One the most remarkable features of animals is their ability to sense changes in their internal physiologic state and then generate flexible behaviors that restore homeostasis. These survival processes are mediated by neural circuits in the brain that sense the state of the body and then convert this information into specific behavioral and autonomic responses. However our understanding of these homeostatic circuits has remained limited due to their structural complexity, as they are embedded within brain regions that contain a vast diversity of intermingled neural cell types. Understanding how this vast cellular diversity s organized into circuits that give rise to behavior is one of the central challenges in neuroscience I describe in this proposal how we have used a technology for activity-dependent RNA sequencing to generate a map of the key thermoregulatory neurons in the mouse brain. I then describe how we will develop two new technologies that will allow us to delineate the complete neural circuit that is downstream of these thermosensitive cells. These transformative new technologies enable the molecular identification of neurons that are anatomically or functionally connected and thereby allow for the first time the systematic application of RNA sequencing to deconstruct the cellular organization of neural circuits in the brain. I further outline how we wil use these new approaches to investigate the logic underlying the distributed and overlapping structure of neural circuits that mediate various aspects of physiologic homeostasis. This analysis takes advantage of information about the cellular organization of these circuits that could not be generated without the new technologies described in this proposal. Thus the experiments in this proposal will generate new tools for the neuroscience community and further apply these tools to address fundamental questions about the neural mechanisms that control homeostatic processes such as thermoregulation and feeding.
The brain contains dedicated neural circuits that control basic processes required for survival such as feeding, drinking and regulation of body temperature. A better understanding of the structure of these circuits might enable the development of more effective therapeutic approaches for common diseases caused by dysregulation of this circuitry such as obesity. This proposal describes the development of new technologies that will enable molecular mapping of these circuits.
| Beutler, Lisa R; Knight, Zachary A (2018) A Spotlight on Appetite. Neuron 97:739-741 |
| Tan, Chan Lek; Knight, Zachary A (2018) Regulation of Body Temperature by the Nervous System. Neuron 98:31-48 |
| 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 |
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