Hypothalamic Neurons that Regulate Feeding Can Influence Sleep/Wake States Based on Homeostatic Need

Abstract

SUMMARY Eating and sleeping represent two mutually exclusive behaviors that satisfy distinct homeostatic needs. Because an animal cannot eat and sleep at the same time, brain systems that regulate energy homeostasis are likely to influence sleep/wake behavior. Indeed, previous studies indicate that animals adjust sleep cycles around periods of food need and availability. Furthermore, hormones that affect energy homeostasis also affect sleep/wake states: the orexigenic hormone ghrelin promotes wakefulness, while the anorexigenic hormones leptin and insulin increase the duration of slow wave sleep. However, whether neural populations that regulate feeding can influence sleep/wake states is unknown. The hypothalamic arcuate nucleus contains two neuronal populations that exert opposing effects on energy homeostasis: agouti-related protein (AgRP)-expressing neurons detect caloric need and orchestrate food-seeking behavior, while activity in pro-opiomelanocortin (POMC)-expressing neurons induces satiety. We tested the hypotheses that AgRP neurons affect sleep homeostasis by promoting states of wakefulness, while POMC neurons promote states of sleep. Indeed, optogenetic or chemogenetic stimulation of AgRP neurons in mice promoted wakefulness while decreasing the quantity and integrity of sleep. Inhibition of AgRP neurons rescued sleep integrity in food-deprived mice, highlighting the physiological importance of AgRP neuron activity for the suppression of sleep by hunger. Conversely, stimulation of POMC neurons promoted sleep states and decreased sleep fragmentation in food-deprived mice. Interestingly, we also found that sleep deprivation attenuated the effects of AgRP neuron activity on food intake and wakefulness. These results indicate that homeostatic feeding neurons can hierarchically affect behavioral outcomes depending on homeostatic need.

The role of the hypothalamus in cortical arousal and sleep homeostasis

“…More relevant is that our chosen approach may have resulted in an activation of circuitries not directly, or not exclusively, related to sleep-wake control. For instance, LPO is adjacent to the lateral hypothalamus circuits which contain GABAergic neurons that promote a wide range of functions -from reward-seeking behaviors to feeding and behavioral arousal (Goldstein et al, 2018;Kosse et al, 2017;Nieh et al, 2016).…”

The Ghrelin-AgRP Neuron Nexus in Anorexia Nervosa: Implications for Metabolic and Behavioral Adaptations

“…These behaviors include disrupted sleep-wake structure and quality with lower slow wave sleep and rapid eye movement sleep, in addition to harm avoidance and social interaction deficits (154)(155)(156). Food restriction protocols in rodents are known to disturb the normal light-dark cycle activity in mice, as shown by food anticipatory activity and a recent study indicating that optogenetic AgRP neuronal activation increased the number and length of wake periods and the duration of non-rapid eye movement (NREM) sleep periods (157). Conversely, chemogenetic inhibition of these same neurons has no effect in satiated mice but reduced NREM sleep and microarousals during NREM sleep in fasted mice (157).…”

“…Food restriction protocols in rodents are known to disturb the normal light-dark cycle activity in mice, as shown by food anticipatory activity and a recent study indicating that optogenetic AgRP neuronal activation increased the number and length of wake periods and the duration of non-rapid eye movement (NREM) sleep periods (157). Conversely, chemogenetic inhibition of these same neurons has no effect in satiated mice but reduced NREM sleep and microarousals during NREM sleep in fasted mice (157). Thus, persistently high AgRP and ghrelin levels as seen in AN (149,150), may also impact behavior via impairing the quality of sleep.…”

Neurogenetic basis for circadian regulation of metabolism by the hypothalamus

“…Intriguingly, recent evidence has linked brain regions involved in regulation of sleep/wake cycles with the same neuronal populations that also regulate fasting/feeding. Specifically, orexigenic AgRP neurons within the arcuate nucleus have been found to promote wakefulness (Goldstein et al 2018), while activating the reciprocal (anorexigenic) POMC neurons promoted sleep. Presently, it is unknown to what extent the local clock in these neurons modulates sleep/wake states and whether they interact with homeostatic sleep regulation.…”