DEVELOPMENT OF PEPTIDERGIC PROJECTIONS FROM ARCUATE NUCLEUS OF HYPOTHALAMUS

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The long range goal of this line of research is to clarify the organization and development of peptidergic neural pathways from the arcuate nucleus of the hypothalamus (ARH) to hypothalamic regions known to mediate neuroendocrine regulation of mammalian homeostasis have evolved to integrate the neural system that control gonadotropin secretion and ingestive behavior. The ARH represents a key neuroanatomical interface between such systems, and its importance for gonadotropin secretion and feeding behavior is well documented. However, the detailed neurological mechanisms underlying these essential functions remain unclear, and little is known about the nuclei of the hypothalamus play key roles in mediating gonadotropin section and feeding behavior and share strong connections with the ARH, as well as with the paraventricular nucleus of the hypothalamus (PVH), which may represent the final common pathway for hypothalamic regulation of energy balance. In addition, each of the these nuclei express receptors for melanocortin and opiatergic peptides, which have been implicated in the regulation of both ingestive behavior and neural development. The overall hypothesis of this proposal is that melanocortin and opiatergic peptides are expressed in projections from the RH to the AVPV, PVH, and DMH, and that these peptides directly influence the development of connections between these nuclei. Anterograde axonal transport and histochemical methods will be used, together with both in vivo and in vitro model systems, to address the following specific aims. Specific Aim 1. Anterograde axonal transport of the tracer PHA-L will be used together with immunohistochemistry to demonstrate the presence of beta- endorphin (betaEND) and alpha melanocyte stimulating hormone (alphaMSH) in projections from the ARH to the AVPV and DMH in adult mice (C57Bl/6J). Specific Aim 2. The fluorescent racer DiI will be used to demonstrate the development of projects from the ARH to the AVPV, PVH and DMH in neonatal male and female mice. Specific Im 3. In situ hybridization will be used to correlate the expression of MC4 and mu or delta opiate receptors in the AVPV, PVH and DMH of neonatal animals with the arrival of inputs to these nuclei from the ARH. Specific Aim 4. DiI will also be used to study the development of neural projections from the RH to the AVPV, PVH and DMH in transgenic mice that lack functional receptors for beta-endorphin or MC4. Specific Aim 5. Axonal transport and immunohistochemistry in transgenic mice that lack functional receptors for beta-endorphin and alpha MSH containing projections from the ARH to the AVPV, PVH or DMH in organotypic hypothalamic explant co-cultures maintained in vitro under defined conditions. These studies will provide novel insights into cellular mechanisms underling the development of hypothalamic neural systems regulating homeostasis, and may also provide clues about the ontogeny of neurological defects related to infertility and obesity.