Prolactin Feedback to Hypothalamic Dopaminergic Neurons

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DESCRIPTION (provided by applicant): Prolactin is absolutely essential for normal lactation and breast milk is considered the optimal nourishment for newborn infants. As part of its role in maintaining the maternal process, prolactin has multiple and important effects within the central nervous system. Although prolactin is critical for some aspects of reproductive success, too much prolactin is detrimental for fertility. Prolactin-secreting tumors are the most prevalent pituitary defect and the resulting hyperprolactinemia causes infertility in men and women. The tuberoinfundibular dopaminergic neurons in the hypothalamus provide the major neuroendocrine control to maintain circulating prolactin levels low, but sufficient, for normal reproductive function. Dopamine acts as the major prolactin-inhibiting factor and prolactin, in turn, feeds back to increase dopaminergic neuronal activity, Tyrosine hydroxylase is the rate-limiting enzyme in dopamine biosynthesis and its activity is highly regulated at the level of transcription of the tyrosine hydroxylase gene and by post-translational control mechanisms such as phosphorylation/dephosphorylation of the existing enzyme. Yet, we know very little about how hypothalamic dopaminergic neurons integrate the prolactin-induced signals to enhance neuronal activity. The proposed studies will utilize several models to elucidate mechanisms involved in prolactin control of tyrosine hydroxylase in hypothalamic dopaminergic neurons. Intact animals will be used to determine the integrative effects of prolactin when all hypothalamic and extrahypothalamic inputs are intact. Primary hypothalamic cell cultures will be used to isolate dopaminergic neurons from extrahypothalamic inputs. Neuronal cell lines will be used to fully explore cellular and molecular mechanisms. Experiments will examine contributions of gene expression and post-translational modifications to increase dopaminergic neuronal function. The expression and phosphorylation/ activation of acute and prolonged prolactin-induced signals within the hypothalamus and specifically within dopaminergic neurons will be analyzed. The roles of these prolactin activated signaling pathways to initiate or sustain the increase in tyrosine hydroxylase activity will be examined. The last set of experiments will evaluate molecular mechanisms that contribute to prolactin enhancement of tyrosine hydroxylase gene expression. Critical new information on prolactin's actions within the central nervous system should result from the proposed experiments.