The long-term goal of this research is to understand neural control of reproductive maturation in males by investigating the interactions between gonadal steroid hormones, steroid-sensitive neural circuits, and peptidergic neuronal systems that initiate the frequent secretion of luteinizing hormone-releasing hormone (LHRH) at the time of puberty. The importance of frequent pulsatile release of LHRH to the onset of gonadal maturation in male humans is well-appreciated. Delayed puberty caused by deficient hypothalamic secretion of LHRH can be treated with pulsatile infusion of LHRH. However, the etiology of this hypothalamic malfunction is not understood. The initiation of frequent release of LHRH at puberty is due in part to a decrease in hypothalamic responsiveness to negative feedback effects of testosterone. Conversely, the pubertal activation of male sexual behavior results in part from an increase in central nervous system responsiveness to behavioral effects of testosterone. Concurrent with these alterations in steroid hormone action within the nervous system are neuroanatomical changes in LHRH-producing neurons and in endogenous opiate-producing neurons.
The specific aims of this project are to 1) identify both the mechanisms that contribute to and the functional significance of previously documented changes within the LHRH and beta-endorphin neuronal systems that occur during activation of the hypothalamic-pituitary-gonadal axis at the time of puberty; 2) investigate heterogeneity of function among LHRH neurons in order to differentiate LHRH neurons that regulate gonadotropin secretion from those that perform functions within the central nervous system within the context of puberty; and, 3) investigate region-specific regulation of steroid receptors by steroid hormones as a possible cellular mechanism for the pubertal shifts in responsiveness to testosterone.
These specific aims will be accomplished by a multidisciplinary approach that includes the use of immunocytochemical identification of peptidergic and steroid receptive neurons, in situ hybridization histochemistry for LHRH messenger RNA, neuronal tract tracing, and in vivo pharmacological manipulations.
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