A better understanding of the mammalian thermoregulatory system may lead to new therapeutic strategies for the treatment of conditions associated with hyperthermia such as infection, drug abuse, and stroke. Classical studies identified the preoptic area (POA) of the anterior hypothalamus as the principal site of mammalian thermoregulation. This region is postulated to contain warm-sensitive neurons that are activated by environmental heat and in response trigger an array of autonomic and behavioral responses that restore temperature homeostasis. An extensive scientific literature accumulated over the past 75 years has supported the existence and importance of these warm-sensitive cells, yet their neurochemical identity remains unknown. For this reason key components of the mammalian thermoregulatory circuit have remained inaccessible to modern genetically-targeted approaches in neuroscience. Recently we have used an approach for activity- based RNA sequencing to identify molecular markers that selectively label these long-sought warm-sensitive cells. We have shown using cell-type-specific optogenetic manipulations that activation of these neurons inhibits brown adipose tissue thermogenesis and lowers body temperature. We have also recorded the activity of these neurons in awake behaving mice and shown that they are activated by ambient heat and inhibited by ambient cold. Thus we have identified a novel, molecularly-defined neural population that functionally resembles the long-sought warm-sensitive cells of the POA. We propose here to apply approaches for genetic and projection-targeted neural manipulation and recording to elucidate the downstream circuit by which these cells control behavioral and autonomic thermoregulation.

Public Health Relevance

Body temperature is controlled by neural circuits in the brain that remain poorly understood. A better understanding of the structure and dynamics of these circuits would advance our ability to develop new therapeutic approaches for the treatment of medical conditions associated with hyperthermia such as stroke, infection and drug abuse. This proposal utilizes state-of-the-art approaches to selectively manipulate and record the activity of the key neurons that control body temperature in mammals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS094781-05
Application #
9900878
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
He, Janet
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Physiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Tan, Chan Lek; Knight, Zachary A (2018) Regulation of Body Temperature by the Nervous System. Neuron 98:31-48
Beutler, Lisa R; Knight, Zachary A (2018) A Spotlight on Appetite. Neuron 97:739-741
Leib, David E; Zimmerman, Christopher A; Poormoghaddam, Ailar et al. (2017) The Forebrain Thirst Circuit Drives Drinking through Negative Reinforcement. Neuron 96:1272-1281.e4
Garrison, Jennifer L; Knight, Zachary A (2017) Linking smell to metabolism and aging. Science 358:718-719
Chung, Shinjae; Weber, Franz; Zhong, Peng et al. (2017) Identification of preoptic sleep neurons using retrograde labelling and gene profiling. Nature 545:477-481
Zimmerman, Christopher A; Leib, David E; Knight, Zachary A (2017) Neural circuits underlying thirst and fluid homeostasis. Nat Rev Neurosci 18:459-469
Beutler, Lisa R; Chen, Yiming; Ahn, Jamie S et al. (2017) Dynamics of Gut-Brain Communication Underlying Hunger. Neuron 96:461-475.e5
Tan, Chan Lek; Cooke, Elizabeth K; Leib, David E et al. (2016) Warm-Sensitive Neurons that Control Body Temperature. Cell 167:47-59.e15
Chen, Yiming; Knight, Zachary A (2016) Making sense of the sensory regulation of hunger neurons. Bioessays 38:316-24
Leib, David E; Zimmerman, Christopher A; Knight, Zachary A (2016) Thirst. Curr Biol 26:R1260-R1265

Showing the most recent 10 out of 13 publications