The neuropeptide Galanin is required for homeostatic rebound sleep following increased neuronal activity

Abstract

Sleep pressure homeostatically increases during wake and dissipates during sleep, but the molecular signals and neuronal substrates that measure homeostatic sleep pressure remain poorly understood. We present a pharmacological assay in larval zebrafish that generates acute, short-term increases in wakefulness followed by sustained rebound sleep after washout. The intensity of global neuronal activity during drug-induced wakefulness predicted the amount of subsequent rebound sleep. Whole brain mapping with the neuronal activity marker phosphorylated extracellular signal-regulated kinase (pERK) identified preoptic Galanin-expressing neurons as selectively active during rebound sleep, and the relative induction of galanin transcripts was predictive of total rebound sleep time. Galanin is required for sleep homeostasis, as galanin mutants almost completely lacked rebound sleep following both pharmacologically induced neuronal activity and physical sleep deprivation. These results suggest that Galanin plays a key role in responding to sleep pressure signals derived from neuronal activity and functions as an output arm of the vertebrate sleep homeostat.

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

“…Though the function of this phenomenon remains almost completely unstudied, ENCORE-D suggests that the period dominated by waking SWA in response to rapid-acting antidepressants represents a physiologically meaningful step for the subacute consolidation of activity-induced synaptic changes, involving alterations in both protein synthesis and energy metabolism, resembling deep or local sleep. Notably, a recent study conducted in zebrafish demonstrates the homeostatic emergence of a sleeplike state immediately following acute administration of pharmacological agents that prominently increase neuronal activation (Reichert et al, 2019).…”

Sleep is bi-directionally modified by amyloid beta oligomers

“…In contrast, epileptogenic drugs like the GABA-receptor antagonist PTZ induce electrophysiological and behavioral seizures ( Baraban et al, 2005 ), which are observed as dramatic rearrangements in zebrafish bout structure ( Figure 1—figure supplement 3D ). The bout structure of Aβ rev , Aβ short , and Aβ long injected fish was highly similar to WT behavior ( Figure 1—figure supplement 3D,E and Figure 1—video 1 ), and the high-frequency bouts (HFB) indicative of seizures ( Reichert et al, 2019 ) were only found in PTZ exposed fish but not Aβ injected larvae ( Figure 1—figure supplement 3D,E ). Together these experiments indicate that exposure to Aβ modulates normal sleep/wake behavior without inducing toxic states.…”

“…Finally, if the behavioral states induced by Aβ are bona fide sleep/wake states, we reasoned that known zebrafish sleep/wake regulatory neurons should be engaged. Galanin-expressing neurons of the preoptic area and hypothalamus are active and upregulate galanin transcription during zebrafish sleep ( Reichert et al, 2019 ). Similarly, ISH for galanin 4–6 hr post-injection of Aβ oligomers revealed that wake-promoting Aβ short slightly decreased (−6%, blinded counts), while sleep-promoting Aβ long slightly increased (+12%, blinded counts), the number of galanin -positive cells in the hypothalamus compared to Aβ rev injected larvae ( Figure 2F–G ).…”

Hypothalamic NMDA receptors stabilize NREM sleep and are essential for REM sleep

“…The LPO hypothalamus is required for both NREM and REM sleep generation and NREM sleep homeostasis (Lu et al, 2002;Lu et al, 2000;Ma et al, 2019;McGinty and Sterman, 1968;Nauta, 1946;Reichert et al, 2019;Sherin et al, 1996;Szymusiak et al, 2007;Zhang et al, 2015). We explored how NMDA receptors on LPO neurons regulate sleep.…”

“…In this structure, GABA/peptidergic neurons, e.g. GABA/galanin neurons, contribute to NREM sleep induction and sleep homeostasis (Chung et al, 2017;Kroeger et al, 2018;Ma et al, 2019;Reichert et al, 2019;Sherin et al, 1996;Zhang et al, 2015). To stay asleep, and prevent insomnia, it seems reasonable to assume that these sleep-promoting neurons would have to stay "on".…”