Functional states shape the spatiotemporal representation of local and cortex-wide neural activity in mouse sensory cortex

Abstract

The spatiotemporal representation of neural activity during rest and upon sensory stimulation in cortical areas is highly dynamic and may be predominantly governed by cortical state. On the mesoscale level, intrinsic neuronal activity ranges from a persistent state, generally associated with a sustained depolarization of neurons, to a bimodal, slow wave-like state with bursts of neuronal activation alternating with silent periods. These different activity states are prevalent under certain types of sedatives or are associated with specific behavioral or vigilance conditions. Neurophysiological experiments assessing circuit activity usually assume a constant underlying state, yet reports of variability of neuronal responses under seemingly constant conditions are common in the field. Even when a certain type of neural activity or cortical state can be stably maintained over time, the associated response properties are highly relevant for explaining experimental outcomes. Here we describe the spatiotemporal characteristics of ongoing activity and sensory-evoked responses under two predominant functional states in the sensory cortices of mice: persistent activity (PA) and slow wave activity (SWA). Using electrophysiological recordings and local and wide-field calcium recordings, we examine whether spontaneous and sensory-evoked neuronal activity propagate throughout the cortex in a state-dependent manner. We find that PA and SWA differ in their spatiotemporal characteristics, which determine the cortical network's response to a sensory stimulus. During PA state, sensory stimulation elicits gamma-based short-latency responses that precisely follow each stimulation pulse and are prone to adaptation upon higher stimulation frequencies. Sensory responses during SWA are more variable, dependent on refractory periods following spontaneous slow waves. Although spontaneous slow waves propagated in anterior-posterior direction in a majority of observations, the direction of propagation of stimulus-elicited wave depends on the sensory modality. These findings suggest that cortical state explains variance and should be considered when investigating multiscale correlates of functional neurocircuit activity.NEW & NOTEWORTHY Here we dissect the cortical representation of brain states based on local photometry recordings and on mesoscale cortical calcium imaging, complemented by electrophysiological recordings in mice. We identify two distinct functional states in the sensory cortices, which differ in their spatiotemporal characteristics on the local and global cortical scales. We examine how intrinsic and stimulus-evoked neuronal activity propagates throughout the cortex in a state-dependent manner, supporting the notion that cortical state is a relevant variable to consider for a wide range of neurophysiological experiments.

Keywords: LFP; brain states; calcium imaging; mouse; sensory cortex.

Graphical abstract

Figure 1.

Camera recordings of transgenic GCaMP6 animals reveal mesoscale spatiotemporal characteristics of two distinct activity states. A: camera recording setup. B: images of different time points during recording of ongoing activity during persistent activity (PA) and slow wave activity (SWA) states. C: mean %df/f across cortical field of view for PA state (top) and SWA state (bottom) shown in B. Shaded region indicates the SD at each time point. D: average probability distributions of mean df/f across animals. Center lines indicate mean probability for each bin, boxes indicate SD, and whiskers indicate minimum and maximum values (n = 9 animals). E: difference of the mean probability distributions (shown in D): positive probabilities indicate higher occurrence during SWA state; negative probabilities indicate higher occurrence in PA state. Significant regions were determined by permutation-based testing and are indicated by horizontal bars with asterisks (P < 0.0001 for all after Bonferroni correction). F: propagation properties for sensory-evoked activity in both states: a brief 10-ms LED light flash to the left eye for visual and a mild electric stimulus (1 mA, 10-ms pulse) to the right forepaw for somatosensory; between 13 and 88 stimuli (40 ± 0.7) for each stimulus modality. G: average cortical area activated upon visual and somatosensory stimuli in SWA and PA states.

Figure 2.

Local dynamics of slow wave activity (SWA) and persistent activity (PA) stated. A: photometry recording in somatosensory cortex (S1) during PA state induced by medetomidine sedation (purple trace; acute Oregon Green-BAPTA-1 AM staining). B: local field potential (LFP) signals under the same conditions show similar signal dynamics (same timescale as in A). C: the spectrogram of the LFP signal in B reflects the ongoing persistent activity, showing continuous frequencies around 15 Hz. D: photometry recording in S1 during isoflurane-induced SWA state (blue trace; acute Oregon Green-BAPTA-1 AM staining) in which stereotypical, long-duration calcium waves interrupted by silence periods become apparent. E: LFP signals under the same conditions show similar dynamics (same timescale as in D). F: the spectrogram of the LFP signal in E reflects the alternation of active and silent periods in the frequency distribution, with the appearance of higher frequencies (around 40 Hz) during slow wave events. G: electric forepaw stimulation pulses (10 ms, 1 mA) reliably evoke calcium response in PA state (single trial response). Vertical scale bar, 0.02% df/f; horizontal scale bar 0.5 s. H: stimulus pulses evoke short-latency LFP spikes during PA state (note that these deflections occur very briefly after the stimulus pulse and for a very short duration in the depiction chosen to be comparable to K). I: the stimulus-locked spectrogram of the LFP trace in H shows time-frequency profiles before and after stimulation pulse (n = 30 events). J: during SWA state the same stimulus pulse evokes a slow calcium wave with a mean probability of 90% (n = 4 animals) that differs in latency, duration, and microarchitecture from an evoked response during PA state in the same animal as shown in G; scale bars same as in G. K: the response properties observed for the calcium signal in J also account for the LFP signal during SWA state. L: the stimulus-locked spectrogram of the LFP recording in K shows time-frequency profiles before and after the stimulation pulse (n = 30 events).

Figure 3.

Sensory processing during slow wave activity (SWA) state. A: photometry-based calcium signals were measured in contralateral somatosensory (S1) and visual (V1) cortex as depicted (or in ipsilateral S1 and V1). B: ongoing slow wave events are synchronized between the 2 recording sites, with events detected in 60% (5 animals, 120 events) of the cases occurring first in S1, suggesting a propagation of waves in anterior-posterior direction. C: cross-correlogram of the 2 depicted signals indicated that the posterior waves follow the anterior ones with variable delays. D: stimulus-evoked slow wave events start in the area of their respective sensory afferents and are detected with stereotypic delays in distant recording sites. Forepaw stimulation [10-ms pulses of 1 mA, interstimulus interval (ISI) 10 s] reliably evokes slow wave events after 73 ms in S1 and after 290 ms in V1 (averages of 20 events each). E: averages of stimulus-locked traces shown in D (line = mean, shading = SE of 30 evoked events; vertical scale bars, 1% df/f; horizontal scale bars, 500 ms). F: visual stimulation (10-ms LED light flash, ISI 10 s) leads to waves occurring after a mean delay of 114 ms in V1 and 340 ms in S1 in the same animal (averages of 20 evoked events). G: averages of traces shown in F (line = mean, shading = SE of 30 evoked events; vertical scale bars, 1% df/f; horizontal scale bars, 500 ms). H: still frames from a df/f movie depicting the propagation of a visually evoked wave. I: quiver plot depicting pixel-by-pixel propagation velocities and direction for visual stimuli. J: still frames from a df/f movie depicting the propagation of a somatosensory-evoked wave. K: quiver plot depicting the pixel-by-pixel propagation velocities and direction for J. Color map indicates response latency for all pixels. L: weighted polar distribution of propagation velocities for visual and somatosensory stimuli for all animals. M: the vector mean propagation velocity and direction for each animal. N: correlation between V1 and S1 for evoked slow waves (left) and delay between V1 and S1 (right).

Figure 4.

Effect of sensory stimuli at different intervals following spontaneous slow waves. A and B: latency to next detected slow wave and the time from last detected slow wave at time of visual and somatosensory stimulation, respectively. Variability in response time is reduced when stimuli are applied outside the refractory period (gray line), which is calculated in C as the time following a spontaneous slow wave after which 90% of stimuli are followed by a slow wave within 500 s. SWA, slow wave activity; S1, somatosensory cortex; V1, visual cortex. D and E: latency of calcium responses in S1 and V1 from time of visual and somatosensory stimulation, respectively. Only stimuli arriving after the refractory period are included.

Figure 5.

Primary responses in the stimulus-encoding sensory area occur before the onset of an evoked slow wave activity (SWA) event. A: electrical recordings of slow waves in 1 animal under 3 conditions: stimulus-triggered averages in visual cortex (V1) (On Stim). B: simultaneous recordings in somatosensory cortex (S1) (Off Stim). Corresponding spectrograms of responses displayed beneath each trace. Dotted line marks the onset time of the visual stimulus.