Defining the contributions of amygdalar circuits to the metabolic responses to homeostatic challenge - Our long-term goal is to understand the contribution of stress-induced neural signals to glucose regulation and the development of metabolic diseases with the aim of developing better therapies. To achieve this goal, we need a more detailed understanding of the neural circuits modulated by internal and external signals that, in turn, regulate metabolic function. In this proposal, wewill create a detailedand systematic analysis of the activity of specific amygdala neural populations in response to stress, determine their physiological roles, identify genetic markers for stress-responsive neural populations with defined projections and assess the contribution of these populations to metabolic regulation in acute and repeated stress. Our pilot data strongly support the activation of specific populations of amygdala neurons in response to stressors and chemogenetic activation of these neurons and circuits rapidly and robustly increases blood glucose. Our proposal will create new insights into the neural populations and circuits that regulate metabolism bring an unprecedented level of precision and specificity by combining cell-type specific neural tracing, spatial transcriptomics and targeted neuromodulation in which we have extensive experience. Without this detailed knowledge, our understanding the contribution of defined amygdala circuits to metabolic responses to stress will remain incomplete. The overall objective of this proposal is to understand the structure, genetic composition and function of defined amygdala circuits. Our central hypothesis is that defined medial amygdala neural populations and their hypothalamic projections are critical to the metabolic responses to stress. The rationale that underlies the proposed research is that internal and external stressors result in profound metabolic responses. However, we do not know the activity or genetic identity of the activated neural populations, their downstream circuits, or physiological roles. These represent major gaps in our understanding. To test our central hypothesis and attain the overall objective, we will a) determine the activity and physiological roles of defined medial amygdala neurons in the glucose response to acute and repeated stress and b) identify the neural activity, function and gene markers for specific downstream circuits that regulate blood glucose in responses to acute and repeated stress. To do so, we will use in vivo calcium imaging to assess neural activity, cell type and circuit- specific neuromodulation to define physiological roles of defined amygdala circuits in the regulation of glucose with stress, and spatial transcriptomics to identify gene markers for neural populations with defined projections contributing to glucose regulation in stress. The proposed studies will provide a comprehensive understanding of the unique biology of medial amygdala circuits regulating metabolic function in response to acute and repeated stress to form a crucial foundation for future studies to identifying potential therapies for stress-associated metabolic diseases such as type 2 diabetes. in response to homeostatic challenges. We will
