Cortical interneurons that specialize in disinhibitory control

Cortical interneurons that specialize in disinhibitory control Pi Hangya Kvitsiani Sanders Huang Kepecs

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Cortical interneurons that specialize in disinhibitory control 2013 Nature 10.1038/nature12676 Pi2013-cortical-interneurons-that-specialize-in-dis Pi2013-cortical-interneurons-that-specialize-in-dis.txt, the project's staged copy 521da0a300556390fed897862bf2e3d2eb5f92d5 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 VIP-expressing cortical interneurons and the disinhibitory circuit they form Quotation withheld because this record is not cleared for redistribution. whether a specific interneuron type mediates disinhibition in vivo, and under what behavioural conditions it is recruited Quotation withheld because this record is not cleared for redistribution. maps one circuit function onto one molecularly defined cell type in two cortical areas, and identifies reinforcement feedback as the condition that recruits it Quotation withheld because this record is not cleared for redistribution. mechanism Quotation withheld because this record is not cleared for redistribution. cortical disinhibition by VIP interneurons Quotation withheld because this record is not cleared for redistribution. electrophysiology electrophysiology Quotation withheld because this record is not cleared for redistribution. mechanisms Light-driven VIP firing inhibits other interneurons, which releases a subset of pyramidal cells from inhibition — an excitation-inhibition-excitation sequence that is the signature of disinhibition. Quotation withheld because this record is not cleared for redistribution. mechanisms Long-range or neuromodulatory inputs recruit VIP cells, and the resulting disinhibition selectively raises the gain of particular pyramidal ensembles. status: the paper's own words: we propose that Quotation withheld because this record is not cleared for redistribution. mechanisms Because the disinhibition lands preferentially on tone-selective neurons, relaying the reinforcement signal through VIP cells could implement cortical learning. Quotation withheld because this record is not cleared for redistribution. mechanisms The same disinhibitory microcircuit appears in two cytoarchitectonically different areas, so it is proposed to be a repeated neocortical motif. Quotation withheld because this record is not cleared for redistribution. the excitation-inhibition-excitation sequence after a light pulse is read as the signature of disinhibition: VIP cells inhibit other interneurons, releasing pyramidal cells Quotation withheld because this record is not cleared for redistribution. VIP cells inhibit a large fraction of Som interneurons and a smaller fraction of Pv interneurons, with different decay constants and depression Quotation withheld because this record is not cleared for redistribution. pyramidal neurons are only a minor monosynaptic target, so the effect on them is indirect Quotation withheld because this record is not cleared for redistribution. the disinhibited population is functionally specific - biased toward tone-responsive, frequency-tuned cells Quotation withheld because this record is not cleared for redistribution. inhibited cells show divisive gain modulation while delayed-activated cells show an additive baseline shift Quotation withheld because this record is not cleared for redistribution. VIP cells are proposed as the substrate by which long-range or neuromodulatory signals raise the gain of specific pyramidal ensembles Quotation withheld because this record is not cleared for redistribution. cell identity in vivo is inferred from spike width and firing rate, then confirmed in vitro with genetic labels and by c-Fos with a pyramidal marker Quotation withheld because this record is not cleared for redistribution. How far this circuit overlaps with the previously described layer 1 disinhibitory circuit is undetermined. what this limits: the relation to the layer 1 circuit: THE EXTENT TO WHICH THESE TWO DISINHIBITORY CIRCUITS OVERLAP REMAINS TO BE DETERMINED, AS ONLY A FRACTION OF LAYER 1 INTERNEURONS EXPRESS VIP Quotation withheld because this record is not cleared for redistribution. The experimenter could not be fully blinded. what this limits: every effect measured in these experiments: CONDUCTING THE EXPERIMENTS REQUIRED MONITORING THE EFFECT OF VIP-PHOTOSTIMULATION ON MULTIUNIT ACTIVITY; THEREFORE, IT WAS NOT POSSIBLE TO FULLY BLIND THE EXPERIMENTER Quotation withheld because this record is not cleared for redistribution. The immunohistochemical estimate of VIP expression specificity and efficiency is not a gold-standard measure. what this limits: the VIP expression specificity figures: IMMUNOHISTOCHEMISTRY IS NOT CONSIDERED A GOLD STANDARD METHOD FOR ASSESSING GENE EXPRESSION, SINCE BOTH ITS SPECIFICITY AND SENSITIVITY DEPENDS ON EXTERNAL factors Quotation withheld because this record is not cleared for redistribution. the experimenter could not be fully blinded, because finding the effect was necessary to position the electrodes; disclosed with its mitigation what this limits: the same scope as limitations[1], with the mitigation: THIS INFORMATION WAS ONLY USED TO GUIDE DECISIONS ABOUT electrode placement Quotation withheld because this record is not cleared for redistribution. immunohistochemistry, used to estimate the specificity of VIP labelling, is stated by the authors not to be a gold standard for gene expression what this limits: the same scope as limitations[2] - the specificity estimate rests on a non-gold-standard assay Quotation withheld because this record is not cleared for redistribution. the exclusion thresholds were relaxed for VIP cells specifically, using light-evoked waveform correlation instead what this limits: the VIP unit sample: SOME OF THE VIP NEURONS DID NOT REACH THE THRESHOLD OF ISOLATION DISTANCE AND L-RATIO. FOR THESE NEURONS, WE EXPLOITED THE WAVEFORM INFORMATION CARRIED BY LIGHT-EVOKED ACTION POTENTIALS Quotation withheld because this record is not cleared for redistribution. analysis windows differed between the two recorded areas, chosen from the observed response latencies what this limits: any comparison of latencies or firing between the two areas: the analysis windows were set separately for each, from the observed response latencies Quotation withheld because this record is not cleared for redistribution. datasets were pooled across layers and areas on the strength of null results rather than demonstrated equivalence what this limits: every pooled result: THERE WAS NO SIGNIFICANT DIFFERENCES IN IPSC AMPLITUDE AND FRACTION OF RESPONDED NEURONS IN DIFFERENT CORTICAL LAYERS AND THE RESULTS WERE COMBINED - pooling on a null, not on demonstrated equivalence Quotation withheld because this record is not cleared for redistribution. the difference in VIP yield between the two areas is attributed to delivery method rather than biology what this limits: the ACx-versus-mPFC yield comparison: THE DIFFERENCE IN THE RELATIVE PROPORTION OF RECORDED VIP NEURONS IN ACx AND mPFC IS LIKELY DUE TO TECHNICAL REASONS - ChR2 WAS DELIVERED VIRALLY INTO mPFC, WHEREAS WE USED A REPORTER LINE (Ai32) FOR ACx Quotation withheld because this record is not cleared for redistribution. the overlap between this circuit and the layer 1 disinhibitory circuit is left undetermined duplicate of: limitations[0] · what this limits: the same scope as limitations[0] - the overlap with the layer 1 circuit is undetermined Quotation withheld because this record is not cleared for redistribution. synchronous optogenetic activation is defended as physiologically plausible by appeal to the homogeneity of the natural response, which is an argument rather than a control what this limits: the synchronous-activation method: THE HOMOGENEOUS BEHAVIOURAL RECRUITMENT OF VIPs SUGGESTS THAT THE SYNCHRONOUS ChR2-MEDIATED ACTIVATION TO PROBE THEIR CIRCUIT FUNCTION WAS PHYSIOLOGICALLY PLAUSIBLE - the plausibility rests on that homogeneity Quotation withheld because this record is not cleared for redistribution. gating and gain modulation as the functions a disinhibitory motif could serve Quotation withheld because this record is not cleared for redistribution. Bayesian information criterion used to choose between additive, divisive and combined descriptions of a tuning-curve change Quotation withheld because this record is not cleared for redistribution. ChR2 expression time held constant and comparable at 4 to 6 weeks across the two mouse lines eliminates: a difference between the lines that is really a difference in how long the opsin had to express - more expression means more current, whatever the cell type does · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. disinhibition here is a specific circuit motif - inhibitory cells targeting other inhibitory cells - not a general loosening of inhibition Quotation withheld because this record is not cleared for redistribution. VIP names a molecular marker used as a cell class; the paper's whole argument is that a marker-defined population has a single circuit function Quotation withheld because this record is not cleared for redistribution. Pv identity in the in vivo data is a PROXY: inferred from narrow spike width and high firing rate, hedged as many but not all and usually Quotation withheld because this record is not cleared for redistribution. gain modulation is split into two distinguishable senses here - divisive (multiplying the tuning curve) versus an additive baseline shift - and the two populations show different ones Quotation withheld because this record is not cleared for redistribution. impact and recruitment are coined by this paper as the two directions of a cell type's role: what it drives, and what drives it Quotation withheld because this record is not cleared for redistribution. SDF, PSTH and PETH are used for the same computed object in this paper, with the renaming declared in the text 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: optogenetic tagging with ChR2 in VIP-Cre mice, tetrode recording in awake mice, slice recording from genetically labelled Som and Pv cells, and an auditory go/no-go task 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: disinhibition - inhibitory neurons that suppress other inhibitory neurons, amplifying local processing a second reading DIFFERING from the recorded value. Recorded: cortical disinhibition by VIP interneurons — 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. extends → previous connectivity-based proposals that VIP interneurons provide disinhibitory control (refs 10-12) Quotation withheld because this record is not cleared for redistribution. confirms → connectivity-based proposals that VIP interneurons specialise in targeting other interneurons Quotation withheld because this record is not cleared for redistribution. extends → the layer 1 disinhibitory circuit enabling associative learning status: the paper's own words: remains to be determined Quotation withheld because this record is not cleared for redistribution. qualifies → the additive account of how VIP activation changes tuning curves Quotation withheld because this record is not cleared for redistribution. supports → the view that different interneuron types perform distinct circuit operations Quotation withheld because this record is not cleared for redistribution. generalises → the disinhibitory motif across cytoarchitectonically different cortical areas Quotation withheld because this record is not cleared for redistribution. VIP interneurons —causes→ Som VIP interneurons Som strength of the relation: 0.95 · note: inhibits: elicited IPSCs from a large fraction Quotation withheld because this record is not cleared for redistribution. VIP interneurons —causes→ Pv VIP interneurons Pv strength of the relation: 0.7 · note: a smaller fraction; the weight carries the difference from the Som connection Quotation withheld because this record is not cleared for redistribution. fast-spiking interneurons —operationalised-as→ Pv fast-spiking interneurons Pv strength of the relation: 0.75 · note: backwards-looking: spike width and rate are the in vivo PROXY for Pv identity, hedged as many but not all and usually Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but fast-spiking interneurons are 'USUALLY expressing' parvalbumin; operationalised-as is loose. Quotation withheld because this record is not cleared for redistribution. divisive gain modulation —contrasted-with→ baseline firing rate divisive gain modulation baseline firing rate differs in: THE AXIS IS MULTIPLICATIVE SCALING VERSUS ADDITIVE OFFSET. 'one-parameter gain modulation models (additive or multiplicative) fitted the light-induced changes in average tuning curves: THE INHIBITED POPULATION SHOWED DIVISIVE GAIN MODULATION, WHEREAS THE CHANGE IN DELAYED ACTIVATED NEURONS WAS CONSISTENT WITH AN ADDITIVE SHIFT OF THE BASELINE FIRING RATE.' Both populations change their firing under the same manipulation; they differ on WHICH PARAMETER OF THE TUNING CURVE moves, which is the distinction the one-parameter models were fitted to decide. · strength of the relation: 1 · note: the two one-parameter models, and the two populations show different ones Quotation withheld because this record is not cleared for redistribution. adaptive spike density function —same-as→ PSTH adaptive spike density function PSTH strength of the relation: 1 · note: a synonymy DECLARED by the authors for this paper - termed ... and abbreviated ... hereinafter. locally true by stipulation; SDF and PSTH are not generally the same object. Quotation withheld because this record is not cleared for redistribution. VIP interneurons —operationalised-as→ disinhibition VIP interneurons disinhibition strength of the relation: 0.9 · note: the paper's central move: one circuit function mapped onto one molecularly defined cell type Audit 2026-09-28: DOUBTFUL - read against its span and kept, but the span maps disinhibitory control onto VIP cells; operationalised-as is loose. 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. statistical-significance statistical-significance Quotation withheld because this record is not cleared for redistribution. t-test t-test Quotation withheld because this record is not cleared for redistribution. t-test t-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. Bayesian information criterion Bayesian information criterion Quotation withheld because this record is not cleared for redistribution. normality test normality test Quotation withheld because this record is not cleared for redistribution. mean mean Quotation withheld because this record is not cleared for redistribution. confidence interval confidence interval Quotation withheld because this record is not cleared for redistribution. bootstrap bootstrap Quotation withheld because this record is not cleared for redistribution. nonlinear least-squares curve fitting nonlinear least-squares curve fitting Quotation withheld because this record is not cleared for redistribution. correlation correlation 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. Bayesian information criterion Bayesian information criterion 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. isolation distance and L-ratio isolation distance and L-ratio Quotation withheld because this record is not cleared for redistribution. VIP-expressing interneurons carry out disinhibitory control across several neocortical areas and are switched on by reinforcement signals. Quotation withheld because this record is not cleared for redistribution. The circuit module is VIP activation transiently suppressing somatostatin interneurons and a subset of parvalbumin interneurons, which respectively control principal-cell input and output. Quotation withheld because this record is not cleared for redistribution. Only a small fraction of pyramidal neurons responded to VIP activation, suggesting they are a minor monosynaptic target of VIP cells. Quotation withheld because this record is not cleared for redistribution. VIP-evoked IPSCs in parvalbumin cells decay about three times faster than in somatostatin cells and depress more strongly with repeated stimulation. Quotation withheld because this record is not cleared for redistribution. Eight percent of c-Fos-positive neurons expressed VIP; the rest expressed the pyramidal marker CaMKIIα. Quotation withheld because this record is not cleared for redistribution. The disinhibited cells in auditory cortex are not random: they are preferentially the tone-responsive, frequency-tuned neurons. Quotation withheld because this record is not cleared for redistribution. VIP stimulation changes tuning curves in two different ways: divisively scaling down the inhibited cells and additively raising the baseline of the delayed-activated cells. Quotation withheld because this record is not cleared for redistribution. In every VIP neuron, punishment (air puff or foot shock) evoked strong phasic activation at short latency. Quotation withheld because this record is not cleared for redistribution. VIP neurons respond to reinforcement uniformly as a class, unlike the heterogeneous responses of the surrounding cortical population. Quotation withheld because this record is not cleared for redistribution. The study maps a specific circuit operation, disinhibition, onto a genetically defined cell type. Quotation withheld because this record is not cleared for redistribution. an excitation-inhibition-excitation sequence appears in two functionally different cortical areas Quotation withheld because this record is not cleared for redistribution. first in vivo demonstration of cell-type-specific disinhibition Quotation withheld because this record is not cleared for redistribution. VIP activation elicited IPSCs in a large fraction of Som interneurons Quotation withheld because this record is not cleared for redistribution. pyramidal cells are only a minor direct target of VIP cells Quotation withheld because this record is not cleared for redistribution. the disinhibited cells are disproportionately tone-responsive and frequency-tuned Quotation withheld because this record is not cleared for redistribution. punishment activates every recorded VIP neuron at short latency, and two different punishments do the same Quotation withheld because this record is not cleared for redistribution. VIP cells respond in unison where the rest of the population responds heterogeneously Quotation withheld because this record is not cleared for redistribution. the divisive gain model beat a baseline shift plus threshold in 22 of 25 inhibited neurons Quotation withheld because this record is not cleared for redistribution. disinhibitory control disinhibitory control Quotation withheld because this record is not cleared for redistribution. tone-responsive neuron tone-responsive neuron Quotation withheld because this record is not cleared for redistribution. adaptive spike density function adaptive spike density function Quotation withheld because this record is not cleared for redistribution. tone-selectivity tone-selectivity Quotation withheld because this record is not cleared for redistribution. ΔResponse ΔResponse Quotation withheld because this record is not cleared for redistribution. disinhibition disinhibition Quotation withheld because this record is not cleared for redistribution. narrow spiking narrow spiking Quotation withheld because this record is not cleared for redistribution. impact impact Quotation withheld because this record is not cleared for redistribution. recruitment recruitment Quotation withheld because this record is not cleared for redistribution. light-induced changes of firing rate light-induced changes of firing rate Quotation withheld because this record is not cleared for redistribution. IPSCs IPSCs Quotation withheld because this record is not cleared for redistribution. ChR2 expression time ChR2 expression time Quotation withheld because this record is not cleared for redistribution. movement bouts movement bouts Quotation withheld because this record is not cleared for redistribution. spike width spike width Quotation withheld because this record is not cleared for redistribution. decay time constant decay time constant Quotation withheld because this record is not cleared for redistribution. ~20% — proportion of recorded cortical cells whose firing rate changed significantly after a single 1 ms VIP light pulse Quotation withheld because this record is not cleared for redistribution. ~10% — share of all cortical interneurons that express VIP Quotation withheld because this record is not cleared for redistribution. 98/343 — single units in awake auditory cortex that could be classified into one of the three light-response groups Quotation withheld because this record is not cleared for redistribution. 5-fold — increase in c-Fos expression in mPFC after VIP photostimulation relative to controls Quotation withheld because this record is not cleared for redistribution. 28/46, 61% — share of delayed-activated neurons that were tone-responsive, versus 29% in the whole population Quotation withheld because this record is not cleared for redistribution. Som: 18±2ms, Pv: 6±1ms — IPSC decay time constants in somatostatin versus parvalbumin interneurons Quotation withheld because this record is not cleared for redistribution. 50±12ms — latency of the peak VIP response to punishment Quotation withheld because this record is not cleared for redistribution. 22 out of 25 neurons — inhibited cells for which the divisive activity-gain model fit better than a baseline shift with threshold Quotation withheld because this record is not cleared for redistribution. NS, 39.0±10.0 ms; WS, 86.5±7.6 ms — offset of light-induced suppression in narrow-spiking versus wide-spiking neurons Quotation withheld because this record is not cleared for redistribution. VIP is about 10% of interneurons and 1-2% of cortical neurons — the size of the population 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 ('interneurons (1–2% of cortical neurons 19 , 20 ) resulted…'). Quotation withheld because this record is not cleared for redistribution. EVIDENCE CORRECTED (RE-GROUNDED - THE POINTER WAS WRONG, NOT THE CLAIM) · ACx 130/495 and mPFC 26/155 cells changed firing — the breadth of the effect EVIDENCE CORRECTED: RE-GROUNDED - THE POINTER WAS WRONG, NOT THE CLAIM. The old evidence was verbatim, anchored and correctly cut, and it contained NONE of this claim's numbers (130, 155, 26, 495). The paper states the claim in one sentence elsewhere and the tagger did not use it. the project, 2026-08-23: 'WE HAVE SPENT THE DAY VERIFYING THAT QUOTES ARE REAL AND NONE OF IT ASKS WHETHER THEY ARE RELEVANT.' Confirmed by reading the claim, the old span and the candidate together; the candidate carries every number AND the claim's own content words. Quotation withheld because this record is not cleared for redistribution. Som decay 18 plus or minus 2 ms, Pv decay 6 plus or minus 1 ms — IPSC kinetics distinguishing the two targets Quotation withheld because this record is not cleared for redistribution. 275 microseconds — the stipulated spike-width cut between narrow and wide spiking Quotation withheld because this record is not cleared for redistribution. isolation distance < 20 or L-ratio > 0.1 — the exclusion thresholds Quotation withheld because this record is not cleared for redistribution. 5-fold — increase in c-Fos after VIP photostimulation Quotation withheld because this record is not cleared for redistribution. 40 of 43 neurons — unaffected by movement bouts, the control for head-restraint movement Quotation withheld because this record is not cleared for redistribution. BIC -399.6, -398.3 and -354.7 — combined, divisive and baseline-shift models for the inhibited group 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/10.1038/nature12676.