Research ArticleNEUROSCIENCE

Distinct roles of parvalbumin and somatostatin interneurons in gating the synchronization of spike times in the neocortex

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Science Advances  22 Apr 2020:
Vol. 6, no. 17, eaay5333
DOI: 10.1126/sciadv.aay5333
  • Fig. 1 Synchronization of whisker stimulation–evoked spike times between granular and subgranular layers in S1.

    (A) Electrophysiology recording in S1 during whisker stimulation in vivo. (B) Estimated location of the 32-channel silicon probe and contact sites in relation to cortical layers (magenta, DiI-stained probe track; blue, DAPI). (C) Spike waveform-based neuron classification in asymmetry index [(ba)/(b + a)] versus spike width (c). Dotted line, decision boundary. Inset: Initial baseline-to-peak amplitude (a), last baseline-to-peak amplitude (b), and spike width (c) of putative excitatory (filled circles) and inhibitory (empty circles) neurons. (D) Whisker stimulation–evoked changes in firing rate for four representative single units in layers (L) 2/3, 4, 5, and 6. Time point 0 denotes whisker stimulation onset. Black bar, whisker stimulation. (E) Peak latency of whisker stimulation–evoked multiunit activity (MUA) in L2/3, L4, L5, and L6 (n = 4 mice, n.s. P > 0.05, one-way ANOVA test). (F) Spike raster plot of putative excitatory neurons in L4, L5, and L6 from one recording trial during whisker stimulation. Gray shade indicates the synchronization time window (±10 ms). Red vertical dotted lines indicate spike times of L4 neurons. (G) Pairwise spike-time coherence scores of spike-timing sequences. Circles indicate pairwise coherence scores between a given neuron in L5 or L6 and the L4 neuron indicated in (F). Vertical dotted line represents the empirically defined threshold for classifying synchronized and nonsynchronized neurons [see (H) and (I)]. (H) Distribution of pairwise spike-time coherence scores of spike-timing sequences in pairs of L4-L5 (top; n = 1837 pairs from 10 mice), L4-L6 (middle; n = 755 pairs from 10 mice), and pairs of L4 and spikes generated from a random Poisson process (bottom; n = 2000 random spike pairs), fitted with log-normal distribution (solid curve). Threshold: Intersection between two log-normal distributions (vertical dotted line). (I) Representative spike-time coherence scores of neuron pairs in L4-L5 (top three panels) and L4-L6 (bottom panel) versus time lag (τ). Neurons with peak coherence scores above threshold (dotted line) are defined synchronized neuron or else nonsynchronized neuron. (J) Representative plot of iFR (0.5 to 4, 4 to 12, 12 to 20, and 20 to 50 Hz, gray color scale) of neurons in L4 and L5/L6. (K) Representative plot of iSR (maximum 1, red color scale) of neurons in L4 and L5/L6. (L) iSR-iFR profile of synchronized neurons in L5 (circle) and L6 (triangle). L5: n = 85 units and L6: n = 49 units recorded from 10 mice (n.s. P > 0.05, Wilcoxon rank sum test). All data are means ± SEM.

  • Fig. 2 Optogenetic activation of PV and SST interneurons gates the synchronization of spike times in a frequency-selective manner.

    (A) Top: Schematic of the injection of AAV-EF1a-DIO-hChR2(ET/TC)-mCherry (ChR2, blue) into S1. Bottom: Electrophysiology recording during whisker stimulation and blue light stimulation (473 nm) in either PV-Cre or SST-Cre mice. (B) ChR2-mCherry–expressing PV (ChR2-PV) interneurons in PV-Cre mice (red, left) and ChR2-mCherry–expressing SST (ChR2-SST) interneurons in SST-Cre mice (red, right) among all cells stained with DAPI (blue). (C) Representative spike waveforms (top), raster plots (middle), and peri-stimulus time histograms (PSTH; bottom) of putative ChR2-PV interneuron (magenta, left) and excitatory neuron (black, right) during blue light stimulation (3.5 s; blue shade) in PV-Cre mice. (D) Same as (C) but for putative ChR2-SST interneuron (orange) in SST-Cre mice. (E and F) PSTHs of putative L4 excitatory neurons (top) and the spike raster plots (bottom) of synchronized neurons in L5 and L6 during whisker stimulation (black horizontal bar) with blue light stimulation (blue shade) in PV-Cre mice (E) and SST-Cre mice (F). Light stimulation preceded whisker stimulation by 500 ms (vertical dotted lines; top). Gray shade indicates the synchronization time window (±10 ms). Red vertical dotted lines indicate the spike times of L4 neurons. (G and H) Distribution of pairwise spike-time coherence scores of neuron pairs in L4-L5 (top; control in PV-Cre mice, 946 pairs; ChR2-PV activation, 938 pairs from nine mice; control in SST-Cre mice, 327 pairs; ChR2-SST activation, 327 pairs from nine mice) and L4-L6 (bottom; control in PV-Cre mice, 260 pairs; ChR2-PV activation, 247 pairs from nine mice; control in SST-Cre mice, 177 pairs; ChR2-SST activation, 203 pairs from nine mice) with ChR2-PV activation (G, magenta) and ChR2-SST activation (H, orange) and in control (light magenta/orange), fitted with log-normal distribution (solid curve). Vertical dotted line: Threshold between synchronized and nonsynchronized neurons (n.s. P > 0.05, Kolmogorov-Smirnov test). (I and J) Representative plot of iFR (four bins: 0.5 to 4, 4 to 12, 12 to 20, and 20 to 50 Hz, gray color scale; top) and iSR (maximum 1, red color scale; bottom) of neurons in L4 and L5/L6 during blue light stimulation in PV-Cre mice (I) and SST-Cre mice (J). Red vertical dotted lines indicate the spike times of the L4 neurons. (K and L) iSR-iFR profiles of synchronized neurons in L5 (circle) and L6 (triangle) during blue light on (filled) and off (empty) in PV-Cre mice (K, magenta; L5, n = 66 units; L6, n = 26 units; nine mice) and in SST-Cre mice (L, orange; L5, n = 46 units; L6, n = 31 units; nine mice). All data are means ± SEM. The number of animals and the isolated single-units are as indicated (***P < 0.001, Wilcoxon rank sum test).

  • Fig. 3 Optogenetic silencing of PV and SST interneurons promotes the synchronization of spike times in a frequency-selective manner.

    (A) Top: Schematic of the injection of AAV-EF1a-DIO-eArch3.0-EYFP (Arch; green) into S1. Bottom: Electrophysiology recording during whisker stimulation and green light stimulation (565 nm) in either PV-Cre or SST-Cre mice. (B) Arch-EYFP–expressing PV interneurons (Arch-PV) in PV-Cre mice (green, left) and Arch-EYFP–expressing SST interneurons (Arch-SST) in SST-Cre mice (green, right) in EYFP among all cells stained with DAPI (blue). (C) Representative spike waveforms (top), raster plots (middle), and PSTHs (bottom) of putative Arch-PV interneuron (magenta, left) and excitatory neuron (black, right) during green light stimulation (3.5 s; green shade) in PV-Cre mice. (D) Same as (C) but for putative Arch-SST interneuron (orange) in SST-Cre mice. (E and F) PSTHs of putative L4 excitatory neurons (top) and the raster plots (bottom) of synchronized neurons in L5 and L6 during whisker stimulation (black horizontal bar) with green light stimulation (green shade) in PV-Cre mice (E) and SST-Cre mice (F). Light stimulation preceded whisker stimulation by 500 ms (vertical dotted lines; top). Gray shade indicates the synchronization time window (±10 ms). Red vertical dotted lines indicate the spike times of L4 neurons. (G and H) Distribution of pairwise spike-time coherence scores of neuron pairs in L4-L5 (top; control in PV-Cre mice, 927 pairs; Arch-PV silencing, 1339 pairs from 8 mice; control in SST-Cre mice, 1085 pairs; Arch-SST silencing, 1464 pairs from 10 mice) and L4-L6 (bottom; control in PV-Cre mice, 225 pairs; Arch-PV silencing, 264 pairs from 8 mice; control in SST-Cre mice, 361 pairs; Arch-SST silencing, 380 pairs from 10 mice) with Arch-PV silencing (G, magenta) and Arch-SST silencing (H, orange) and in control (light magenta/orange), fitted with log-normal distribution (solid curve). Vertical dotted line: Threshold between synchronized and nonsynchronized neurons (*P < 0.05 and ***P < 0.001, Kolmogorov-Smirnov test). (I and J) Representative plot of iFR (four bins: 0.5 to 4, 4 to 12, 12 to 20, and 20 to 50 Hz, gray color scale; top) and iSR (maximum 1, red color scale; bottom) of neurons in L4 and L5/L6 during green light stimulation in PV-Cre mice (I) and SST-Cre mice (J). Red vertical dotted lines indicate the spike times of the L4 neurons. (K and L) iSR-iFR profiles of synchronized neurons in L5 (circle) and L6 (triangle) during green light on (filled) and off (empty) in PV-Cre mice (K, magenta; L5, n = 78 units; L6, n = 30 units; 8 mice) and in SST-Cre mice (L, orange; L5, n = 86 units; L6, n = 37 units; 10 mice). All data are means ± SEM. The number of animals and the isolated single units are as indicated (***P < 0.001, Wilcoxon rank-sum test).

  • Fig. 4 PV and SST interneurons preferentially recruit feedforward and feedback inhibition for frequency-selective gating of spike-timing synchronization.

    (A) Schematic of a three-layer network model consisting of 200 single-compartment Hodgkin-Huxley excitatory neuron models (triangles) and 50 inhibitory interneuron models (circles) that provide feedforward inhibition (FFI; magenta) and feedback inhibition (FBI; orange) at 7:3 ratio. (B) Spike raster plot of the model in response to spike-timing sequence recorded in granular layer in S1 in vivo (red). Dots indicate spikes. A subset of neurons (40 neurons) in the input layer (LINPUT) received the input (red dots), while the rest spiked spontaneously (black dots), reflecting sparseness. (C) Representatives of iFR (four bins: 0.5 to 4, 4 to 12, 12 to 20, and 20 to 50 Hz, gray color scale; top) and iSR (maximum 1, red color scale; bottom) of neurons in LINPUT-L3 pair in each model. Red lines in LINPUT are the input spike-timing sequences. Black dots are spikes in L3. (D) iSR-iFR profile of network model with FFI:FBI ratio at 7:3 (pink). In vivo–recorded iSR-iFR profile in the control condition (black filled circles, black dashed line) are plotted together for comparison. (E) Euclidean similarity of iSR-iFR profiles between in vivo data in control condition and simulation of the network model with different ratio of FFI:FBI showing 7:3 as the optimal ratio for the synchronization of spike times. Different ratios of FFI:FBI color-coded as different shades of magenta to orange. (F) iSR-iFR profile in response to increase in synaptic weights of FFI (ΔWFFI > 0) complemented by decrease in synaptic weights of FBI (ΔWFBI < 0) in the network model to balance inhibition (filled magenta circle). ChR2-PV activation (blue filled circles, magenta dashed line), ChR2-SST activation (blue filled circles, orange dashed line), Arch-PV silencing (green filled circles, magenta dashed line), and Arch-SST silencing (green filled circles, orange dashed line) are plotted together for comparison. In vivo data represent means ± SEM. (G and H) Same as (B) and (C) but in a network model with ΔWFFI > 0 and ΔWFBI < 0 in the model. (I) Four-dimensional Euclidean similarity of iSR-iFR profiles between in silico model in (F) and in vivo data in each condition. Magenta bar, optogenetic manipulation of PV interneuron in vivo; orange bar, optogenetic manipulation of SST interneuron in vivo. Blue and green shades indicate ChR2 activation with blue light and Arch silencing with green light in each interneuron subtypes, respectively. (J to M) Same as (F) to (I) but with ΔWFBI > 0 complemented by ΔWFFI < 0 in the network model to balance inhibition. The corresponding iSR-iFR profile is shown in filled orange circles in (J). (N) Cartoon summarizing the frequency-selective gating of spike-timing synchronization by PV and SST interneurons through preferential activation of FFI and FBI.

  • Table 1 Membrane properties in the Hodgkin-Huxley type excitatory neuron and inhibitory interneuron model.

    Cell typeExcitatory neuronInhibitory
    interneuron
    Diameter and length
    (μm)
    7040
    Capacitance (μF/cm2)1.01.0
    Membrane resistance
    (ohm·cm2)
    23,0006,000
    Axial resistance
    (ohm·cm)
    5050
    Maximal conductance
    of ILeak (gLeak, S/cm2)
    0.00004380.000167
    gNa (S/cm2)0.0120.015
    gKDR (S/cm2)0.00150.004
    gKM (S/cm2)0.000005
  • Table 2 Synapse model properties between excitatory neurons and inhibitory interneurons.

    Synapses
    (presynaptic
    neuron–
    postsynaptic
    neuron)
    Excitatory
    neuron–
    excitatory
    neuron
    Excitatory
    neuron–
    inhibitory
    neuron
    Inhibitory
    neuron–
    excitatory
    neuron
    Maximal
    conductance
    (gsyn, μS)
    0.00740.00120.00743
    Rise time
    constant
    rise, ms)
    0.10.21.0
    Decay time
    constant
    decay, ms)
    0.20.34.5
    Reversal
    potential of
    synapse
    (Erev, mV)
    00−70

Supplementary Materials

  • Supplementary Materials

    Distinct roles of parvalbumin and somatostatin interneurons in gating the synchronization of spike times in the neocortex

    Hyun Jae Jang, Hyowon Chung, James M. Rowland, Blake A. Richards, Michael M. Kohl, Jeehyun Kwag

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