Scattered GnRH neurons in the primate hypothalamus perform different functions and engage in selective interactions. To establish which interactions are relevant to neuroendocrine regulation, (1) We will identify neuroendocrine GnRH neurons in the primate, and determine the afferent inputs involved in their control. We will identify neuroendocrine GnRH neurons in pre-ovulatory female primates by retrograde labeling from the median eminence (ME) and immunocytochemical (ICC) staining for GnRH with. DAB. We will use ICC staining with colloidal gold (red) to identify their specific afferents, e.g. dopamine (DA), norepinephrine (NE), and serotonin (5-HT), the peptide beta-endorphin (b-E), gamma-aminobutyric acid (GABA), and the excitatory amino acids (EAAs) glutamate and aspartate. Synapses will be characterized at the electron microscopic (EM) level and quantified. (2) We will determine which afferents mediate estrogen (E2) and progesterone (P4) feedback on neuroendocrine GnRH neurons. Since GnRH neurons lack E2 receptors, inhibitory feedback is thought to occur through afferent DA, b-E, or GABA neurons, which concentrate E2 and in some cases P4. We will use ICC staining with heavy metal-intensified DAB (black) to reveal neuronal nuclei containing E2 receptors in pre-ovulatory female primates, and identify neuroendocrine GnRH neurons with standard DAB (brown). We will perform ICC staining for DA, b-E, or GABA neurons with colloidal gold to identify which afferents mediate E2 feedback. Types and numbers of synapses will be evaluated by EM and quantified. Using the same protocol, we will perform ICC staining for P4 receptors and determine which afferents mediate P4 feedback. We will repeat these studies in early follicular and mid-luteal phase animals to examine feedback sites and effects of changing steroid levels. Puberty in primates involves reactivation of the dormant prepubertal GnRH pulse generator. While this implies that a competent GnRH neuronal system is present in juveniles, neuroanatomical changes which ma , enhance pulsatile GnRH secretion have yet to be assessed. (3) We will determine if GnRH neuronal connections or afferent synapses are altered during the peripubertal period. We will perform double EM ICC staining for GnRH. neurons (with DAB) and their afferents (with colloidal gold) in prepubertal and adult male monkeys. We will quantify and compare the types, characteristics, and numbers of GnRH neuronal interactions and afferent synapses. Using serial plasma LH measurements (by RIA), we will identify peripubertal (nocturnal LH surge) animals, perform ICC staining, and evaluate participation of the neural changes observed. In subsequent studies, we will examine prepubertal and peripubertal female monkeys and quantify their GnRH neurointeractions. We will compare the data to that previously obtained in adult, cycling females, and correlate the observed changes with associated peripubertal events. Together, these studies will elucidate the nature of GnRH neuronal control, the generation of pulsatile GnRH secretion, and assess neuroanatomical changes contributing to the onset of puberty.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Biochemical Endocrinology Study Section (BCE)
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Goldsmith, P C; Boggan, J E; Thind, K K (1997) Estrogen and progesterone receptor expression in neuroendocrine and related neurons of the pubertal female monkey hypothalamus. Neuroendocrinology 65:325-34
Thind, K K; Goldsmith, P C (1997) Expression of estrogen and progesterone receptors in glutamate and GABA neurons of the pubertal female monkey hypothalamus. Neuroendocrinology 65:314-24
Thind, K K; Goldsmith, P C (1995) Glutamate and GABAergic neurointeractions in the monkey hypothalamus: a quantitative immunomorphological study. Neuroendocrinology 61:471-85
Goldsmith, P C; Thind, K K; Perera, A D et al. (1994) Glutamate-immunoreactive neurons and their gonadotropin-releasing hormone-neuronal interactions in the monkey hypothalamus. Endocrinology 134:858-68
Thind, K K; Boggan, J E; Goldsmith, P C (1993) Neuropeptide Y system of the female monkey hypothalamus: retrograde tracing and immunostaining. Neuroendocrinology 57:289-98
Thind, K K; Boggan, J E; Goldsmith, P C (1991) Interactions between vasopressin- and gonadotropin-releasing-hormone-containing neuroendocrine neurons in the monkey supraoptic nucleus. Neuroendocrinology 53:287-97
Goldsmith, P C; Boggan, J E; Thind, K K (1991) Opioid synapses on vasopressin neurons in the paraventricular and supraoptic nuclei of juvenile monkeys. Neuroscience 45:709-19
Thind, K K; Goldsmith, P C (1989) Corticotropin-releasing factor neurons innervate dopamine neurons in the periventricular hypothalamus of juvenile macaques. Synaptic evidence for a possible companion neurotransmitter. Neuroendocrinology 50:351-8
Thind, K K; Goldsmith, P C (1988) Infundibular gonadotropin-releasing hormone neurons are inhibited by direct opioid and autoregulatory synapses in juvenile monkeys. Neuroendocrinology 47:203-16
Song, T; Nikolics, K; Seeburg, P H et al. (1987) GnRH-prohormone-containing neurons in the primate brain: immunostaining for the GnRH-associated peptide. Peptides 8:335-46

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