Department of Biology, Loyola University Chicago, Chicago, Illinois, United States of America.
Penn Chronobiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS Genet. 2019 Nov 6;15(11):e1008478. doi: 10.1371/journal.pgen.1008478. eCollection 2019 Nov.
Circadian rhythms allow animals to coordinate behavioral and physiological processes with respect to one another and to synchronize these processes to external environmental cycles. In most animals, circadian rhythms are produced by core clock neurons in the brain that generate and transmit time-of-day signals to downstream tissues, driving overt rhythms. The neuronal pathways controlling clock outputs, however, are not well understood. Furthermore, it is unclear how the central clock modulates multiple distinct circadian outputs. Identifying the cellular components and neuronal circuitry underlying circadian regulation is increasingly recognized as a critical step in the effort to address health pathologies linked to circadian disruption, including heart disease and metabolic disorders. Here, building on the conserved components of circadian and metabolic systems in mammals and Drosophila melanogaster, we used a recently developed feeding monitor to characterize the contribution to circadian feeding rhythms of two key neuronal populations in the Drosophila pars intercerebralis (PI), which is functionally homologous to the mammalian hypothalamus. We demonstrate that thermogenetic manipulations of PI neurons expressing the neuropeptide SIFamide (SIFa) as well as mutations of the SIFa gene degrade feeding:fasting rhythms. In contrast, manipulations of a nearby population of PI neurons that express the Drosophila insulin-like peptides (DILPs) affect total food consumption but leave feeding rhythms intact. The distinct contribution of these two PI cell populations to feeding is accompanied by vastly different neuronal connectivity as determined by trans-Tango synaptic mapping. These results for the first time identify a non-clock cell neuronal population in Drosophila that regulates feeding rhythms and furthermore demonstrate dissociable control of circadian and homeostatic aspects of feeding regulation by molecularly-defined neurons in a putative circadian output hub.
昼夜节律使动物能够协调彼此的行为和生理过程，并将这些过程与外部环境周期同步。在大多数动物中，昼夜节律是由大脑中的核心时钟神经元产生和传递时间信号到下游组织来驱动明显的节律。然而，控制时钟输出的神经元途径还不是很清楚。此外，中枢时钟如何调节多个不同的昼夜节律输出也不清楚。鉴定昼夜节律调节的细胞成分和神经元回路，越来越被认为是解决与昼夜节律紊乱相关的健康病理的关键步骤，包括心脏病和代谢紊乱。在这里，我们基于哺乳动物和黑腹果蝇昼夜和代谢系统的保守成分，利用最近开发的一种喂食监测器，来描述果蝇脑间核（PI）中两个关键神经元群体对昼夜节律性摄食节律的贡献，PI 在功能上与哺乳动物下丘脑同源。我们证明，PI 神经元中表达神经肽 SIFamide（SIFa）的热敏操纵以及 SIFa 基因突变会破坏摄食-禁食节律。相比之下，PI 中表达果蝇胰岛素样肽（DILP）的附近神经元群体的操纵会影响总食物摄入量，但不会破坏摄食节律。这两个 PI 细胞群体对摄食的不同贡献伴随着通过 Trans-Tango 突触映射确定的截然不同的神经元连接。这些结果首次在果蝇中确定了一个非生物钟细胞神经元群体，它调节摄食节律，并且进一步证明了分子定义的神经元对昼夜节律和摄食调节的稳态方面的可分离控制在一个假定的昼夜节律输出枢纽中。
