The previous interest of this laboratory in the neural regulation of progestin-induced prolactin secretion in primates has evolved into a broader interest in the regulation of serotonin neural function by ovarian steroids. The serotonin neural system projects to nearly every area of the forebrain and serotonin plays a major role in the regulation of numerous autonomic and cognitive neural processes. Thus, understanding the action of ovarian steroids in the serotonin neural system has relevance to many aspects of mental health and function in women. This proposal continues our search, at a cellular and molecular level, for neural targets of progesterone (P) which are unique from the action of estrogen (E) and it initiates studies to determine the mechanism by which E exerts differential effects on the expression of 3 pivotal genes: tryptophan hydroxylase (TPH), the serotonin reuptake transporter (SERT), and the 5-HT1A autoreceptor, in serotonin neurons of macaques. The overall hypothesis is that progesterone (P) has unique, undiscovered, genomic actions in the serotonin neural system which elevate 5-HT neurotransmission. Estrogen (E) is required for the induction and maintenance of nuclear P receptors and E alone changes the expression of pivotal genes related to serotonin synthesis, uptake, and neuronal firing. The molecular actions of E may be mediated by ER-beta and could involve a protein-protein interaction with nuclear factor kappa B (NF-kB).
Aim 1 will obtain definitive evidence that addition of P to an E regimen increases serotonin neurotransmission by application of microdialysis and measurement of serotonin in the extracellular compartment of terminal fields in steroid-treated macaques.
Aim 2 will determine the functional consequences of previously reported changes in TPH, SERT, and 5-HT1A autoreceptor gene expression in serotonin neurons of macaques treated with E and P.
Aim 3 will determine the effect of E and P on degradative mechanisms of serotonin. Gene expression and function of monoamine oxidase (MAO-A) will be determined in the dorsal raphe and hypothalamic termina1 field.
Aim 4 will seek the expression of ER-beta and determine if nuclear factor kappa B (NF-kB) is co-expressed and regulated by E or P in serotonin neurons of macaques.
Aim 5 will use laser capture to obtain pure populations of serotonin neurons from steroid-treated macaques and amplify their RNA for examination of genes related to phosphorylation events. These experiments will (1) further the hypothesis that E and P increase serotonin neural function and (2) initiate investigations of the mechanism of action of E and P in serotonin neurons.
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