State-Dependent Modulation of Activity in Distinct Layer 6 Corticothalamic Neurons in Barrel Cortex of Awake Mice

Abstract

Layer 6 corticothalamic (L6 CT) neurons are in a strategic position to control sensory input to the neocortex, yet we understand very little about their functions. Apart from studying their anatomical, physiological and synaptic properties, most recent efforts have focused on the activity-dependent influences CT cells can exert on thalamic and cortical neurons through causal optogenetic manipulations. However, few studies have attempted to study them during behavior. To address this gap, we performed juxtacellular recordings from optogenetically identified CT neurons in whisker-related primary somatosensory cortex (wS1) of awake, head-fixed mice (either sex) free to rest quietly or self-initiate bouts of whisking and locomotion. We found a rich diversity of response profiles exhibited by CT cells. Their spiking patterns were either modulated by whisking-related behavior (~28%)or not (~72%). Whisking-responsive neurons exhibited either increases, activated-type, or decreases in firing rates, suppressed-type, that aligned with whisking onset better than locomotion. We also encountered responsive neurons with preceding modulations in firing rate before whisking onset. Overall, whisking better explained these changes in rates than overall changes in arousal. Whisking-unresponsive CT cells were generally quiet, with many having low spontaneous firing rates, sparse-type, and others being completely silent. Remarkably, the sparse firing CT population preferentially spiked at the state transition point when pupil diameter constricted and the mouse entered quiet wakefulness. Thus, our results demonstrate that L6 CT cells in wS1 show diverse spiking patterns, perhaps subserving distinct functional roles related to precisely timed responses during complex behaviors and transitions between discrete waking states.

Primary somatosensory cortex bidirectionally modulates sensory gain and nociceptive behavior in a layer-specific manner

“…Behavioral determinants and circuit mechanisms controlling L6-CT output pathways are only beginning to be studied, e.g., refs. 64 , 65 , let alone those that potentially lead to L6 hyperactivity or synchronization. Interestingly, there appears to be a strong link between pain states and increased S1 activity 66 , 67 and cortical synchronization 31 , 32 , 68 .…”

Dynamic corticothalamic modulation of the somatosensory thalamocortical circuit during wakefulness

“…In addition, we provide evidence for the effect of this dynamic modulation on S1 neurons and find non-monotonic changes in S1 RS and FS ongoing activity as well as FS stimulus-evoked activity. Collectively, L6CT neurons play a role in the continuous and context-dependent modulation of thalamocortical sensory signaling through motor corollary signals, arousal, and other behavioral states (Augustinaite & Kuhn, 2020; Clayton et al, 2021; Dash et al, 2022; Reinhold et al, 2023; Vélez-Fort et al, 2018), and we provide comprehensive evidence for the effect of the L6CT feedback mechanism across such facets.…”

“…However, it is only from recent work that we are beginning to understand the precise contexts in which these neurons become engaged and exert their influence, expanding the range of observed L6CT activity patterns. In addition to being responsive to sensory stimuli (Augustinaite & Kuhn, 2020; Briggs & Usrey, 2009; Swadlow, 1989; Zhou et al, 2010), L6CT neuron activity is also modulated by extra-sensory features, such as head rotation (Vélez-Fort et al, 2018), motor-preparation (Clayton et al, 2021), whisking (Dash et al, 2022) and locomotion (Augustinaite & Kuhn, 2020). Additionally, L6CT neurons serve as a circuit mechanism for brain state-dependent modulation of the FO thalamus (Reinhold et al, 2023).…”

Motor Control of Distinct Layer 6 Corticothalamic Feedback Circuits

“…Another possibility is that CT neurons integrate motor and arousal signals. There is clear evidence from studies in various sensory systems and species that arousal/state signals are present in CT neurons (Swadlow and Weyand, 1987; Steriade, 2001; Stoelzel et al, 2017; Augustinaite and Kuhn, 2020; Clayton et al, 2021; Dash et al, 2022; Reinhold et al, 2023), but direct evidence for whisker motor and arousal signal integration is lacking.…”