Human body temperature increases during wakefulness and decreases during sleep. The body temperature rhythm (BTR) is a robust output of the circadian clock and is fundamental for maintaining homeostasis, such as generating metabolic energy and sleep, as well as entraining peripheral clocks in mammals. However, the mechanisms that regulate BTR are largely unknown. Therefore, there is a crucial need to identify the molecular mechanisms that regulate BTR. Drosophila are ectotherms, and their body temperatures are close to ambient temperature; therefore, flies select a preferred environmental temperature to set their body temperature. We identified a novel circadian output, the temperature preference rhythm (TPR), in which the preferred temperature in flies increases during the day and decreases at night. TPR thereby produces a daily body temperature rhythm. Fly TPR shares many features with mammalian BTR. During the current grant term, we established that Diuretic hormone 31 receptor (DH31R), a Drosophila calcitonin receptor family protein, mediates TPR, and we demonstrated that the closest mouse homolog of DH31R, calcitonin receptor (Calcr), is essential for normal BTR in mice. Importantly, both TPR and BTR are regulated in a distinct manner from locomotor activity rhythms, and neither DH31R nor Calcr regulate locomotor activity rhythms. Together, our findings suggest that DH31R/Calcr is an ancient and specific mediator of BTR. Thus, understanding fly TPR will provide fundamental insights into the molecular and neural mechanisms that control BTR in mammals. The goal of this proposal is to determine the molecular and neural mechanisms of TPR. Our recent study suggests that DH31 acts on clock neurons via DH31R to regulate TPR. Although DH31 primarily activates DH31R, DH31 can also activate the Pigment dispersing factor receptor (PDFR), required for locomotor activity rhythms, at a modest level in vitro. Because PDFR does not play a major role in daytime TPR, we expect that DH31R and PDFR are expressed in different cells. In addition to the identification of crucial ligand-receptor interactions, we recently found that master clock cells, the dorsal clock neurons 2 (DN2s), control TPR but not locomotor activity rhythms. The central hypothesis of this proposal: DN2s have temporally-regulated contacts with DN1ps and control rhythmic expression of DH31, which activates DH31R in PDFR-negative DN1ps, resulting in TPR.
In Aim 1, we will elucidate the physical and functional relationship between DN1ps and DN2s to control TPR.
In Aim 2, we will determine the mechanism that sets rhythmic DH31 expression in DN1ps.
In Aim 3, we will determine the mechanism by which DH31R-expressing neurons control TPR. This project will contribute to a mechanistic understanding of fly TPR. The outcomes of this study should ultimately provide a novel mechanistic understanding of the mammalian BTR.

Public Health Relevance

Circadian rhythm is important for human physiology, including sleep and metabolism. This project will contribute to a mechanistic understanding of a form of Drosophila circadian output known as temperature preference rhythm, which shares many features with mammalian body temperature rhythm. Understanding the mechanisms of fly temperature preference rhythm will expand the current understanding of mammalian body temperature rhythm, sleep disorders, and general sleep-associated issues, such as jet lag or the sleep disturbances common to night-shift workers.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Sesma, Michael A
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Cincinnati Children's Hospital Medical Center
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Umezaki, Yujiro; Hayley, Sean E; Chu, Michelle L et al. (2018) Feeding-State-Dependent Modulation of Temperature Preference Requires Insulin Signaling in Drosophila Warm-Sensing Neurons. Curr Biol 28:779-787.e3
Goda, Tadahiro; Doi, Masao; Umezaki, Yujiro et al. (2018) Calcitonin receptors are ancient modulators for rhythms of preferential temperature in insects and body temperature in mammals. Genes Dev 32:140-155
Tang, Xin; Roessingh, Sanne; Hayley, Sean E et al. (2017) The role of PDF neurons in setting the preferred temperature before dawn in Drosophila. Elife 6:
(2017) Correction: Goda et al., ""Drosophila DH31 Neuropeptide and PDF Receptor Regulate Night-Onset Temperature Preference"". J Neurosci 37:3102
Goda, Tadahiro; Tang, Xin; Umezaki, Yujiro et al. (2016) Drosophila DH31 Neuropeptide and PDF Receptor Regulate Night-Onset Temperature Preference. J Neurosci 36:11739-11754
Head, Lauren M; Tang, Xin; Hayley, Sean E et al. (2015) The influence of light on temperature preference in Drosophila. Curr Biol 25:1063-8
Goda, Tadahiro; Leslie, Jennifer R; Hamada, Fumika N (2014) Design and analysis of temperature preference behavior and its circadian rhythm in Drosophila. J Vis Exp :e51097
Tang, Xin; Platt, Michael D; Lagnese, Christopher M et al. (2013) Temperature integration at the AC thermosensory neurons in Drosophila. J Neurosci 33:894-901