This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project examines the effect of estrogen (E) and progesterone (P) on serotonin neural function in macaques. Serotonin governs many autonomic and higher order neural functions. An elevation in serotonin neurotransmission is expected to benefit arousal, elevate mood and improve cognitive function. We are now pursing the hypothesis that ovarian hormones also improve serotonin neuron survival and serotonin neuronal plasticity. We examined DNA fragmentation in serotonin neurons of the dorsal raphe nucleus with a TUNEL assay and found that E?P treatment for one month significantly reduced TUNEL positive cells in ovarectomized female macaques. This indicates that ovarian steroids act on DNA repair mechanisms. Subsequently, we found that 64 probe sets related to DNA repair were increased by E?P in laser-captured serotonin neurons. In addition, we determined the effect of ovarian steroid administration on gene expression related to dendritic spine protrusion in laser-captured serotonin neurons. We found that E?P treatment for one month significantly increased expression of RhoA, Rac and cdc42 and their downstream effectors on a rhesus macaque microarray and confirmed these changes with qRT-PCR. These expression changes would increase spine proliferation on dendrites of serotonin neurons. Finally, we found that fenfluramine, a serotonin releaser that increases prolactin secretion, was less effective in macaques that were ovariectomized for 3 years compared to tubally ligated ovarian intact controls.
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