Cellular and Synaptic Physiology of the Dorsomedial Hypothalamus

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Stressful stimuli trigger rapid and requisite changes that allow organisms to effectively cope with stress and restore homeostasis. While this response can be beneficial in the short term, prolonged exposure to stress can result in the disruption of numerous important physiological processes, including appetite regulation. The mechanisms underlying the link between stress and appetite; however, are poorly understood. The long term goal of my research program is to characterize the cellular, molecular, and synaptic mechanisms that underlie stress-induced alterations in food intake and metabolism. Numerous feeding circuits in the brain play an important role in regulating appetite and body weight, but no region is as fundamentally linked to stress and appetite as the dorsomedial nucleus of the hypothalamus (DMH). The DMH processes neural signals related to stress and satiety and I have recently demonstrated that stress triggers a functional rewiring of inhibitory synapses in the DMH such that presumed satiety neurons are inhibited. This is accomplished by alterations of two key signals that regulate neuronal communication in the DMH: endocannabinoids and nitric oxide. Much remains unknown, however, regarding the mechanisms by which stress influences synaptic function and endocannabinoid and nitric oxide signaling/interactions in the DMH. The behavioral consequences with respect to appetite regulation are also unknown. Thus, our short term objectives are threefold. First, we will use whole cell patch clamp electrophysiology to determine the effect of various stressors on synaptic transmission and changes in synaptic strength mediated by endocannabinoids and nitric oxide (Objective 1). Second, because endocannabinoids and nitric oxide interact to regulate neuronal communication in the DMH, we will study the mechanisms of these interactions and the effect of stress using electrophysiological and molecular (immunohistochemistry) techniques (Objective 2). Third, we will address the physiological consequences of endocannabinoid and nitric oxide administration in the DMH. Specifically, we will determine the effect of endocannabinoids and nitric oxide, and their interactions, in the DMH on food intake and body weight in naïve and stressed animals. (Objective 3). Together, these studies will provide important insight into the effect of stress on appetite regulation.