Role of Somatostatin-Positive Cortical Interneurons in the Generation of Sleep Slow Waves

Abstract

During non-rapid eye-movement (NREM) sleep, cortical and thalamic neurons oscillate every second or so between ON periods, characterized by membrane depolarization and wake-like tonic firing, and OFF periods, characterized by membrane hyperpolarization and neuronal silence. Cortical 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 I and can block excitatory transmission presynaptically, at glutamatergic terminals, and postsynaptically, at apical dendrites, without inhibiting the soma. In freely moving male mice, we show that SOM+ cells can fire immediately before slow waves and their optogenetic stimulation during ON periods of NREM sleep triggers long OFF periods. Next, we show that chemogenetic activation of SOM+ cells increases slow-wave activity (SWA), slope of individual slow waves, and NREM sleep duration; whereas their chemogenetic inhibition decreases SWA and slow-wave incidence without changing time spent in NREM sleep. By contrast, activation of parvalbumin+ (PV+) cells, the most numerous population of cortical inhibitory neurons, greatly decreases SWA and cortical firing, triggers short OFF periods in NREM sleep, and increases NREM sleep duration. Thus 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 slow waves are a defining feature of non-rapid eye-movement (NREM) sleep and are thought to be important for many of its restorative benefits. Yet, the mechanism by which cortical neurons abruptly and synchronously cease firing, the neuronal basis of the slow wave, remains unknown. Using chemogenetic and optogenetic approaches, we provide the first evidence that links a specific class of inhibitory interneurons-somatostatin-positive cells-to the generation of slow waves during NREM sleep in freely moving mice.

General anaesthesia disrupts complex cortical dynamics in response to intracranial electrical stimulation in rats

“…At the network level, this phenomenon give rise to slow wave oscillations in the spontaneous EEG observed during NREM sleep and general anaesthesia, where periods of HF activity alternate with OFF-periods of HF suppression 19,20,17,18 . Neuronal down-states are thought to be generated mainly by activity-dependent K + currents 34,35 and/or synaptic fatigue and inhibition 36,37 and it has been suggested that the same mechanisms may be triggered by the initial response to cortical stimulation. The "induced down-state" would then interrupt the deterministic and long-lasting sequence of complex neuronal interactions that are thought to give high PCI 13,14,15 .…”

Allatostatin-C/AstC-R2 Is a Novel Pathway to Modulate the Circadian Activity Pattern in Drosophila

“…Inhibitory somatostatin (SST) interneurons are present in the mammalian equivalent of a central core clock, the suprachiasmatic nucleus (SCN) [39] [40] [41]. SST interneurons are also known to affect sleep [42] and circadian behaviors [40]. Interestingly, SST is associated with proper adaptation under photoperiod conditions for both diurnal and nocturnal mammals [43-45], suggesting a highly conserved function with AstC/AstC-R2 for adaptation under different equinox environments.…”

Local sleep-like cortical reactivity in the awake brain after focal injury

“…The hallmark of physiological sleep is the occurrence of slow waves and OFF-periods, often referred to in the sleep literature as cortical bistability (7,10). OFF-periods are caused by the enhancement of adaptation (or activity-dependent) K+ currents, brought about by decreased levels of neuromodulation from brainstem activating systems (36)(37)(38)(39) and/or by increased inhibition (40)(41)(42). Due to these mechanisms, cortical neurons tend to plunge into a silent, hyperpolarized state, lasting few hundred milliseconds, after an initial activation (10).…”