Circadian Regulation of the Dorsomedial Hypothalamic Nucleus and Its Impact on Energy Homeostasis

点击翻译按钮获取中文摘要

PROJECT SUMMARY Systems regulating circadian timing and energy homeostasis are tightly integrated, and increasing evidence suggests that circadian disruption (e.g., induced by sleep restriction, or eating during the normal resting period) predisposes to obesity and metabolic syndrome in humans. Thus, an improved understanding of the neurobiological determinants of feeding time has direct translation to human health and may inform novel therapeutic and dietary strategies to combat metabolic dysfunction. In mammals, circadian rhythms of metabolism and behavior are organized by the light-controlled “master clock” located in the hypothalamic suprachiasmatic nucleus (SCN). In harmony with environmental light-dark cycles, this biological pacemaker expresses rhythmic neuronal and molecular activity that encodes and transmits time cues to downstream brain areas and subordinate clocks to align their activity. However, how rhythmic outflow from the SCN is decoded to align diverse physiological and behavioral processes, including feeding, is poorly understood. Among downstream targets of the SCN implicated in feeding is the dorsomedial hypothalamic nucleus (DMH). Our recent findings suggest that the activity of DMH neurons expressing the leptin receptor (DMHLepR) is critical for the consolidation of feeding to the appropriate photoperiod in mice, such that inactivation of DMHLepR neurons promotes obesity and increased light-cycle intake in both male and female mice. Our preliminary data further show that DMHLepR neurons receive input from the subparaventricular zone (SPZ), a critical relay of circadian timing from the SCN, and exhibit diurnal variation in basal and food-evoked activity. Based on these observations, we hypothesize that DMHLepR neurons integrate clock time and sensory inputs regarding food availability to regulate daily feeding time in mice. As a first step to understanding how DMHLepR neurons are regulated, we propose to first identify and characterize neural afferents by both histology and Channelrhodopsin-assisted circuit mapping (CRACM). We will next evaluate whether afferent input from the SPZ, which putatively conveys clock time from the SCN, is required for normal circadian feeding and metabolism in mice. To better understand how DMHLepR activity may regulate feeding behaviors, we will characterize the temporal activity dynamics of this population via both in vitro and in vivo multi-unit electrophysiology approaches. Finally, we will examine how DMHLepR activity is influenced by altered feeding and lighting schedules, and the requirement of SPZ input for these effects. This work is expected to improve our understanding of the neural networks underlying endogenous rhythms in behavior, feeding, and metabolism, and thereby inform the development of new therapeutic and dietary strategies for the treatment of humans with metabolic dysfunction.