The long term goal of this research program is to elucidate the neuroendocrine mechanisms that underlie the timing of the onset of puberty in the rhesus monkey, a representative higher primate. In man and monkey, the prepubertal hiatus in gonadotropin secretion, which is responsible for the protracted delay from birth until puberty in this species, is occasioned by an interruption of pulsatile hypothalamic GnRH release. The restraint on the GnRH pulse generator during prepubertal development is largely imposed by mechanisms of extra-gonadal origin. Since a comparable control system does not appear to operate in non-primate species, studies of puberty in the monkey have particular relevance to the understanding of this fundamental event in human development.
The Specific Aims of this proposal are to: 1) further examine the hypothesis that puberty is triggered by activation of the NMDA receptor; 2) begin to examine the view that the onset of puberty is governed by either a growth tracking device (somatometer) or a time keeping device (clock) in the central nervous system; 3) determine whether thyroid hormone is necessary for manifestation of the restraint imposed upon the hypothalamic GnRH pulse generator during prepubertal development. Using the rhesus monkey as an experimental paradigm, physiological and pharmacological approaches will be brought to bear upon the question of the neurobiological basis of the prepubertal hiatus in pulsatile GnRH release from the primate hypothalamus. The notion that activation of the NMDA receptor is involved in triggering puberty will be examined directly by measuring release rates of Glu and Asp in hypothalamus using push-pull perfusion, and by determining whether NMDA receptor antagonists interrupt the onset of puberty. The technique of cross-perfusion, using extracorporal circuits and centrifugal pumps permanently coated with bioactive heparin, will be used to test whether circulating signals relay information on body growth to the somatometer, and thereby determine the time of puberty. The notion of a pubertal clock, on the other hand, will be examined by rearing male monkeys from birth in an artificial photoperiod cycle consisting of 16 weeks of long days and 16 weeks of short days. This is expected to entrain the circannual cycle to an abbreviated calendar year, and therefore to induce precocious puberty if a pubertal clock monitors time by tracking circannual cycles. When chronic access to the hypothalamus and venous circulation is required, remote withdrawal-infusion devices will be employed that do not demand either restraint or tranquilization of the experimental primate.
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