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 TGF? 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 TGF? 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.

Public Health Relevance

Though sex differences exist in a wide variety of neuropsychiatric and neurological disorders, little is known about the ways in which sex chromosomes can modulate the development and function of the brain. Here, we will take advantage of a simple but very powerful genetic model system, the nematode C. elegans, to identify the regulatory mechanisms by which the genetic sex of individual neurons can modulate their properties. The new information provided by this research will enable subsequent studies in more complex model systems, including mice.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Sesma, Michael A
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University of Rochester
School of Medicine & Dentistry
United States
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Fagan, Kelli A; Luo, Jintao; Lagoy, Ross C et al. (2018) A Single-Neuron Chemosensory Switch Determines the Valence of a Sexually Dimorphic Sensory Behavior. Curr Biol 28:902-914.e5
Barr, Maureen M; García, L Rene; Portman, Douglas S (2018) Sexual Dimorphism and Sex Differences in Caenorhabditis elegans Neuronal Development and Behavior. Genetics 208:909-935
Portman, Douglas S (2017) Sexual modulation of sex-shared neurons and circuits in Caenorhabditis elegans. J Neurosci Res 95:527-538
García, L René; Portman, Douglas S (2016) Neural circuits for sexually dimorphic and sexually divergent behaviors in Caenorhabditis elegans. Curr Opin Neurobiol 38:46-52
Ryan, Deborah A; Miller, Renee M; Lee, KyungHwa et al. (2014) Sex, age, and hunger regulate behavioral prioritization through dynamic modulation of chemoreceptor expression. Curr Biol 24:2509-17