Reproduction in males is governed by hormonal communication linking the brain and the;testis. The brain integrates cues from the environment and hormonal signals from the testis to govern the secretion of gonadotropin-releasing hormone (GnRH) from neurons in the forebrain and hypothalamus. GnRH directs the synthesis and release of the gonadotropins, LH and FSH, which exert control over testicular function. Testosterone from the testis then acts on the brain to provide the primary signal to regulate sexual differentiation, gonadotropin secretion, gender identity, and libido. Androgens, including testosterone and related compounds, are being used for male contraception, as well as for the treatment of delayed puberty, hypogonadism, osteoporosis, sexual dysfunction, cachexia and related disorders, and their development and use will continue to grow??as will the demand for more information about their actions on the brain. The primary objective of this research is to discover the molecular and cellular basis of testosterone's action in the forebrain of the male macaque, a primate whose reproductive physiology closely resembles that of man.
The specific aims of this project are focused on learning more about the role of 4 particular neuropeptides-??cocaine- and amphetamine-regulated transcript (CART), agouti-related protein (AgRP), melanin-concentrating hormone (MCH), and galanin-like peptide (GALP)??in the control of gonadotropin secretion and as molecular targets for the action of testosterone and other related androgens on the brain. Using systems, cellular, and molecular biological techniques, we will examine the effects of these neuropeptides on LH secretion, test the hypothesis that the genes coding for the peptides .are targets for androgen regulation, identify the mechanisms involved in signal transduction, and begin to map the synaptic circuitry linking these particular molecules to GnRH neurons. Understanding the cellular and molecular actions of androgens in the brain of a primate, whose reproductive physiology is similar to humans, is the first step toward the goal of putting androgenic compounds into use that have maximum therapeutic benefits with minimal deleterious side effects. Over time, the knowledge provided by these studies will be an aide to the development of improved strategies for addressing the problems of overpopulation, increasing options for family planning, and treating disorders of reproduction in men.
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