Opening Holes in the Blanket of Inhibition: Localized Lateral Disinhibition by VIP Interneurons

Opening Holes in the Blanket of Inhibition: Localized Lateral Disinhibition by VIP Interneurons Karnani Jackson Ayzenshtat Hamzehei Sichani Manoocheri Kim Yuste

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Opening Holes in the Blanket of Inhibition: Localized Lateral Disinhibition by VIP Interneurons 2016 The Journal of Neuroscience 10.1523/jneurosci.3646-15.2016 Karnani2016-opening-holes-in-the-blanket-of-inhibition-l Karnani2016-opening-holes-in-the-blanket-of-inhibition-l.txt, the project's staged copy ba3f755e392e443392a98d2420927379cac415e3 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 spatial extent over which a single VIP interneuron disinhibits the surrounding cortical network Quotation withheld because this record is not cleared for redistribution. how excitatory activity can propagate at all through a cortex covered by blanket inhibition Quotation withheld because this record is not cleared for redistribution. measures the disinhibitory reach of a single VIP cell by four independent methods and converges on about 120 microns, giving the blanket-of-inhibition problem a quantitative answer Quotation withheld because this record is not cleared for redistribution. mechanism Quotation withheld because this record is not cleared for redistribution. localized lateral 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 A VIP cell inhibits nearby SOM cells, which removes the SOM-mediated blanket inhibition on local pyramidal cells and thereby lets excitation spread through that patch. Quotation withheld because this record is not cleared for redistribution. mechanisms The horizontally narrow VIP axon confines the disinhibitory action to a small cylindrical volume of cortex, setting the size of the hole. Quotation withheld because this record is not cleared for redistribution. mechanisms During locomotion many VIPs are recruited at once, so the disinhibition from any single stimulated VIP is swamped and loses its spatial structure. Quotation withheld because this record is not cleared for redistribution. the problem: SOM, PV and chandelier cells inhibit most or all pyramidal cells within their axonal arbors, which in principle should stop excitation propagating at all Quotation withheld because this record is not cleared for redistribution. the interneuron population looks designed to block both fast and slow excitatory activity, since PV and SOM are driven by fast and slow inputs respectively Quotation withheld because this record is not cleared for redistribution. VIP cells inhibit nearby SOM cells, and SOM cells inhibit pyramidal cells, so activating one VIP opens a local hole in the inhibitory blanket Quotation withheld because this record is not cleared for redistribution. two-photon spiral scanning excites one targeted VIP and not its neighbours, which is what makes single-cell activation possible Quotation withheld because this record is not cleared for redistribution. the disinhibitory effect requires concurrent sensory drive - there must be activity for the hole to admit Quotation withheld because this record is not cleared for redistribution. two possible regimes: single VIPs opening tiny patches, or a few nearby VIPs together opening larger ones Quotation withheld because this record is not cleared for redistribution. All recordings came from layer 2/3, so the conclusions do not necessarily hold for deeper layers. what this limits: every conclusion in the paper, by layer: AS ALL OUR RECORDINGS WERE FROM LAYER 2/3, THEY ONLY APPLY THERE, and VIPs MAY MEDIATE QUALITATIVELY DIFFERENT EFFECTS IN THE DEEPER LAYERS Quotation withheld because this record is not cleared for redistribution. Slice measurements of spatial reach may underestimate the true extent because processes are cut. what this limits: the spatial-reach measurement: OUR IN VITRO RESULTS MAY BE UNDERESTIMATES DUE TO THE INEVITABILITY OF CUT PROCESSES IN BRAIN SLICES Quotation withheld because this record is not cleared for redistribution. The correlational in vivo data are directionally ambiguous: nearby cells could be driving the VIPs rather than the reverse. what this limits: the direction of the in vivo effect: the results are consistent with VIPs disinhibiting nearby cortex BUT MIGHT EQUALLY ARISE FROM the nearby cells driving the VIPs Quotation withheld because this record is not cleared for redistribution. all recordings are from layer 2/3 and the authors say the conclusions only apply there what this limits: the same scope as limitations[0] - layer 2/3 only Quotation withheld because this record is not cleared for redistribution. slice results may underestimate the reach because processes are cut what this limits: the same scope as limitations[1] - cut processes underestimate reach Quotation withheld because this record is not cleared for redistribution. the correlational results could equally reflect nearby cells driving the VIPs rather than the reverse, which is why the optogenetic experiment was needed duplicate of: limitations[2] · what this limits: the same scope as limitations[2] - the correlation does not fix the direction Quotation withheld because this record is not cleared for redistribution. during locomotion the spatial structure disappears, attributed to many more VIPs being recruited what this limits: the spatial-structure result outside quiescence: DURING LOCOMOTION EPOCHS THE DISTANCE DEPENDENCE WAS SCRAMBLED, attributed to recruitment of many more VIPs Quotation withheld because this record is not cleared for redistribution. six cells were inhibited rather than disinhibited and were set aside as under 1% of the sample what this limits: the completeness of the disinhibition account: BECAUSE THE INHIBITED CELLS FORMED <1% OF ALL CELLS, WE DID NOT ANALYZE THEM FURTHER, THOUGH WE NOTE THEY MAY BE SOMS - cells that behaved oppositely were set aside Quotation withheld because this record is not cleared for redistribution. the requirement for sensory stimulation is supported by data not shown what this limits: the stated requirement for sensory stimulation: it WAS REQUIRED FOR SEEING THE DISINHIBITORY EFFECT OF SINGLE VIP ACTIVATION (DATA NOT SHOWN) - the condition for the central effect rests on data not in the paper Quotation withheld because this record is not cleared for redistribution. the spotlight metaphor, imported as the functional interpretation of a local disinhibitory hole Quotation withheld because this record is not cleared for redistribution. attractors, offered as what selectively sculpted circuits might implement Quotation withheld because this record is not cleared for redistribution. the same analysis re-run triggering on the other cells, mostly pyramidal cells, instead of the original trigger cells eliminates: a result that follows from which cell was chosen as the trigger rather than from the population structure · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. blanket of inhibition is the specific claim that SOM, PV and chandelier cells inhibit most or all pyramidal cells within their arbors indiscriminately - it is what makes disinhibition necessary rather than merely available Quotation withheld because this record is not cleared for redistribution. the hole is measured four different ways - axon extent, paired connectivity, activity correlation, and single-cell optogenetics - and reported as a radius of about 120 microns, equivalently a diameter of about 240 Quotation withheld because this record is not cleared for redistribution. spotlight of attention is used as an analogy for what a local disinhibitory hole could implement, not as a claim that it does Quotation withheld because this record is not cleared for redistribution. disinhibited is defined operationally as a visual response increasing by more than two standard deviations during VIP activation 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: two-photon optogenetic activation of individual VIP cells with C1V1 during calcium imaging in vivo, plus paired slice recordings and morphological reconstruction 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: lateral disinhibition in neocortex a second reading DIFFERING from the recorded value. Recorded: localized lateral 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 → Kapfer et al. (2007), Silberberg and Markram (2007) and Murayama et al. (2009) on SOM-mediated frequency-dependent disynaptic inhibition Quotation withheld because this record is not cleared for redistribution. replicates → Zhang et al. (2014) on the uniquely localized disinhibitory effect of VIP cells Quotation withheld because this record is not cleared for redistribution. extends → Pi et al. 2013 and Fu et al. 2014 on the VIP to SOM disinhibitory motif - both independently tagged in this corpus Quotation withheld because this record is not cleared for redistribution. supports → Zhang et al., who also found VIPs uniquely localised with a radius under 200 microns Quotation withheld because this record is not cleared for redistribution. supports → morphological reports that VIP axons are horizontally restricted Quotation withheld because this record is not cleared for redistribution. extends → Fu et al. 2014 on locomotion driving VIP activity, by showing the spatial structure is lost in that state Quotation withheld because this record is not cleared for redistribution. VIP —causes→ SOM VIP SOM strength of the relation: 0.95 · note: inhibits. same edge as Fu2014 and Pi2013 - three corpus papers now carry it, from three labs Quotation withheld because this record is not cleared for redistribution. SOM —causes→ pyramidal cells SOM pyramidal cells strength of the relation: 0.95 Quotation withheld because this record is not cleared for redistribution. VIP —operationalised-as→ spotlight of attention VIP spotlight of attention strength of the relation: 0.4 — the record marks this weak · note: explicitly an analogy - may therefore enable. the low weight carries that this is offered, not shown Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but VIP interneurons 'MAY' enable propagation by generating a spotlight of attention; operationalised-as is loose and hedged. Quotation withheld because this record is not cleared for redistribution. SOM —operationalised-as→ lateral inhibition SOM lateral inhibition status: ATTRIBUTED, NOT MEASURED HERE: the span reports what the field holds - 'disynaptic lateral inhibition between nearby pyramidal cells' 'Quotation withheld' - with three citations (Kapfer et al. 2007; Silberberg and Markram 2007; Adesnik et al. 2012). This paper's own title is 'Opening holes in the blanket of inhibition', so the received account is the thing it goes on to complicate. · strength of the relation: 0.9 · 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 lateral inhibition 'IS THOUGHT TO work through' SOMs - a mechanism; operationalised-as is loose. Quotation withheld because this record is not cleared for redistribution. rank sum test rank sum test 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. t-test t-test Quotation withheld because this record is not cleared for redistribution. correlation correlation Quotation withheld because this record is not cleared for redistribution. z-test z-test Quotation withheld because this record is not cleared for redistribution. standard deviation standard deviation 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. rank sum test rank sum test Quotation withheld because this record is not cleared for redistribution. Z test against zero by distance bin Z test against zero by distance bin Quotation withheld because this record is not cleared for redistribution. pairwise Pearson correlation against intersomatic distance pairwise Pearson correlation against intersomatic distance Quotation withheld because this record is not cleared for redistribution. Optogenetically silencing SOM interneurons abolished the disynaptic inhibition between paired pyramidal cells, giving direct loss-of-function evidence that SOMs mediate lateral inhibition. Quotation withheld because this record is not cleared for redistribution. Activating VIP interneurons during the presynaptic spike train also blocked the disynaptic inhibition, showing VIPs can veto lateral inhibition. Quotation withheld because this record is not cleared for redistribution. Reconstructed VIP axons were narrower than SOM or PV axons and descended away from the pia. Quotation withheld because this record is not cleared for redistribution. SOMs postsynaptic to a VIP were significantly closer to it than unconnected SOMs, so VIP inhibitory output is spatially restricted. Quotation withheld because this record is not cleared for redistribution. Two-photon activation of a single VIP in vivo disinhibited visual responses selectively in cells near the stimulated VIP. Quotation withheld because this record is not cleared for redistribution. The disinhibitory reach of one VIP cell measured about 120 μm in radius, i.e. a hole roughly 240 μm across. Quotation withheld because this record is not cleared for redistribution. Spontaneous VIP activity was closely tied to activity within a 50 um radius, whereas pyramidal-cell activity showed only weak distance dependence. Quotation withheld because this record is not cleared for redistribution. The spatial localization of the single-VIP effect disappeared during locomotion. Quotation withheld because this record is not cleared for redistribution. disinhibited cells sat significantly closer to the activated VIP than cells in general, 66 against 101 microns Quotation withheld because this record is not cleared for redistribution. the effective disinhibitory radius of a single VIP is about 120 microns Quotation withheld because this record is not cleared for redistribution. equivalently, VIPs open holes of about 240 microns diameter in the SOM blanket Quotation withheld because this record is not cleared for redistribution. connected VIP-SOM pairs sat closer together than unconnected ones, 112 against 163 microns Quotation withheld because this record is not cleared for redistribution. 33 of 638 cells were disinhibited and 6 were inhibited by single-VIP activation Quotation withheld because this record is not cleared for redistribution. the spatial structure of the effect disappears during locomotion Quotation withheld because this record is not cleared for redistribution. targeting a neighbouring VIP did not excite the recorded one, establishing single-cell resolution Quotation withheld because this record is not cleared for redistribution. blanket of inhibition blanket of inhibition Quotation withheld because this record is not cleared for redistribution. disinhibition disinhibition Quotation withheld because this record is not cleared for redistribution. frequency-dependent disynaptic inhibition (FDDI) frequency-dependent disynaptic inhibition (FDDI) Quotation withheld because this record is not cleared for redistribution. holes in the blanket of inhibition holes in the blanket of inhibition Quotation withheld because this record is not cleared for redistribution. locomotion epoch locomotion epoch Quotation withheld because this record is not cleared for redistribution. blanket of inhibition blanket of inhibition Quotation withheld because this record is not cleared for redistribution. disinhibited cells disinhibited cells Quotation withheld because this record is not cleared for redistribution. two-photon optogenetic activation two-photon optogenetic activation Quotation withheld because this record is not cleared for redistribution. distance from spiral target distance from spiral target Quotation withheld because this record is not cleared for redistribution. change in visual responses change in visual responses Quotation withheld because this record is not cleared for redistribution. 33/638 cells — cells whose visual responses were significantly disinhibited by single-VIP activation, out of all imaged cells Quotation withheld because this record is not cleared for redistribution. ∼240 μm — diameter of the disinhibitory hole a VIP opens in SOM-mediated blanket inhibition Quotation withheld because this record is not cleared for redistribution. 440 ± 53 μm, 233 ± 29 μm — vertical and horizontal axon extent of VIP cells, against 756 ± 85 / 615 ± 82 μm for SOMs Quotation withheld because this record is not cleared for redistribution. 41 ± 16 ms — onset latency of the disynaptic inhibition in the second pyramidal cell after the spike train began Quotation withheld because this record is not cleared for redistribution. six of eight — individual VIP cells successfully driven to spike by targeted two-photon spiral stimulation in slices Quotation withheld because this record is not cleared for redistribution. 112 ± 25 μm vs 163 ± 14 μm, p = 0.01 — intersomatic distance of SOMs connected versus not connected to a recorded VIP Quotation withheld because this record is not cleared for redistribution. ∼233 μm/2 = 116 μm ... ∼112 μm — convergent anatomical and functional estimates of a single VIP's lateral reach Quotation withheld because this record is not cleared for redistribution. about 120 microns — effective disinhibitory RADIUS of a single VIP cell Quotation withheld because this record is not cleared for redistribution. about 240 microns — the same result expressed as a DIAMETER - not a discrepancy with the 120 figure Quotation withheld because this record is not cleared for redistribution. axons about 233/2 = 116 microns laterally; SOMs inhibited within about 112; correlations raised at 75 to 150; optogenetic disinhibition within 60 to 120 — four independent estimates of one quantity, converging on about 120 microns Quotation withheld because this record is not cleared for redistribution. connected 112 plus or minus 25 microns, not connected 163 plus or minus 14, p = 0.01 — VIP to SOM connection probability against distance Quotation withheld because this record is not cleared for redistribution. disinhibited 66 plus or minus 9 microns against all cells 101 plus or minus 2, p = 0.002 — how much closer the affected cells were Quotation withheld because this record is not cleared for redistribution. 33 disinhibited, 6 inhibited, 599 unchanged of 638 cells across 27 experiments — the classification outcome Quotation withheld because this record is not cleared for redistribution.

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