Identification of a Brainstem Circuit Controlling Feeding

• Published in: Cell Vol. 170; no. 3; pp. 429 - 442.e11
• Main Authors: Nectow, Alexander R., Schneeberger, Marc, Zhang, Hongxing, Field, Bianca C., Renier, Nicolas, Azevedo, Estefania, Patel, Bindiben, Liang, Yupu, Mitra, Siddhartha, Tessier-Lavigne, Marc, Han, Ming-Hu, Friedman, Jeffrey M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.07.2017
• Subjects: agonists; Animals; Appetite Regulation; Body Weight; Brain - physiology; brain stem; dorsal raphe nucleus; Dorsal Raphe Nucleus - cytology; Dorsal Raphe Nucleus - metabolism; Electrophysiology; energy balance; energy homeostasis; Fasting; feeding; food intake; gamma-aminobutyric acid; Hunger; hypothalamus; leptin resistance; locomotion; locomotor activity; Male; Mice; Mice, Inbred C57BL; Mice, Obese; neurons; Neurons - metabolism; obesity; Optogenetics; receptors; transporters; dorsal raphe nucleus; body weight; leptin resistance; feeding; locomotor activity; energy homeostasis; obesity
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2017.06.045

Hunger, driven by negative energy balance, elicits the search for and consumption of food. While this response is in part mediated by neurons in the hypothalamus, the role of specific cell types in other brain regions is less well defined. Here, we show that neurons in the dorsal raphe nucleus, expressing vesicular transporters for GABA or glutamate (hereafter, DRNVgat and DRNVGLUT3 neurons), are reciprocally activated by changes in energy balance and that modulating their activity has opposite effects on feeding—DRNVgat neurons increase, whereas DRNVGLUT3 neurons suppress, food intake. Furthermore, modulation of these neurons in obese (ob/ob) mice suppresses food intake and body weight and normalizes locomotor activity. Finally, using molecular profiling, we identify druggable targets in these neurons and show that local infusion of agonists for specific receptors on these neurons has potent effects on feeding. These data establish the DRN as an important node controlling energy balance. [Display omitted] [Display omitted] •Fasting activates DRNVgat neurons; re-feeding activates DRNVGLUT3 neurons•Activation of DRNVgat neurons increases and DRNVGLUT3 suppresses feeding•Inhibiting DRNVgat neurons in obese mice reduces food intake and body weight•DRN neurons can be regulated pharmacologically to drive changes in food intake A combination of brain mapping and molecular pharmacology approaches identifies specific neurons in the dorsal raphe nucleus as being important regulators of feeding behavior.