Sexual differentiation of the vertebrate brain is mediated by both hormone-dependent and cell-autonomous genetic mechanisms. However, how these genetic mechanisms contribute to sex differences in neural function, behavior and disease susceptibility remains unknown. In the nematode C. elegans, sexual differentiation occurs largely through cell-autonomous mechanisms, providing an ideal model to identify conserved regulators of this process. To this end, we are studying a sexually dimorphic response to ascaroside sex pheromones in C. elegans. Ascarosides elicit attraction in males but not in hermaphrodites. However, we find that genetically sex-reversing the state of shared neural circuits is sufficient to largely sex-reverse ascaroside attraction, indicating that sexual modulation of circuits common to both sexes is important for this sexually dimorphic behavior. It is unclear how the genetic sex of the nervous system regulates the properties of isomorphic circuitry and the function of individual neurons. One possibility is that the circuit contains key sexually regulated sensory and interneurons that modulate how ascaroside information is processed by the circuit. These sexually dimorphic neurons respond to ascarosides in a sex-dependent manner to elicit changes in activity that propagate throughout the circuit and change behavior. Sexually dimorphic neuron function is likely caused by sex differences in gene expression, however it is unclear what those differences in gene expression are and how they are regulated.
In Specific Aim 1, I will determine how genetic sex modulates the function of the ascaroside attraction circuit. This will be achieved by sex-reversing groups of neurons to identify sites whose function is modulated by sex. Then I will record neuron activity to ask how sex regulates the properties of the entire circuit. The mechanisms by which genetic sex modulates neuron function are unknown but it is likely through sexually regulating genes expressed by that neuron.
In Specific Aim 2, I will determine how genetic sex regulates gene expression to alter neuron function. I will employ both a candidate and screen approach to identify sexually regulated genes that permit ascaroside attraction. Then I will use calcium recordings to understand how these genes contribute to the sexually dimorphic neuron function. Together, these studies will provide novel insight into how genetic mechanisms of sex determination influence neural function.
By studying a sexually dimorphic behavior in the nematode C. elegans, we hope to uncover conserved genetic mechanisms through which sex chromosomes directly affect the neurophysiological properties of a neuron. These mechanisms may play important roles in many neurological and psychiatric diseases, particularly those that show strong sex biases, such as autism, schizophrenia, Parkinson's disease, and epilepsy.
| 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 |
| Fagan, Kelli A; Portman, Douglas S (2014) Sexual modulation of neural circuits and behavior in Caenorhabditis elegans. Semin Cell Dev Biol 33:3-9 |
