Abstract
Neurogenesis in the adult brain has become an exciting research area in the past three decades. With the advent of new scientific methods and techniques, researchers have been able to identify and characterize new cells proliferating throughout the brain. In mammals, the main areas for adult neurogenesis are the subventricular zone and dentate gyrus of the hippocampus (DG). However, more recent research has identified newly proliferated cells in other brain regions, such as the neocortex, amygdala and hypothalamus. Environmental factors, both external and internal, have been shown to increase or decrease cell proliferation and/or survival in several of these brain regions; examples of these factors include environmental enrichment, social interaction, chemosensory stimuli, steroid hormones and neurotransmitters.
In this dissertation, social environment and gonadal steroid hormones are examined for their influence on cell proliferation and/or survival in the adult vole brain. Prairie (Microtus ochrogaster) and/or meadow (M. pennsylvanicus) voles were used as animal models based on unique aspects of their physiology and behavior. The cell proliferation marker 5-bromo-2’-deoxyuridine (BrdU) was employed to identify newly proliferated cells throughout the adult brains. In the first series of experiments, we examined for the effects of male exposure and social isolation on neurogenesis in the adult female prairie vole, a monogamous and highly social species. Male exposure enhanced the proliferation of new cells in the amygdala and hypothalamus in comparison to social isolation or female exposure, and the newly proliferated cells coexpressed neuronal markers, indicating that new neurons are being produced in response to the environmental stimuli. Group differences in the number of cells undergoing apoptosis were minimal, so social environment exerted its effects most likely on cell proliferation, rather than on cell death. As voles may be induced into ovulation by male exposure, we hypothesized that the male exposure enhanced cell proliferation via an associated increase in serum estrogen. Thus, in the next study, we compared ovariectomized female prairie and meadow voles to determine the effects of estrogen on cell proliferation in the adult vole brain. Treatment with estradiol benzoate (EB) significantly enhanced the density of BrdU-labeled cells in the amygdala, particularly in the posterior cortical (pCorA) and medial (pMeA) nuclei, in meadow, but not prairie, voles, and similar percentages of BrdU-labeled cells displayed a neuronal or glial phenotype. Estrogen receptor alpha (ERa) was also mapped in the brain of intact females from both species; meadow voles had a higher density of BrdU-labeled cells containing ERa in the pCorA, but not pMeA or DG, in comparison to prairie voles. Furthermore, many of the BrdU-labeled cells in the brain of both species coexpressed ERa labeling, allowing for the possibility of a direct effect of estrogen on cell proliferation. These data suggest that estrogen has a species-specific effect on neurogenesis, possibly by acting directly on the proliferating cells. Finally, in the last series of experiments, the effects of testosterone and its metabolites on adult neurogenesis were examined in the amygdalae of castrated male meadow voles. Treatment with testosterone propionate (TP) in the castrated males resulted in plasma testosterone levels similar to intact males following mating, and TP treatment enhanced the density of BrdU-labeled cells in the amygdala compared to control treatment. EB also exerted a similar effect as TP on the density of BrdU labeled cells, but 5a-dihydrotestosterone (DHT) was ineffective. A larger proportion of the BrdU labeled cells in the amygdala were identified as neurons, whereas a lesser percentage was glia. In addition, a time course study indicated that BrdU labeled cells were present in the amygdala as early as 30-min following an acute injection of BrdU. Together, these data indicate that social environment affects neuronal proliferation in a stimulus- and site-specific manner in adult female prairie voles and gonadal steroid hormones enhance cell proliferation in the amygdala of adult female and male meadow voles, possibly by acting directly on proliferating cells locally within the amygdala.
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