Kisspeptin Neurons in the Arcuate Nucleus of the Hypothalamus Orchestrate Circadian Rhythms and Metabolism.

Successful reproduction in female mammals is precisely timed and must be able to withstand the metabolic demand of pregnancy and lactation. We show that kisspeptin-expressing neurons in the arcuate hypothalamus (Kiss1ARH) of female mice control the daily timing of food intake, along with the circadian regulation of locomotor activity, sleep, and core body temperature. Toxin-induced silencing of Kiss1ARH neurons shifts wakefulness and food consumption to the light phase and induces weight gain. Toxin-silenced mice are less physically active and have attenuated temperature rhythms. Because the rhythm of the master clock in the suprachiasmatic nucleus (SCN) appears to be intact, we hypothesize that Kiss1ARH neurons signal to neurons downstream of the master clock to modulate the output of the SCN. We conclude that, in addition to their well-established role in regulating fertility, Kiss1ARH neurons are a critical component of the hypothalamic circadian oscillator network that times overt rhythms of physiology and behavior.

The Dorsal Medial Habenula Minimally Impacts Circadian Regulation of Locomotor Activity and Sleep.

In nocturnal rodents, voluntary wheel-running activity (WRA) represents a self-reinforcing behavior. We have previously demonstrated that WRA is markedly reduced in mice with a region-specific deletion of the transcription factor Pou4f1 (Brn3a), which leads to an ablation of the dorsal medial habenula (dMHb). The decrease in WRA in these dMHb-lesioned (dMHbCKO) mice suggests that the dMHb constitutes a critical center for conveying reinforcement by exercise. However, WRA also represents a prominent output of the circadian system, and the possibility remains that the dMHb is a source of input to the master circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. To test this hypothesis, we assessed the integrity of the circadian system in dMHbCKO mice. Here we show that the developmental lesion of the dMHb reduces WRA under both a light-dark cycle and constant darkness, increases the circadian period of WRA, but has no effect on the circadian amplitude or period of home cage activity or the daily amplitude of sleep stages, suggesting that the lengthening of period is a result of the decreased WRA in the mutant mice. Polysomnographic sleep recordings show that dMHbCKO mice have an overall unaltered daily amplitude of sleep stages but have fragmented sleep and an overall increase in total rapid eye movement (REM) sleep. Photoresponsiveness is intact in dMHbCKO mice, but compared with control animals, they reentrain faster to a 6-h abrupt phase delay protocol. Circadian changes in WRA of dMHbCKO mice do not appear to emerge within the central pacemaker, as circadian expression of the clock genes Per1 and Per2 within the SCN is normal. We do find some evidence for fragmented sleep and an overall increase in total REM sleep, supporting a model in which the dMHb is part of the neural circuitry encoding motivation and involved in the manifestation of some of the symptoms of depression.