Puberty is a developmental stage between childhood and adulthood during which reproductive function is attained. Many disorders, including precocious and delayed puberty, and problems associated with these disorders, originate at this stage. Moreover, the onset of puberty at the normal age is very important, as any deviation from peer age can result in psychological perturbation. For these reasons, investigations of the mechanisms controlling the onset of puberty, using the non-human primate as a model, are essential and would contribute to the understanding and management of human clinical cases. The long-term objective of this research is to investigate the role of the hypothalamus in the control of the onset of puberty. The goal of this proposal is to test the hypothesis that the determining factor for the onset of puberty is the maturation of regulatory mechanisms for pulsatile LHRH release.
Four specific aims are proposed to test this main hypothesis.
The first aim i s to test the hypothesis that gamma-aminobutyric acid (GABA) inhibits LHRH release in the immature hypothalamus and that the removal of inhibition as a consequence of maturation triggers the onset of puberty.
This aim will be accomplished by 1) measuring the release of GABA in the stalk-median eminence (5-ME) during development using a push-pull perfusion method, 2) examining the effects of long-term infusion of the GABA/A antagonist bicuculline into the base of the third ventricle on the onset of puberty and 3) testing the effects of antisense oligodeoxynucleotides for glutamic acid decarboxylase(GAD) mRNAs on LHRH release. GAD is the synthetic enzyme forming GABA from glutamate and is derived from two different genes.
The second aim i s to test the hypothesis that the reduction of GABA release in prepubertal monkeys results in a concomitant increase in glutamate release.
This aim will be accomplished by 1) measuring glutamate release in the 5-ME simultaneously with GABA release during development, 2) examining the effects of glutamate and NMDA on LHRH release and 3) infusing NMDA antagonists into the 5-ME of the animal treated with an antisense oligodeoxynucleotide for GAD mRNA.
The third aim i s to investigate the role of GABA and other neurotransmitters in puberty using an animal model in which the timing of puberty is altered. The release pattern of LHRH, GABA, glutamate, norepinepherine and neuropeptide Y in the 5- ME will be determined in a monkey model of precocious puberty, which is induced by lesions of the posterior hypothalamus.
The fourth aim i s to examine the hypothesis that the pubertal increase in LHRH release is due to the elimination of inhibitory inputs to LHRH neurons, and subsequent establishment of selected neuronal pathways and/or neuronal networks responsible for the adult pattern of LHRH release. Formation of synapses in general and GABAergic synapses specifically onto the cell bodies and neuroterminals of LHRH neurons during postnatal development will be assessed by immunocytochemistry and electron microscopy. Results from these projects will not only provide evidence to support the proposed hypothesis, but will also clarify the mechanism by which the hypothalamus controls the onset of puberty.
Showing the most recent 10 out of 63 publications
