Sex and physiological State dependent molecular characterization of circuits governing parental behavior

PROJECT SUMMARY/ABSTRACT Parental care is essential for offspring well-being and survival yet requires a significant invest from adults without immediate benefit, suggesting the existence of hard-wired mechanisms governing its control. Despite the importance of this evolutionarily controlled behavior, parental behaviors vary greatly between animals of different sex, physiological state, and genetic background. Previous studies examining sex- and state- dependent influences on parental behavior have lacked the cell-type resolution critical to understanding how specific circuit components are modulated. The long timescale (hours to days) of changes affecting parenting behaviors suggests that neural circuits respond through dynamic gene expression changes. Through the use of intersectional genetics and single cell analysis I have established exquisitely specific access to two key neuronal hubs controlling parenting behavior. Preliminary results comparing Mothers, Fathers, and Virgin animals suggest potential transcriptional, epigenetic, and biophysical differences that are dependent on the animal’s sex and physiological state. During the K99 phase of the work proposed here I will rigorously assess sex- and state-dependent transcriptional changes, as well as their biophysical and behavioral implications, using the latest tools for cell-type specific recording and manipulation. I will uncover gene regulatory networks that give rise to observed transcriptional changes and will develop new intersectional tools to modulate gene expression in a cell-type specific manner. The successful completion of these Aims will reveal the molecular mechanisms though which sex and state mediate transcriptional reprograming to affect the function of this conserved behavioral circuit. Genetic variation also contributes to differences in the display of parental care. Preliminary results utilizing genetically distinct mouse strains show dramatic differences in parenting behavior and suggest a genetic contribution to behavioral variation. In the independent R00 phase of this proposal, I will perform a forward-genetic screen utilizing a well-characterized panel of genetically diverse mice to find genomic variants that contribute to parental behavior. The cell-type specific gene regulatory networks revealed in the previous Aims will then be used to assess the causal role of individual variants, providing a level of molecular explanation unobtainable with previous genetic mapping experiments. Furthermore, the successful completion of this project will provide a platform for future experiments aimed at understanding how genetic variants contribute to gene expression that ultimately affects animal behavior. The training phase of the award will be conducted in the laboratory of Dr. Catherine Dulac at Harvard University. In addition, I will be mentored by the outstanding team of scientists on my advisory committee that will assist with specific training goals as well as career guidance. In my application I have outlined a comprehensive plan for the acquisition of conceptual, technical, and professional skills that will enable my transition to an independent research position.