Homeostatic mechanisms, including thermoregulation, are essential for maintaining physiologic balance in warm-blooded mammals. Specialized neuronal circuits involving the brainstem, hypothalamus, spinal cord, and periphery regulate heat generation and dissipation processes that keep body temperature within a narrow physiologically acceptable window, even in the face of large ambient temperature swings. Brainstem serotonergic (5-HT) neurons comprise one key component of this thermoregulatory network;evidence suggests that they modulate downstream thermogenic mechanisms by synapsing on neurons in the spinal cord that project peripherally to control vasoconstriction, brown fat metabolism and shivering responses. In line with previous findings, work in our lab has established by direct experimental means (via inducible neuronal silencing) that brainstem 5-HT neurons are indeed required for maintaining 37C body temperature, even at room temperature (23C). Further, our recent functional and genetic studies suggest that the critical subset of 5-HT neurons responsible for maintenance of body temperature derive from rhombomeres 6-8 (r6-8) of the developing hindbrain and ultimately populate the lower brainstem raphe, as silencing other subsets fails to reproduce the dramatic temperature phenotype observed upon perturbation of the entire 5-HT system. Here we propose to test this prediction directly. Utilizing an intersectional pharmacogenetic neuronal silencing tool recently engineered in our lab to inducibly and reversibly suppress action potential firing in discrete 5-HT neuron subtypes, we will perturb this r6-8-derived 5-HT subset in the awake freely behaving mouse in a series of thermoregulatory assays (Aim 1). We will then determine how silencing 5-HT neuron subsets impinges on heat conservation and generation machinery (Aim 2), and we will map the downstream innervation targets of these neurons to better understand their role in thermoregulation (Aim 3). The identification and characterization of the specific 5-HT neuron subtype that participates in body temperature modulation will advance our understanding of a fundamental homeostatic mechanism, and our implementation of these innovative genetic tools will open the door to further investigation of these neuron types and circuits which are so essential to basic mammalian survival.

Public Health Relevance

Neurons that secrete serotonin as their neurotransmitter of choice are among the most varied in function in the human brain, affecting behavioral and physiological functions such as mood, appetite and respiratory drive;this project aims to identify and study the subset of serotonergic neurons responsible for modulating the control of body temperature. Maintenance of body temperature is crucial for nearly every physiological function in the human body, yet the serotonergic neurons modulating this process have not been directly identified and studied in-depth. We hope to elucidate the downstream mechanisms controlled by these neurons as well as the central nervous system targets they communicate with, the knowledge of which will advance understanding of a fundamental aspect of mammalian physiology that is absolutely critical for survival, as well as help us better understand diseases which involve hyper- or hypo-thermia.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Neurological Sciences Training Initial Review Group (NST)
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He, Janet
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Harvard Medical School
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Hennessy, Morgan L; Corcoran, Andrea E; Brust, Rachael D et al. (2017) Activity of Tachykinin1-Expressing Pet1 Raphe Neurons Modulates the Respiratory Chemoreflex. J Neurosci 37:1807-1819