The nervous system generates behavior through the coordinated activity of neural circuits. Our long-term goal is to understand how sex-specific behaviors, such as mating, nursing, and aggression are encoded by neural circuits. In mice, these behaviors are regulated to a large extent by olfactory cues, and by the steroid hormones secreted by the gonads. In addition, these dimorphic behaviors can be elicited in socially naive animals, suggesting that the neural pathways mediating these behaviors are likely to be genetically encoded. We are taking a molecular genetic approach to characterize these neural circuits, and to understand how such circuits integrate olfactory and hormonal cues to generate meaningful behavior.
One area of research in the laboratory focuses on identifying neural pathways that respond to testosterone, estradiol, and progesterone. These gonadal hormones are critical mediators of male and female-specific behaviors, and identifying the neuronal pools that respond to these steroids provides a good starting point to delineate circuits that regulate dimorphic behaviors. The circulating levels of these hormones are different between the sexes (testosterone predominates in males, estradiol and progesterone in females) and we anticipate that some of the neurons that respond to these steroids will manifest physical or molecular dimorphisms. This prediction has been borne out by our studies in which we have tagged neurons expressing the androgen receptor with reporter genes.
Sexual dimorphisms in behavior arise from physical or molecular differences in neural circuits. The research described above aims primarily to identify groups of neurons that are dimorphic by virtue of cell number or connectivity using genetic reporters. A second set of experiments in the laboratory is aimed at uncovering molecular differences between male and female brains. We are taking several molecular strategies to attempt to identify such dimorphisms in gene expression. Dimorphic patterns of gene expression will provide insight in the development and function of neural circuits that mediate sex-specific behaviors. In addition, such genes will also be utilized as genetic tools to drive expression of heterologous toxins to functionally characterize such neural circuits.
Studies from many laboratories provide evidence for the surprising finding that estradiol is required for both male- and female-specific behaviors. Does estradiol act on distinct brain regions to affect these behaviors? In addition, what is the nature of the interaction between testosterone- and estradiol-signaling in the control of male behaviors? Finally, since estradiol is virtually undetectable in the male circulation, how might estradiol influence male behaviors? These and related issues are the focus of a series of developmental studies that we are approaching using gene targeting.
What is the behavioral contribution of sexual dimorphisms in the brain? We are designing novel genetic strategies that afford inducible and regionally restricted functional manipulation of dimorhpic neuronal populations. Genetically lesioned animals will be assayed using a sensitive series of behavioral tests for mating, aggression, nursing and territorial marking. In future experiments, we also plan to implement electrophysiological techniques to elucidate the activity of particular neuronal subsets during sex-specific behaviors.
Interested in the research that we do?
For postdoctoral inquiries please contact Nirao Shah, MD, PhD (see contact page for contact information).
Prospective graduate students should contact the graduate program of their choice at UCSF (see links page).