173-OR: Medial Amygdala Projections Regulate the Metabolic Responses to Internal and External Signals

Abstract

Medial amygdala projections regulate the metabolic responses to internal and external signals The brain is a crucial part of the complex system that controls blood glucose in response to internal signals and external stressors. However, we do not know whether distinct CNS circuits regulate metabolism in response to internal state (fed vs. fasted) and environmental cues. Here we used detailed mapping of activated neurons, circuit tracing and projection-specific neural manipulation to determine the contribution of medial amygdala (MeA) neurons and circuits to the metabolic response to internal and external signals. Fasting, refeeding and stressors that increase blood glucose significantly activate MeA neurons. MeA neurons are synaptically connected to organs crucial to metabolic control and chemogenetic activation of MeA neurons significantly increased blood glucose, independent of pancreatic hormone release, and suppressed feeding. We identified the bed nucleus of the stria terminalis (BNST) and ventromedial hypothalamus (VMH) as major downstream projections from the MeA. MeA neurons projecting to BNST and to VMH are distinct neural populations activated by metabolic and emotional stress. Targeted activation of MeA neurons projecting to VMH but not to BNST MeA neurons mimicked the glycemic responses to fasting and stress with significantly impaired glucose tolerance, increased hepatic gluconeogenesis and a more rapid recovery from hypoglycemia, without increased corticosterone or epinephrine. Conversely, targeted ablation of MeA neurons projecting to VMH significantly reduced blood glucose and blunted the hyperglycemic response to stress. These data reveal a critical role for the MeA-VMH circuit in glucose regulation in response to internal and external signals. Future work will assess how this pathway is disrupted in diabetes and its contribution to the associations between diabetes and mental health disorders. Disclosure K. Devarakonda: None. A. Alvarsson: None. M. Jimenez gonzalez: None. R. Li: None. V. E. Lehmann: None. S. Stanley: None. Funding American Diabetes Association/Pathway to Stop Diabetes (1-17-ACE-31 to S.S.); National Institutes of Health (R01NS097184, OT2OD024912); U.S. Department of Defense (W81XWH-20-1-0345, W81XWH-20-1-0156); Charles H. Revson Foundation (18-25); Swedish Society