Sleep and wake in a model of the thalamocortical system with Martinotti cells

Abstract

The mechanisms leading to the alternation between active (UP) and silent (DOWN) states during sleep slow waves (SWs) remain poorly understood. Previous models have explained the transition to the DOWN state by a progressive failure of excitation because of the build‐up of adaptation currents or synaptic depression. However, these models are at odds with recent studies suggesting a role for presynaptic inhibition by Martinotti cells (MaCs) in generating SWs. Here, we update a classical large‐scale model of sleep SWs to include MaCs and propose a different mechanism for the generation of SWs. In the wake mode, the network exhibits irregular and selective activity with low firing rates (FRs). Following an increase in the strength of background inputs and a modulation of synaptic strength and potassium leak potential mimicking the reduced effect of acetylcholine during sleep, the network enters a sleep‐like regime in which local increases of network activity trigger bursts of MaC activity, resulting in strong disfacilitation of the local network via presynaptic GABAB1a‐type inhibition. This model replicates findings on slow wave activity (SWA) during sleep that challenge previous models, including low and skewed FRs that are comparable between the wake and sleep modes, higher synchrony of transitions to DOWN states than to UP states, the possibility of triggering SWs by optogenetic stimulation of MaCs, and the local dependence of SWA on synaptic strength. Overall, this work points to a role for presynaptic inhibition by MaCs in the generation of DOWN states during sleep.

Somatostatin neuron contributions to cortical slow wave dysfunction in adult mice exposed to developmental ethanol

“…These neurons play important roles in sleep physiology, which is also disrupted by P7 ethanol exposure (Figure 1) (Wilson et al, 2016;Lewin et al, 2018;Apuzzo et al, 2020). Through cell type-specific, optogenetic targeting of SST neurons in neocortex of saline control mice, we could evoke cortical slow-waves across the anterior-posterior axis of the cortex (Figure 2) and enhance delta band oscillation amplitude (Figure 4) during sleep as has previously been reported (Funk et al, 2017;Bugnon et al, 2022). However, in P7 ethanol exposed mice, the efficacy of this optogenetic manipulation was severely impaired, suggesting an SST neuron contribution to ethanol effects on slowwave sleep cortical activity (Wilson et al, 2016;Apuzzo et al, 2020).…”

“…Furthermore, closed-loop stimulation of PFC SST neurons in phase with spontaneous slow-waves enhanced delta band oscillation power during the stimulation. These results support the hypothesized role of SST neurons in cortical slow-wave oscillations that occur during non-REM sleep (Kuki et al, 2015;Funk et al, 2017;Niethard et al, 2018;Adamantidis et al, 2019;Bugnon et al, 2022), though do not exclude contributions of other cell types.…”

“…Cortical interneurons are capable of a variety of forms of plasticity ( McFarlan et al, 2022 ). Specifically, the majority of cortical SST neurons are Martinotti cells ( Funk et al, 2017 ; Bugnon et al, 2022 ) which have extensive axonal outputs targeting multiple layers but especially layer I where they could influence a relatively large population of pyramidal neurons ( Wang et al, 2004 ; Funk et al, 2017 ). A decrease in the number or efficacy of these cells could decrease slow-wave amplitude by reducing the down-state magnitude and or synchrony.…”

“…One class of GABAergic cells involved in cortical sleep-related oscillations is somatostatin expressing (SST) neurons ( Kuki et al, 2015 ; Xu et al, 2015 ; Yavorska and Wehr, 2016 ; Funk et al, 2017 ; Espinosa et al, 2019 ; Bugnon et al, 2022 ). In rodents, SST neurons in the neocortex help promote slow wave neural oscillations by inducing 100–200 ms of inhibition (i.e., a cortical down-state) following the excitation induced by thalamic and cortical excitation of pyramidal cells as shown both in vivo ( Funk et al, 2017 ) and in computational modeling ( Bugnon et al, 2022 ). Cortical SST neuron activity is phase locked to cortical slow wave oscillations ( Funk et al, 2017 ).…”

“…As a starting point, we focused on a single important variable out of the myriad factors involved in sleep physiology and sleep function. We used optogenetic activation of spared SST neurons in ethanol exposed and saline control mice to manipulate cortical slow-wave activity ( Funk et al, 2017 ; Bugnon et al, 2022 ). Identifying mechanisms of developmental ethanol-induced sleep impairments is a first step toward cell-targeted treatment.…”