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.
