistribution. 268 and 37 — pyramidal cells and interneurons recorded from four freely moving mice Quotation withheld because this record is not cleared for redistribution. 12% — share of participating units that are interneurons, which nonetheless carry the sequence Quotation withheld because this record is not cleared for redistribution. 1.8 ms — lead of pyramidal over interneuron spiking within a ripple cycle Quotation withheld because this record is not cleared for redistribution. 4.7-fold vs 1.8-fold — rate increase of pyramidal cells against interneurons during induced ripples - the signature of direct versus indirect drive Quotation withheld because this record is not cleared for redistribution. 3 and 3 — sessions with consistent and with reversed pyramidal-only sequences, out of eleven Quotation withheld because this record is not cleared for redistribution.

The full text of this article is not redistributable, so it is not included here. The evidence sentences are withheld with it; the tag layer and its grounding status remain. The article itself is at https://doi.org/10.1073/pnas.1508785112.