Role of somatostatin-positive cortical interneurons in the generation of sleep slow waves

Abstract

SUMMARYCortical slow waves – the hallmark of NREM sleep - reflect near-synchronous OFF periods in cortical neurons. However, the mechanisms triggering such OFF periods are unclear, as there is little evidence for somatic inhibition. We studied cortical inhibitory interneurons that express somatostatin (SOM), because ∼70% of them are Martinotti cells that target diffusely layer 1 and can block excitatory transmission presynaptically, at glutamatergic terminals, and postsynaptically, at apical dendrites, without inhibiting the soma. In freely moving mice, we show that SOM+ cells can fire immediately before slow waves and their optogenetic stimulation triggers neuronal OFF periods during sleep. Next, we show that chemogenetic activation of SOM+ cells increases slow wave activity (SWA), the slope of individual slow waves, and the duration of NREM sleep; whereas their chemogenetic inhibition decreases SWA and slow wave incidence without changing time spent asleep. By contrast, activation of parvalbumin+ (PV+) cells, the most numerous population of cortical inhibitory neurons, greatly decreases SWA and cortical firing. These results indicate that SOM+ cells, but not PV+ cells, are involved in the generation of sleep slow waves. Whether Martinotti cells are solely responsible for this effect, or are complemented by other classes of inhibitory neurons, remains to be investigated.

Cortical circuit activity underlying sleep slow oscillations and spindles

“…According to this scenario, low SOM-In activity during spindles nesting in slow oscillation upstates would play a permissive role for dendritic calcium activity, facilitating the induction of persisting plasticity at dendritic synapses in Pyr cells. Although this view is tentative, as we did not directly assess dendritic calcium activity, it concurs well with findings in awake mice showing that low SOM-In activity, in the presence of strong perisomatic inhibition of Pyr cells, facilitates dendritic synaptic plasticity upon encoding of motor memories in these cells (47,55,59). Moreover, during SWS, after motor memory encoding dendritic plasticity was shown to occur, as a consequence of reactivated representations, on select apical branches of Pyr cells (60) and dendritic calcium activity was found to be distinctly increased during spindles (54).…”

“…They found in natural sleeping cats that the slow oscillation downstate was preceded by a longer (100-300 ms) chloride-mediated inhibitory barrage that was likely mediated by long-range afferent inputs to inhibitory interneurons. The rather similar time course observed here for the increase in SOM-In activity preceding the slow oscillation downstate, together with findings that optogenetic stimulation of SOM-Ins can induce slow oscillations (47), speaks for a contribution of SOM-Ins in initialization of the slow oscillation downstate. This view is further supported by our observation that PV-In activity gradually decreased in the same time interval (i.e., before the downstate), as SOM-Ins are known to directly inhibit PV-Ins and a number of other cortical interneurons (48).…”

“…While our calcium imaging study reveals a distinct pattern of activity in cortical circuits associated with slow oscillations and spindles, it did not include any intervention. Thus, the central question of causality (i.e., to what extent the observed changes in calcium activity characterizing slow oscillation and spindles indeed play a causal role in the regulation of these EEG events) remains to be resolved (47).…”

Novel concepts in sleep regulation

“…We know that, at least partially, this process takes place during (slow wave) sleep. Slow waves, initiated in cortex, are in key position. During the UP‐state of the low oscillation, fast hippocampal activity (sharp wave ripples, 150‐250 Hz) is transmitted to cortical networks .…”

Optogenetics: Solving the Enigma of Sleep

“…With the cortical neurons, the off-states of these cells occur nearly simultaneously with one another. A study combining optogenetic and chemogenetic techniques investigated somatostatin-positive (SOM) inhibitory interneurons in the cortex revealed a connection between cortical SOM neurons and the generation of the slow waves in NREM sleep [47].…”