Project Summary Energy balance and body weight control result from coordinated appetitive and physiological responses to nutrient and hormonal signals informing the caloric status of the animal. Complex hypothalamic neural networks are critical in organizing these responses. Our previous studies identified an essential role for brain-derived neurotrophic factor (BDNF) in central neural circuits regulating food intake and body weight. BDNF is a major regulator of synaptic transmission and plasticity in the mature brain and is synthesized and released by excitatory neurons in an activity-dependent manner. Among known energy balance centers, it is most abundant in the ventromedial hypothalamus (VMH), where it plays a required satiety role in the adult animal. Accordingly, its expression and that of its receptor TrkB, is elevated there in the fed state and depletion of BDNF in this region results in over-eating and excessive weight gain in mice. Neurons in the VMH are predominantly glutamatergic and mediate food intake suppression when activated. It is now recognized that feeding circuits are not hardwired but highly plastic and remodel in response to caloric signals to meet the energy demands of the animal. This form of synaptic plasticity has been well studied in the arcuate nucleus of the hypothalamus but not in the VMH. This exploratory project will investigate whether dynamic changes in GABAergic transmission occur in response to energy cues in the VMH to mediate energy balance control. Although GABAergic neurons are largely absent in the VMH, inhibitory GABAergic fibers originating elsewhere and GABAA receptors are abundant in this region. We will test the hypothesis that increased phasic (synaptic) GABAergic inhibition in the fed state provides feedback control of anorexigenic BDNF+ cells in the VMH to prevent neuronal over excitation and extended anorexia. Furthermore, we will determine whether tonic (extrasynaptic) GABAergic currents negatively regulate these cells in the fasted state to restore energy stores. In total, these investigations will inform how homeostatic changes in synaptic and extrasynaptic GABAergic transmission regulate VMH BDNF+ neurons to promote energy balance and metabolic health.