Neuronal Mechanisms for Sleep/Wake Regulation and Modulatory Drive

Abstract

Humans have been fascinated by sleep for millennia. After almost a century of scientific interrogation, significant progress has been made in understanding the neuronal regulation and functions of sleep. The application of new methods in neuroscience that enable the analysis of genetically defined neuronal circuits with unprecedented specificity and precision has been paramount in this endeavor. In this review, we first discuss electrophysiological and behavioral features of sleep/wake states and the principal neuronal populations involved in their regulation. Next, we describe the main modulatory drives of sleep and wakefulness, including homeostatic, circadian, and motivational processes. Finally, we describe a revised integrative model for sleep/wake regulation.

A Clock-Driven Neural Network Critical for Arousal

“…Historically, investigations of the neural basis of arousal have focused on neuromodulatory circuits, but there is growing recognition that GABA/glutamatergic neurons likely form the core substrate for arousal, which is tuned by neuromodulatory networks 3,19,20 . We thus used our scRNA-Seq dataset to characterize the repertoire of neuromodulatory receptors in mWAKE + neurons across hypothalamic sub-groups, and particularly in the DMH (Fig.…”

“…Current-clamp and voltage-clamp recordings were performed from norepinephrine-expressing cells in the locus coeruleus (TH + ), in the presence of optogenetic activation of ChR2-expressing terminals in the LC. Slices were exposed to blue light (480 nm) from the upper lens for 2 s at different stimulation frequencies(5,10,20, and 50 Hz) triggered by the Digidata 1440A.ImmunohistochemistryMice were deeply anesthetized with a ketamine/xylazine mixture then fixed by transcardial perfusion with 4% paraformaldehyde (PFA). Brains were subsequently drop-fixed in 4% PFA for 24-48 hr and transferred into 1x PBS before being sectioned at 40 μm thickness using a vibratome (VT1200S, Leica).…”

Orexin receptor antagonists for the treatment of insomnia and potential treatment of other neuropsychiatric indications

“…Orexin neurons fire with circadian rhythmicity, with higher firing rates (and subsequent orexin levels) during periods of wakefulness, and lower or absent firing rates during sleep (Eban‐Rothschild, Appelbaum, & De Lecea, ; Lee, Hassani, & Jones, ; Takahashi, Lin, & Sakai, ). This pattern results in about a 50% reduction in orexin levels during sleep in animal studies (Gotter et al., ; Taheri et al., ; Zeitzer et al., ).…”

The role of the hypothalamus in cortical arousal and sleep homeostasis

“…However, individuals also possess a striking ability to adapt the timing and duration of sleep in response to a variety of intrinsic and extrinsic factors (Ungurean et al, 2020). The key regulators of "adaptive sleep architecture" are: (i) homeostatic sleep need; (ii) the endogenous circadian clock; and (iii) the necessity to satisfy other physiological and behavioral needs such as feeding or the avoidance of danger (Eban-Rothschild et al, 2018). It is unknown how and in what form these numerous signals are integrated within the neural circuitry that generates the rapid and stable transitions between sleep and wake states.…”

“…The property of sleep and wake as brain states with flexible intensities on a global and local level suggests an additional complexity which is difficult to reconcile with a simple flip/flop switch model. For example, there is evidence to suggest that wake "intensity" contributes to the build-up of global homeostatic sleep need (Fisher et al, 2016;Vassalli and Franken, 2017), and the balance between intrinsic and extrinsic arousal-promoting and sleep-promoting signals ultimately determines the probability of state switching (Eban-Rothschild et al, 2018;Lazarus et al, 2019).…”