Nirao Shah, MD, PhD

Molecular and Neural Control of Sexually Dimorphic Behaviors

My lab is interested in understanding how the brain encodes sexually dimorphic social behaviors such as mating and territorial aggression.  We use our understanding of sensory, hormonal, and neuropeptide signaling to gain an entry point into the molecular and neural circuits that control these behaviors.  We have three broad research programs in my group.  We wish to characterize the circuits that control mate choice, social attachment to mates, and sex-typical displays of mating, territorial aggression, and parental care.  As detailed below, we use molecular, genetic, behavioral, and electrophysiological approaches to characterize these circuits.

Current Projects

Neural circuit control of mate choice
We have recently identified specific genes, including a chemosensory receptor, and neural pathways that inhibit male fruit flies from courting individuals of other drosophilid species.  We are using the powerful molecular genetic tools available in fruit flies to further characterize this “no-go” courtship pathway, using a combination of behavioral, imaging and neural tracing approaches.  We also wish to understand how the neural circuit that inhibits interspecies mating has evolved.

Neural circuit control of social attachment behaviors
Humans can form long-term social attachments or bonds with their spouse as well as other individuals.  It has been difficult to study the neurobiological basis of such adult bonds because traditional models such as worms, flies, and mice do not form social attachments.  By contrast, prairie voles, small mouse-sized rodents, form an enduring bond with their mating partner such that they reject other potential mates.  This social attachment is regulated by the neuropeptide hormones vasopressin and oxytocin.  We are currently developing reverse genetic tools for voles, including induced pluripotent stem cells, to identify and functionally characterize the neuropeptide-responsive circuits that control social attachment.

Neural circuit control of sexually dimorphic behaviors
Sex hormones such as testosterone, estrogen, and progesterone exert a profound influence on the display of sexually dimorphic behaviors such as mating and aggression.  Many labs, including my lab, have identified the neurons that express sex hormone receptors.  How these neurons control sexually dimorphic behaviors is poorly understood.  To address this issue directly, we (in collaboration with Jim Wells’ lab at UCSF) recently developed a novel genetic approach to ablate a progesterone receptor expressing set of neurons in the adult mouse ventromedial hypothalamus.  We find that these neurons control mating and fighting in males and sexual receptivity in females.  We are now developing electrophysiological approaches to characterize these neurons in freely moving mice.  We are also genetically ablating other sex hormone-responsive neurons in the mouse brain in order to identify their role in sex-typical displays of mating and aggression.

Molecular control of sexually dimorphic behaviors
Sex hormones exert long-lasting developmental and short-acting adult effects on the neural circuits that control sexually dimorphic behaviors.  The molecular mechanisms underlying these effects are poorly understood.  We have recently identified many sexually dimorphically expressed genes in the adult mouse hypothalamus whose expression patterns are controlled by sex hormones.  We find that mice bearing null mutations of these genes exhibit a highly modular deficit in one or the other sexually dimorphic behavior such that other behaviors are unaffected.  We are now expanding our search to identify such sex hormone regulated genes in different brain regions.  The long-lasting developmental effects of sex hormones are likely regulated by epigenetic programming.  We are interested in identifying these epigenetic programs using chromatin immunoprecipitation and deep sequencing.  Together, these molecular studies will provide a mechanistic insight into how sex hormones control social behaviors, and they will also provide genetic tools to further manipulate the underlying neural circuits.