Noradrenergic modulation of identified, potentially energy homeostasis regulating neurons in the paraventricular nucleus of the hypothalamus

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Highly dynamic neuronal networks in the hypothalamus play an important role in the regulation of body weight and energy balance. These control circuits adjust food intake and energy expenditure according to the needs of the organism and the availability of fuel sources in the periphery of the body. Mismatch between energy intake and expenditure can cause metabolic disorders including obesity and type 2 diabetes mellitus, whose prevalence is increasing in Western societies. To better understand and counteract obesity and associated metabolic disorders, increasing efforts are being made to define the control mechanisms that regulate body weight and energy homeostasis.The paraventricular nucleus of hypothalamus (PVH) is an important autonomic control center, which integrates signals from neuronal, neuroendocrine, and autonomous pathways to regulate autonomic processes, including renal and cardiovascular functions, and stress responses. The PVH is also crucial for controlling the energy balance. Since manipulation of the noradrenergic system in the hypothalamus modifies feeding behavior and food intake, we ask whether the catecholamine noradrenalin is a direct modulator of energy homeostasis-regulatory neurons in the PVH. This question is of particular relevance, since recent studies in primates suggest that noradrenergic neurons of the locus cereuleus play a critical role in processing of reward information.We will address this question in three steps: First, we will analyze the modulatory effect of noradrenalin on intrinsic electrophysiological properties of identified PVH neurons by performing perforated patch clamp recordings in brain slices. Second, we will use cell type-specific transcriptomics to build an inventory of adrenergic receptors that are expressed in the different types of PVH neurons and potentially could mediate the noradrenergic modulation of these neurons. Third, functional pharmacology will be used to test which of the expressed adrenergic receptors are functional and how they contribute to the net modulatory effect of NA. The proposed experiments, will define in detail the biophysical and cellular mechanisms that mediate modulation of the different PVH neuron types by noradrenalin. We expect that these results will foster our understanding of how reward and metabolic signals are processed at the single-cell and circuit level in this prominent autonomic control center.