The long term goals of this program are to elucidate the mechanisms of control of the biosynthesis of thyrotropin-releasing hormone (TRH) in a discrete population of neurons in the hypothalamic paraventricular nucleus (PVN) that is critical for the regulation of anterior pituitary TSH secretion and determine how this regulatory system is perturbed in disease states characterized by low circulating thyroid hormone and inappropriately low TSH (sick euthyroid syndrome) and by adverse physiologic conditions. The importance of type 2 thyroxine deiodinase (D2) production by ependymal tanycytes, the transport of T4 across the blood-CSF barrier through the choroid plexus and the concentration of thyroid hormones in the CSF on feedback regulation by thyroid hormone on TRH gene expression in the PVN will be determined by interfering with these processes experimentally or depleting thyroid hormone in the CSF and identifying the amount of systemically administered thyroid hormone required to return proTRH mRNA in the PVN in hypothyroid animals to normal. Using an adenovirus shuttle system to reduce the concentration of specific thyroid hormone receptor (TR) isoforms in TRH neurons in the PVN or increase the expression of TRalpha2, we will identify the TR subtype(s) necessary for neuron-specific repression of the TRH gene by thyroid hormone. On the basis that leptin, a fat-derived circulating protein, can restore proTRH mRNA levels to normal in the PVN of fasting animals, we will study the importance of this protein in resetting the set point for feedback regulation by thyroid hormone on hypophysiotropic TRH and determine whether leptin exerts its central actions to modulate proTRH gene expression by direct effects on TRH secretion, indirectly through neuropeptide Y (NPY) or glucocorticoid secretion, or by regulating the amount of T4 transported through the choroid plexus into the CSF. In addition, by ablating brainstem catecholamine projection pathways to one side of the PVN, we will determine whether these pathways also contribute to resetting the sensitivity of TRH in the PVN to feedback regulation by thyroid hormone and mediate altered responses of proTRH mRNA to cold exposure. The importance of pituitary adenylate cyclase-activating polypeptide (PACAP) alone, or in conjunction with catecholamines in the regulation of hypophysiotropic TRH will be studied in vitro and by determining whether microinjection of these substances in vivo into the PVN will induce the phosphorylation of CREB in TRH neurons.
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