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Scaling down of balanced excitation and inhibition by active behavioral states in auditory cortex

Abstract

Cortical sensory processing is modulated by behavioral and cognitive states. How this modulation is achieved by changing synaptic circuits remains largely unknown. In awake mouse auditory cortex, we found that sensory-evoked spike responses of layer 2/3 (L2/3) excitatory cells were scaled down with preserved sensory tuning when mice transitioned from quiescence to active behaviors, including locomotion, whereas L4 and thalamic responses were unchanged. Whole-cell voltage-clamp recordings revealed that tone-evoked synaptic excitation and inhibition exhibited a robust functional balance. The change to active states caused scaling down of excitation and inhibition at approximately equal levels in L2/3 cells, but resulted in no synaptic changes in L4 cells. This lamina-specific gain control could be attributed to an enhancement of L1-mediated inhibitory tone, with L2/3 parvalbumin inhibitory neurons also being suppressed. Thus, L2/3 circuits can adjust the salience of output in accordance with momentary behavioral demands while maintaining the sensitivity and quality of sensory processing.

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Figure 1: Behavioral state–dependent modulation of spike responses in the mouse A1.
Figure 2: Gain modulation of auditory responses by behavioral state.
Figure 3: Activity of thalamic neurons and summary of SNR under different behavioral states.
Figure 4: Properties of synaptic responses in quiescence.
Figure 5: Modulation of synaptic responses by behavioral state.
Figure 6: Modulation of resting membrane potential and resting conductance by behavioral state.
Figure 7: Changes of activity of PV neurons between different behavioral states.
Figure 8: Role of L1 in the behavioral state–dependent L2/3-specific gain modulation.

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Acknowledgements

We thank B. Zingg and L.Y. Li for the help on viral injection and Nissl staining. This work was supported by grants to L.I.Z. from the US National Institutes of Health (R01DC008983) and the David and Lucile Packard Foundation (Packard Fellowships for Science and Engineering). H.W.T. was supported by US National Institutes of Health grant R01EY019049. Z.X., L.I.Z. and F.L. were supported by grants from the National Natural Science Foundation of China (U1301225, 31228013, 31200831) and a 973 program (2014CB943002).

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Authors

Contributions

L.I.Z., Z.X. and H.W.T. conceived and supervised the study. M.Z. and F.L. performed all of the experiments. L.L., H.L. and X.R.X. contributed to data collection. M.Z., F.L., H.W.T. and L.I.Z. performed data analysis. H.W.T. and L.I.Z. wrote the manuscript.

Corresponding authors

Correspondence to Zhongju Xiao, Huizhong W Tao or Li I Zhang.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Superimposed power spectra of LFP recorded during three different behavioral states.

The power spectra were smoothed by averaging pixel values using a sliding window.

Supplementary Figure 2 Confirmation of laminar location of recorded cells.

(a) From left to right, confocal image of brain sections of A1 showing the Nissl staining, the fluorescence expression pattern in a Scnn1a-Tg3-Cre X Ai14 mouse (Nissl staining in blue), the distribution of thalamocortical axons (overexposed to reveal detailed structures) in a wildtype mouse injected in the MGBv with a non-floxed AAV virus encoding EYFP, reconstructed morphology of two example pyramidal neurons recorded in L2/3 and L4, and recovered depths of another seven recorded pyramidal cells (L2/3 cells are labeled as black and L4 cells are labeled as red). Cortical layers are labeled. (b) Comparison of the reconstructed cell depth and corrected cortical depth based on micromanipulator readings. The unity line is shown.

Supplementary Figure 3 Plot of scaling factor versus cortical depth of the cell.

The horizontal dashed line marks scaling factor of 1. The vertical line marks the boundary between L2/3 and L4, i.e. 360 ± 10 μm below the pia surface. N = 32 cells. Within L2/3, there is no correlation between scaling factor and cell depth (r = -0.26).

Supplementary Figure 4 The slope of linear regression for “A” versus “Q” response levels as measured by charge transfer.

Data are presented similarly as in Fig. 5o. Solid symbol represents mean ± s.d. Red dash line indicates slope of 1. There is no significant difference between excitation and inhibition in L2/3 cells (P = 0.2242, t = 1.304, unpaired t-test, n = 11, 7)

Supplementary Figure 5 I-V curves derived from the same cell at different states.

(a) BF-tone evoked synaptic currents (averaged from 8 repeats for “quiet” state and 5 repeats for “active” state) of an example cell recorded under different clamping voltages. Vertical arrow marks tone onset. Note that baseline currents have been subtracted. Scale: 100 pA and 20 ms. (b) Current-voltage (I-V) relationship under different behavioral states plotted for the same cell in (a). The current value was averaged within a 1 ms window at 25 ms post tone onset (around the peak of the inward current, marked by dash line “I” in (a)). Bar = s.d. Note that the slope became shallower in active states, indicating that there was a reduction of total evoked synaptic conductance. (c) I-V relationship for currents averaged within a 1 ms window at 54 ms post tone onset (marked by the dash line “II” in (a)). Note that the reversal potential was more negative than in (b) due to a lower instantaneous E/I ratio.

Supplementary Figure 6 Series resistance (Rs) values in different behavioral states.

(a) Series resistance was measured by injecting negative square pulses (50 ms, -5 mV) in an example voltage-clamp recording experiment. Rs was calculated from the transient current at the onset of the testing pulse. Rs values before, during (red) and after a running epoch are shown. Averaged response traces to test pulses are shown on the top. Simultaneously recorded speed is shown at the bottom. (b) Summary of average Rs values during epochs of quiescence and the following epochs of locomotion. N = 8 cells.

Supplementary Figure 7 Comparison of synaptic amplitudes during the whole recording session and before, during and after epochs of active behaviors.

(a) Top, time course of behavioral states in a typical 6.25-minutes recording session. Epochs of quiescence and active states are marked by black and red lines respectively. Note that quiescence and active states are intermingled in the course of a typical experiment. Middle, trace of recorded plate rotating speed is shown. Arrow indicates speed = 0. Scale: 10 cm s-1, 20 s. Bottom, evoked peak excitatory conductance in response to 70 dB BF tones during Q and A states. The Rs was also monitored for this recording session. (b) Top, enlarged speed trace within the time window marked by two dash lines in (a). Bottom, overlapped raw traces of recorded excitatory currents in response to 70 dB BF tones before, during and after this epoch of locomotion. Thick bar indicates tone duration (50 ms). (c,d) Summary of average peak amplitude of evoked excitatory (c) or inhibitory (d) conductance in response to 70 dB BF tones before, during and after an epoch of locomotion. N = 11 cells in (c), 7 cells in (d). Solid symbol represents mean ± s.e.m. *P < 0.05, ***P < 0.001, Wilcoxon signed rank test. (e) Average peak amplitudes of evoked excitatory conductances in response to 70 dB BF tones at the start and end of a recording session. There is no significant difference (P = 0.1475, Z = 1.467, n = 11, Wilcoxon signed rank test).

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Zhou, M., Liang, F., Xiong, X. et al. Scaling down of balanced excitation and inhibition by active behavioral states in auditory cortex. Nat Neurosci 17, 841–850 (2014). https://doi.org/10.1038/nn.3701

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