Why do males and females behave differently in response to the same sensory cues? Behavioral sex- specificity is most evident in the displays of social behaviors by males and females in response to identical social cues. According to classical models of brain sex differentiation, molecular and architectural differences in brain circuitry are responsible for mediating sex differences in behavior. Alternatively, male and female brains may share a central circuit that is modulated differently. Strong support for this second model emerged from studies of Trpc2 knockout mice in which vomeronasal sensing is impaired, and from recent observations in various animal species including humans. In turn, these data raise the question - how does the brain generate behavior sex specificity? Moreover, little is known about how changes in circulating hormones and neural activity during puberty activate dormant neural circuits for sex specific behaviors ? a process likely to be associated with coordinated changes in synaptic strength and gene expression. I am developing a powerful new tool for studying in situ gene expression dynamics in genetically defined neural circuits. I will use this approach and test the hypothesis that gene expression programs during puberty act on similar circuits in males and females to determine the sex specificity of social behaviors. In preliminary experiments, I have genetically identified a subset of neurons in the mouse hypothalamus that gate behavioral sex-specificity. In the research proposed here, I will investigate the development and function of this neural circuit associated with behavioral sex-specificity by fulfilling the following aims:
In Aim 1, I will establish the role of genetically identified neurons in the hypothalamus in gating behavioral sex-specificity using cre-dependent viral tools for cell ablation. Next, I will use a novel tool for cell type specific gene expression analysis to examine the molecular changes in these neurons over puberty.
In Aim 2, I will use cre-dependent viral tools to trace the monosynaptic inputs and outputs of these neurons. Finally, in Aim 3, I will use whole cell patch clamp electrophysiology combined with optogenetics and gene expression analysis to examine input specific synaptic and molecular changes in these neurons that accompany the transition through puberty. The training phase of the award, conducted in the laboratories of Dr. Catherine Dulac and Dr. Venkatesh Murthy at Harvard University, outlines a comprehensive plan for the acquisition of technical and professional skills that will enable my transition to an independent research position. The successful completion of this project will provide a platform for future experiments aimed at understanding the development and architecture of neural circuits underlying social behaviors.

Public Health Relevance

Sex specific social interactions are a fundamental feature of the human experience and are crucial for individual and societal well-being. Moreover, several neuropsychiatric disorders such as Autism, Schizophrenia and Depression are characterized by sex differences in their prevalence, age of onset and severity. Understanding the molecular and neural circuit basis for the development and expression of behavioral sex- specificity is thus critical to understanding social behavior in normal and pathological contexts.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Career Transition Award (K99)
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National Institute of Child Health and Human Development Initial Review Group (CHHD)
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Freund, Lisa S
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Harvard University
Schools of Arts and Sciences
United States
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Moffitt, Jeffrey R; Bambah-Mukku, Dhananjay; Eichhorn, Stephen W et al. (2018) Molecular, spatial, and functional single-cell profiling of the hypothalamic preoptic region. Science 362: