Genetic and Hormonal Mechanisms of Sex Differences in the Nervous System

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Though they have important significance for many neuropsychiatric and neurological disorders, sex differences in the brain and the mechanisms that underlie these remain poorly understood. Importantly, recent studies have highlighted the key role of genetic sex in the nervous system, which acts together with hormonal cues to regulate sexual differentiation of the brain and of behavior. However, very little is known about how genetic sex might modulate neural development and function. Here, we take advantage of a recently described sex difference in the function of a single C. elegans sensory neuron pair, AWA, to better understand these pathways. Because there is strong evidence that conserved mechanisms that link genetic sex to neural function, these studies will provide a mechanistic framework that will enable future candidate-driven studies in mammalian systems. Based on extensive preliminary data, we hypothesize that cell-autonomous “genetic sex” dynamically modulates TGFβ signaling to bring about the sex difference in AWA sensory function. In Aim 1, we will identify transcription factors that specify the sexually dimorphic state of the AWA neurons using two complementary functional genomic approaches. In Aim 2, we will identify the regulatory mechanism targeted by genetic sex to modulate AWA function. Recent data indicate that TGFβ signaling is likely to be this mechanism. In Aim 3, we will identify the mechanism that controls the timing of the effects of genetic sex on AWA. Steroid hormone signaling has been implicated in this role, indicating that there may be deep evolutionary connections between steroids and genetic sex. Together, these studies will provide an integrated molecular-genetic framework that links genetic sex to a terminal effector of behavior, something that currently exists in no system.