Neuroendocrine mechanisms of natural reproductive aging in female rats
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Female reproductive senescence is widespread among mammalian species, but menopause is limited to species with menstrual cycles. While hormonal changes at menopause have profound impacts in the lives of women at middle age, the complex mechanisms underlying this process remain obscure. All three levels of the hypothalamic-pituitary-gonadal (HPG) axis are involved in reproductive aging, and evidence highlights a critical role for the dysregulation of gonadotropin-releasing hormone (GnRH) neurons, the hypothalamic cells that drive reproductive function. To investigate neuroendocrine mechanisms that may initiate and perpetuate reproductive decline at each step in the transition to acyclicity, I utilized an ovarian-intact middle-aged female rat model of natural reproductive senescence. These studies focused on three hypothalamic nuclei that are known to control GnRH activity: the anteroventral periventricular nucleus (AVPV), the site of positive hormone feedback onto GnRH neurons; the arcuate nucleus (ARC), the site of negative feedback; and the median eminence (ME), the site of GnRH release, with the following specific aims: 1) Characterize neuroendocrine gene and protein expression in female rats throughout the natural transition to acyclicity; 2) Determine the effects of chronic N-methyl-D-asparate receptor subunit 2b (NMDAR-NR2b) inhibition in acyclic females; and 3) Examine neuroendocrine gene expression during premature reproductive senescence after perturbation of the HPG axis. The results of these studies identified novel molecular and cellular changes with age and reproductive cycle status in the ARC and ME, two regions that are underappreciated for their roles in reproductive senescence. Surprisingly, few molecular targets were identified in the AVPV, a region that is much better-studied in this context. In the ME and ARC, I found changes in transcription factors and evidence of altered hormone feedback via changes in sex steroid hormone receptors and enzyme expression with reproductive aging. I also discovered decreased expression of genes for the excitatory neuropeptides, kisspeptin and neurokinin B, as well as decreased percentage of kisspeptin immunoreactive cells and their co-expression with estrogen receptor alpha in the ARC. And finally, in the ME, neurotrophic factor expression was changed with age, and the presence and phosphorylation state of the NR2b subunit of the NMDA receptor contributes to a greater inhibitory tone with acyclicity. Together these studies have identified novel pathways, especially in the ARC and ME, that are related to reproductive decline. Furthermore, changes in the hypothalamic neural and glial network of neurotransmitters, neuropeptides, hormone receptors and other transcription factors are likely contributing to altered responses to hormonal feedback and decreased excitatory drive for GnRH release.