Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)


Neuroscience Institute

First Advisor

Nancy G Forger


Sex differences in the brain underlie sex-specific behaviors and physiological processes, and may help to explain male- or female-biased neuropsychiatric disorders. Some of the best-studied neural sex differences depend on differential cell death in males and females, but other sex differences persist even if cell death is prevented. These include sex differences in stable patterns of gene expression, or what we refer to as the differentiation of neurochemical phenotype. The mechanisms contributing to sex differences in neurochemical phenotype are unknown, but epigenetic modifications, such as DNA methylation, control cell phenotype “decisions” throughout the body in developing animals. We recently discovered that expression of enzymes that place or remove DNA methylation marks peaks during the first week of life in the mouse brain and overlaps with the perinatal critical period of sexual differentiation. Thus, my over-arching hypothesis is that sex differences in DNA methylation early in life underlie sexual differentiation of cell phenotype. I tested this using a combination of techniques, including: pharmacological inhibition of DNA methyltransferases, siRNA knock-down of Ten-eleven-translocases, immunohistochemistry, pyrosequencing, and in situ hybridization. The results of this dissertation demonstrate that 1) neonatal inhibition of DNA methylation abolishes several sex differences in cell phenotype in the hypothalamus; 2) DNA methylation and demethylation both contribute to sex differences in the development of one cell type (estrogen receptor alpha, ERα) in the hypothalamic ventromedial nucleus (VMH) and arcuate nucleus, in a region-specific manner; and 3) sexual differentiation of cell phenotype in the VMH is not present at birth, but develops over the first few postnatal weeks and involves a developmental decrease in cell marker expression of Tac1, Rprm, and Pdyn, specifically in males. In summary, we demonstrate that neonatal DNA methylation and demethylation establish neurochemical cell phenotype in a sex- and brain region-specific manner, providing the first studies demonstrating a mechanism by which sexual differentiation of neuronal cell type occurs.


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