Functional dissection of a molecularly identified female-specific neural pathway in mice

PROJECT SUMMARY/ABSTRACT A central goal of modern neuroscience is to link genetically defined neural circuits with specific behaviors. Deep sequencing studies have revealed an incredible transcriptional heterogeneity of neuronal subtypes within populations previously thought to be homogeneous. Despite the discovery of such molecular heterogeneity, the functional and behavioral relevance of these recently genetically defined neuronal cell types is largely unknown. Our application addresses this gap in knowledge by focusing on the neuronal control of social behaviors. Social interactions, ranging from non-vocal communication to complex language to core behaviors such as courtship or aggression, are important for mental well-being and reproductive success. The neural circuits underpinning these diverse behaviors have been difficult to disentangle, with non-genetically targeted approaches yielding phenotypes in multiple behavioral domains. Here we propose to characterize how progesterone and estrogen receptor alpha expressing neurons (Pvl neurons) in the ventromedial hypothalamus ventrolateralis (VMHvl) regulate social behaviors. Our deep sequencing studies reveal distinct neuronal cell types within the population of Pvl neurons, with one of them restricted exclusively to females. Using newly developed Cre and Flpo mouse strains that mark this female-restricted neuronal cell type within Pvl neurons, we will determine its activity (Specific Aim 1), behavioral function (Specific Aim 2), and functional connectivity (Specific Aim 3) as these relate to female social behaviors. Together, our studies will uncover the activity dynamics, function, and connectivity of a genetically defined neuronal cell type of Pvl neurons; in parallel, we will also characterize the complementary set of remaining Pvl neurons and test their participation ins social behaviors. Thus, our research aims to understand how genetically defined cellular heterogeneity within a neuronal population relates to functional specificity in the control of social behaviors, a critical issue in neuroscience. Health Relatedness: Diverse neurodegenerative conditions and mental illnesses manifest with devastating clinical symptoms as well as a range of deficits in social and emotional behaviors. Pvl neurons within the VMHvl represent a critical hub that regulates diverse core, developmentally programmed social behaviors that differ between the sexes. Rare case reports of lesions in proximity to this region show dramatic alterations in social behaviors. Our studies therefore will provide new insights into fundamental questions in neuroscience, and they also have the potential to shed light on how dysfunction in pathways emanating from the VMHvl alters social behavior in disease states.