Development of Leptin-Sensitive Hypothalamic Pathways

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DESCRIPTION (provided by applicant): The long-range goal of this research is to understand how the adipocyte-derived hormone leptin acts on hypothalamic neurons to regulate development of central neural pathways involved in the regulation of mammalian homeostasis. Central to this goal is determining how leptin influences development of neural projections from the arcuate nucleus of the hypothalamus (ARM) to the paraventricular nucleus (PVH), key sites for integration of information related to peripheral energy stores and neuroendocrine demands. During the past project period we demonstrated that leptin is required for normal development of ARM projections, yet the long-term functional consequences of postnatal leptin remain to be established, and the critical period is not clearly defined. The overall hypothesis addressed in this proposal is that exposure to leptin during a discrete postnatal critical period is sufficient to permanently organize projections from the arcuate nucleus of.the hypothalamus that regulate food intake and key aspects of energy metabolism, and that alterations in neonatal nutrition during this developmental critical period influence growth through accompanying changes in levels of circulating leptin. We will test this hypothesis by using mouse models to address the following specific aims. First, we will evaluate the ability of postnatal leptin exposure to functionally rescue deficits in adult ob/ob mice (Specific Aim 1). Second, we will utilize neuroanatomical techniques to assess the impact of postnatal leptin exposure on identified neural inputs to PVH neurons in adult ob/ob mice (Specific Aim 2). Third, we will utilize the physiological and neuroanatomical assays developed during the first 2 specific aims to define the critical period for the developmental actions of leptin on projections of NPY/AgRP and POMC neurons in the ARM, and to identify associated long term physiological consequences (Specific Aim 3). Finally, we will study the impact of altered nutrition on the postnatal leptin surge and determine whether exogenous postnatal leptin can influence the pattern of catch up growth observed in mice derived from over- and under-nutritional postnatal environments (Specific Aim 4). The results of the proposed research will contribute significantly to our emerging appreciation of leptin as a key developmental factor in the hypothalamus, and may provide clues about how the neonatal nutritional environment imposes enduring consequences on brain architecture and the regulation of energy balance throughout life.