Inhibitory Actions Unified by Network Integration

Inhibitory Actions Unified by Network Integration Seybold Phillips Schreiner Hasenstaub

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Inhibitory Actions Unified by Network Integration 2015 Neuron 10.1016/j.neuron.2015.09.013 Seybold2015-inhibitory-actions-unified-by-network-integr Seybold2015-inhibitory-actions-unified-by-network-integr.txt, the project's staged copy 3e2032da6b9acf770588e27988938cfc36d42385 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 divisive and subtractive suppression can be assigned to particular interneuron types at all Quotation withheld because this record is not cleared for redistribution. how activating somatostatin- or parvalbumin-positive interneurons changes auditory cortical responses to tones Quotation withheld because this record is not cleared for redistribution. the suppression type specific to an interneuron class can be masked by the network it is embedded in, so the property is not a property of the class Quotation withheld because this record is not cleared for redistribution. mechanism Quotation withheld because this record is not cleared for redistribution. divisive versus subtractive cortical inhibition Quotation withheld because this record is not cleared for redistribution. electrophysiology electrophysiology Quotation withheld because this record is not cleared for redistribution. mechanisms Threshold nonlinearity in a convergent network converts the linear suppression type: suppressed inputs falling below the output neuron's spiking threshold turn subtractive inhibition of single neurons into divisive inhibition of the network, and vice versa Quotation withheld because this record is not cleared for redistribution. mechanisms Because most cortical input to a neuron is intracortical, activating interneurons changes the firing of the neuron's own converging and recurrent inputs, adding a second-order effect on top of the direct linear effect on that neuron Quotation withheld because this record is not cleared for redistribution. mechanisms Rectification of input firing rates (rates cannot go negative) makes subtractive suppression act most strongly at each input neuron's preferred frequency, which the connectivity function then passes on as a divisive-looking loss of drive at the target's best frequency Quotation withheld because this record is not cleared for redistribution. most cortical input is intracortical, so changing inhibition changes the firing of a neuron's own inputs as well as the neuron, producing effects single-neuron models do not predict Quotation withheld because this record is not cleared for redistribution. in a network model, threshold nonlinearities plus the strength of suppression of a cell's inputs determine whether the observed effect looks divisive, subtractive or both Quotation withheld because this record is not cleared for redistribution. the character of suppression in downstream neurons is set by their own thresholds and connections rather than by what happened upstream Quotation withheld because this record is not cleared for redistribution. further sources of the same masking are available: interneurons are themselves tuned and receive organised excitation, and many types inhibit one another Quotation withheld because this record is not cleared for redistribution. local subnetworks with different intrinsic or connectional properties can interpret the same inhibition differently Quotation withheld because this record is not cleared for redistribution. Both interneuron populations were driven nonselectively and with diffuse timing, unlike their natural recruitment, so type-specific functional differences may have been washed out. what this limits: what the optogenetic experiment tests: BOTH POPULATIONS OF INTERNEURONS WERE ACTIVATED IN A NONSELECTIVE AND TEMPORALLY DIFFUSE MANNER, unlike their recruitment during normal brain operation Quotation withheld because this record is not cleared for redistribution. Optogenetic stimulation parameters were not matched between the awake and anesthetized preparations. what this limits: the awake-versus-anaesthetised comparison: SOME OF THE OPTOGENETIC PARAMETERS (LIGHT STRENGTH, OPTICAL FIBER DIAMETER) WERE NOT IDENTICAL BETWEEN the two preparations Quotation withheld because this record is not cleared for redistribution. The proposed network mechanism is only one of several possible routes to the masking effect, and the paper does not exclude the others it lists. what this limits: the proposed network mechanism: THIS SECOND-ORDER EFFECT OF INHIBITORY ACTIVITY ON EXCITATORY TUNING IS MERELY ONE AMONG MANY MECHANISMS BY WHICH THIS MASKING PHENOMENON MAY EMERGE Quotation withheld because this record is not cleared for redistribution. both interneuron populations were driven nonselectively and diffusely in time, so differences arising from their natural response dynamics would not appear here what this limits: the same scope as limitations[0] - differences arising from selective recruitment cannot appear in this design Quotation withheld because this record is not cleared for redistribution. the masking mechanism demonstrated is offered as one among many rather than as the mechanism what this limits: the masking mechanism as an explanation: THIS SECOND-ORDER EFFECT OF INHIBITORY ACTIVITY ON EXCITATORY TUNING IS MERELY ONE AMONG MANY MECHANISMS BY WHICH THIS 'MASKING' PHENOMENON MAY EMERGE Quotation withheld because this record is not cleared for redistribution. the driver lines are stated to have under ten percent misexpression, which bounds but does not remove off-target activation what this limits: results reported by driver line: the lines are consistent with established expression patterns, with a stated misexpression rate that bounds rather than removes off-target labelling Quotation withheld because this record is not cleared for redistribution. the divisive/subtractive decomposition, carried from cable theory into claims about interneuron classes in intact cortex Quotation withheld because this record is not cleared for redistribution. a minimal threshold-nonlinear network used to show that the transformation between the two is possible in principle Quotation withheld because this record is not cleared for redistribution. temporal profiles of the tone response computed with and without blue-light illumination, in the same isolated single units across cortical layers eliminates: a difference between cells or sessions rather than an effect of the optogenetic manipulation - the light-off condition is the same unit, minutes apart · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. DIVISIVE and SUBTRACTIVE are defined here as parameters of a straight line fitted to suppressed against control responses - slope below one is divisive, intercept below zero is subtractive - so they are properties of a FIT, not observed categories Quotation withheld because this record is not cleared for redistribution. the framework's central question presupposes that the answer belongs to the interneuron type; this paper's result is that the question is asked at the wrong level Quotation withheld because this record is not cleared for redistribution. the anatomical prediction is precise and well founded - dendritic synapses change current without changing somatic conductance, perisomatic ones change conductance - and it is confirmed in vitro on single cells Quotation withheld because this record is not cleared for redistribution. the decisive observation is that neurons recorded AT THE SAME TIME on the same probe are suppressed in different ways, which rules out animal-to-animal and preparation variability by construction Quotation withheld because this record is not cleared for redistribution. light was set to a level that suppressed firing to about half of control in most units, so the manipulation is calibrated by its effect rather than by its intensity Quotation withheld because this record is not cleared for redistribution. claim_type: critique a second reading DIFFERING from the recorded value. Recorded: mechanism — 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: optogenetic activation of Cre-defined interneuron classes with 16-site laminar recording of tone responses, threshold-linear regression of suppressed on control responses, and a network model 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: mixtures of divisive and subtractive suppression from either interneuron class, differing between neurons recorded at the same time a second reading DIFFERING from the recorded value. Recorded: divisive versus subtractive cortical inhibition — 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. replicates → prior reports of low (<10%) misexpression in Sst-Cre and Pvalb-Cre driver lines (Cardin et al., 2009; Sohal et al., 2009; Cardin et al., 2010; Kerlin et al., 2010; Taniguchi et al., 2011; Adesnik et al., 2012; Kvitsiani et al., 2013; Pfeffer et al., 2013) Quotation withheld because this record is not cleared for redistribution. critiques → the framework in which each interneuron type is assigned a fixed divisive or subtractive function Quotation withheld because this record is not cleared for redistribution. reconciles → the apparently irreconcilable visual cortex findings about Sst and Pvalb interneuron effects Quotation withheld because this record is not cleared for redistribution. qualifies → in vitro demonstrations that somatic and dendritic inhibition suppress single pyramidal neurons divisively and subtractively Quotation withheld because this record is not cleared for redistribution. contradicts → the standard prediction that activating Pvalb and Sst interneurons implements divisive and subtractive suppression respectively Quotation withheld because this record is not cleared for redistribution. divisive —contrasted-with→ subtractive divisive subtractive strength of the relation: 1 · note: CRITERION, AND IT IS A FIT: slope of one with a negative intercept is subtractive, slope below one with a zero intercept is divisive. Both are parameters of a regression, not observations Quotation withheld because this record is not cleared for redistribution. interneuron —part-of→ network interneuron network strength of the relation: 1 · note: THE LEVEL ERROR IN ONE SENTENCE: network interactions determine the systems-level effects of neuron-level manipulations, and that is what makes the literature look contradictory Audit 2026-09-28: DOUBTFUL - read against its span and kept, but interneurons within networks; part-of is loose. Quotation withheld because this record is not cleared for redistribution. threshold —causes→ divisive threshold divisive strength of the relation: 1 · note: in the model, varying threshold and the strength of input suppression alone moves the apparent effect between divisive, subtractive and both Audit 2026-09-28: DOUBTFUL - read against its span and kept, but threshold nonlinearities can transform subtractive into divisive inhibition; causes 'divisive' is terse. Quotation withheld because this record is not cleared for redistribution. network —causes→ suppression network suppression strength of the relation: 1 · note: the character of suppression downstream is set by the downstream cell's own properties, whatever happened upstream - hence 'masked' Audit 2026-09-28: DOUBTFUL - read against its span and kept, but the span says suppression character was set by intrinsic properties and connections; causes is loose. Quotation withheld because this record is not cleared for redistribution. Sst —causes→ bandwidth Sst bandwidth strength of the relation: 1 · note: SIGN: narrowing - and by the same amount as Pvalb, so bandwidth does not separate the classes either Quotation withheld because this record is not cleared for redistribution. A1 —part-of→ auditory cortex A1 auditory cortex strength of the relation: 1 · note: identified functionally, by short latency and the tonotopic reversal, rather than by coordinates 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. Wilcoxon rank-sum test Wilcoxon rank-sum test Quotation withheld because this record is not cleared for redistribution. G-test of independence G-test of independence Quotation withheld because this record is not cleared for redistribution. bootstrap bootstrap Quotation withheld because this record is not cleared for redistribution. regression regression Quotation withheld because this record is not cleared for redistribution. t-test t-test Quotation withheld because this record is not cleared for redistribution. coefficient of determination coefficient of determination Quotation withheld because this record is not cleared for redistribution. permutation test permutation 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. confidence interval confidence interval 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. g-test g-test Quotation withheld because this record is not cleared for redistribution. rank-sum rank-sum Quotation withheld because this record is not cleared for redistribution. sign-rank sign-rank Quotation withheld because this record is not cleared for redistribution. Optogenetically activating either somatostatin- or parvalbumin-positive interneurons produced a mixture of divisive and subtractive suppression of auditory cortical tone responses, and neurons recorded at the same time were often suppressed in qualitatively different ways. Quotation withheld because this record is not cleared for redistribution. The proportions of divisive, subtractive, mixed and neither-type suppression did not differ significantly between Sst+ and Pvalb+ activation. Quotation withheld because this record is not cleared for redistribution. About half of suppressed units showed divisive-only suppression (slope below 1 with intercept not below 0), with the remainder split between subtractive-only, mixed, and neither, for both interneuron families. Quotation withheld because this record is not cleared for redistribution. A threshold-linear (slope-plus-intercept) description captured most of the variance of suppression for both interneuron types, so the suppression of individual neurons was well described as a linear transformation. Quotation withheld because this record is not cleared for redistribution. Bandwidth changes did not differ between activating Sst+ and Pvalb+ interneurons. Quotation withheld because this record is not cleared for redistribution. Neurons within one cortical column are not equally affected by broad interneuron activation. Quotation withheld because this record is not cleared for redistribution. In the network model, both divisive and subtractive suppression at single cells can produce divisive-like suppression of the net drive to a downstream neuron. Quotation withheld because this record is not cleared for redistribution. In the model, a downstream neuron's suppression type was set by its own intrinsic properties and connections, regardless of whether its inputs were suppressed divisively or subtractively. Quotation withheld because this record is not cleared for redistribution. activating either interneuron class produced mixtures of divisive and subtractive suppression rather than one or the other Quotation withheld because this record is not cleared for redistribution. the proportions of suppression types did not differ between the two classes, g-test p = 0.54 Quotation withheld because this record is not cleared for redistribution. a linear framework accounted for a high proportion of the variance of suppression in both strains Quotation withheld because this record is not cleared for redistribution. both classes narrowed frequency tuning bandwidths, and the distributions of change did not differ Quotation withheld because this record is not cleared for redistribution. THE DECISIVE OBSERVATION: neurons recorded simultaneously on one probe were suppressed in uncorrelated ways Quotation withheld because this record is not cleared for redistribution. which rules out preparation and animal-to-animal variability, and the same was seen in awake animals Quotation withheld because this record is not cleared for redistribution. all four suppression types appeared for both classes in awake mice too, again with no difference in proportions Quotation withheld because this record is not cleared for redistribution. THE PREDICTION THAT FAILED: from synapse location and morphology, the standard prediction is that Pvalb+ activation divides and Sst+ activation subtracts Quotation withheld because this record is not cleared for redistribution. the proposed explanation is that most cortical input is intracortical, so inhibition changes a neuron's inputs as well as the neuron Quotation withheld because this record is not cleared for redistribution. and a network model shows that varying only threshold and input suppression strength moves the apparent effect between divisive and subtractive Quotation withheld because this record is not cleared for redistribution. so a class's characteristic suppression can be MASKED by the network it sits in Quotation withheld because this record is not cleared for redistribution. this reconciles the in vitro clarity with the in vivo mixture rather than treating the discrepancy as a problem Quotation withheld because this record is not cleared for redistribution. the visual cortex literature contains every combination of the two assignments, described as apparently irreconcilable Quotation withheld because this record is not cleared for redistribution. the same masking should appear in any network of appreciable complexity, and several further routes to it are named Quotation withheld because this record is not cleared for redistribution. local subnetworks can interpret the same inhibition differently even inside one global network Quotation withheld because this record is not cleared for redistribution. anaesthetised and awake preparations agreed despite differing optogenetic parameters, suggesting the masking is robust Quotation withheld because this record is not cleared for redistribution. SCOPE STATED: both populations were driven nonselectively and diffusely in time, so natural differences in their dynamics could not show up Quotation withheld because this record is not cleared for redistribution. light was set near 40 microwatts, which suppressed firing to about half of control in most units Quotation withheld because this record is not cleared for redistribution. somatostatin cells are about a quarter of cortical interneurons and target mainly distal dendrites Quotation withheld because this record is not cleared for redistribution. Pvalb is expressed in roughly ~50% of cortical inhibitory interneurons, including subtypes whose axons form baskets around the soma or chandeliers on the axon initial segment Quotation withheld because this record is not cleared for redistribution. subtractive suppression subtractive suppression Quotation withheld because this record is not cleared for redistribution. divisive suppression divisive suppression Quotation withheld because this record is not cleared for redistribution. iceberging iceberging Quotation withheld because this record is not cleared for redistribution. divisive divisive Quotation withheld because this record is not cleared for redistribution. subtractive subtractive Quotation withheld because this record is not cleared for redistribution. A1 A1 Quotation withheld because this record is not cleared for redistribution. divisively suppressed neuron divisively suppressed neuron Quotation withheld because this record is not cleared for redistribution. subtractively suppressed neuron subtractively suppressed neuron Quotation withheld because this record is not cleared for redistribution. firing rate over time firing rate over time Quotation withheld because this record is not cleared for redistribution. suppression suppression Quotation withheld because this record is not cleared for redistribution. bandwidth bandwidth Quotation withheld because this record is not cleared for redistribution. threshold threshold Quotation withheld because this record is not cleared for redistribution. regression slope regression slope Quotation withheld because this record is not cleared for redistribution. y-intercept y-intercept Quotation withheld because this record is not cleared for redistribution. g-test p = 0.54 — No detectable difference between Sst+ and Pvalb+ activation in the proportions of divisive, subtractive, mixed and neither suppression types (anesthetized mice) Quotation withheld because this record is not cleared for redistribution. n = 35 of 76 units; n = 27 of 63 units — Number of light-suppressed units showing divisive-only suppression, in Sst-ChR2 and Pvalb-ChR2 mice respectively Quotation withheld because this record is not cleared for redistribution. n = 145 of 250 / n = 91 of 154 — Number of recorded single units that were tone-responsive in the Sst and Pvalb mouse lines Quotation withheld because this record is not cleared for redistribution. median r 2 = 0.73 ± 0.17 / 0.81 ± 0.17 — Median quality of the linear (threshold-linear) fit to suppression in awake Sst and Pvalb mice Quotation withheld because this record is not cleared for redistribution. rank-sum p = 0.63 — No difference between Sst+ and Pvalb+ activation in the distribution of bandwidth changes Quotation withheld because this record is not cleared for redistribution. 40 µW / 50% / 65%–75% — Light power used in anesthetized recordings, the typical degree of firing suppression it produced, and the fraction of units so suppressed Quotation withheld because this record is not cleared for redistribution. g-test p = 0.54 — the null on which the whole argument turns: suppression-type proportions did not differ between classes Quotation withheld because this record is not cleared for redistribution. roughly 25% — share of cortical interneurons expressing somatostatin Quotation withheld because this record is not cleared for redistribution. ~50% — share expressing parvalbumin Quotation withheld because this record is not cleared for redistribution. near 40 µW — light power, chosen to suppress firing to about half of control Quotation withheld because this record is not cleared for redistribution. <10% — misexpression in the driver lines, the bound on off-target activation WHOSE RESULT THIS IS: Pfeffer et al., 2013 ) who found - THE EVIDENCE FOR THIS ROW ATTRIBUTES THE WORK TO SOMEBODY ELSE. The cited name is the subject of a result verb and the sentence carries no first-person marker, so the finding, quantity or definition is the CITED author's rather than this record's. The claim is true and the quote is verbatim - what is wrong is whose result the corpus says it is. Nothing edited, nothing withdrawn: the row is marked so a page can name the source. Where the record is a commentary or review, its claim relations layer usually already names the paper being discussed - the record knows at one layer and forgets at another. 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/10.1016/j.neuron.2015.09.013.