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Neuroscience Graduate Program at UCSF

Faculty - Nirao Shah, M.D./Ph.D.

Molecular and Neural Control of Sexually Dimorphic Behaviors


Research Description

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.

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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.

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Lab Members

Osama Ahmed, Graduate Student
Maricruz Alvarado, Technician
Maxim Borius, Technician
Catriona Carey, Lab Manager
Eleanor Fraser, Postdoctoral Fellow
Mattias Karlsson, Ephys Core Director
Devanand Manoli, Postdoctoral Fellow
Mayra Melville, Administrative Assistant
Jessica Tollkuhn, Postdoctoral Fellow
Elizabeth Unger, Graduate Student
Shivani Vaidhyanathan, Cal undergrad
Taehong Yang, Postdoctoral Fellow

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Selected Publications

Wu MV, Manoli DS, Fraser EJ, Coats JK, Tollkuhn J, Honda SI, Harada N, and Shah NM.  Estrogen masculinizes neural pathways and sex specific behaviors. Cell 139: 61-72 (2009).

Juntti SA, Tollkuhn J, Wu MV, Fraser EJ, Soderborg T, Tan S, Honda SI, Harada N, and Shah, NM. The androgen receptor governs the execution, but not programming, of male sexual and territorial behaviors. Neuron 66:260-272 (2010).

Wu MV and Shah NM. Control of masculinization of the brain and behavior.  Curr Opin Neurobiol 21:116-123 (2011). Review.

Xu X, Coats JK, Yang CF, Wang A, Ahmed OA, Alvarado M, Izumi T, and Shah NM.  Modular genetic control of sexually dimorphic behaviors. Cell 148:596-607 (2012).

Manoli DS, Subramanyam D, Carey C, Sudin E, Van Westerhuyzen JA, Bales KL, Blelloch R, and Shah NM. Generation of induced pluripotent stem cells from the prairie vole.  PLoS One 7(5):e38119 (2012).

Yang CF, Chiang M, Gray DC, Prabhakaran M, Alvarado M, Juntti SA, Unger EK, Wells JA, and Shah NM.  Sexually dimorphic neurons in the ventromedial hypothalamus govern mating in both sexes and aggression in males. Cell 153:896-909 (2013).

Manoli DS, Fan P, Fraser EJ, and Shah NM.  Neural control of sexually dimorphic behaviors.  Curr Opin Neurobiol 23:330-338 (2013). Review.

Fan P, Manoli DS, Ahmed OM, Chen Y, Agarwal N, Kwong S, Cai AG, Neitz J, Renslo A, Baker BS, and Shah NM.  Genetic and neural mechanisms that inhibit Drosophila from mating with other species.  Cell 154:89-102 (2013).

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Nirao Shah, M.D./Ph.D.



Email

nms@ucsf.edu

Phone

415-514-4381

Office Address

UCSF Mission Bay, Box 2722
Rock Hall, room 348B
1550 4th Street
San Francisco, CA 94158-2324

Other Websites

Biomedical Sciences Graduate Program

Eli and Edythe Broad Center of Regeneration Medicine and Stem cell Research

Lab Website

PIBS Website

TETRAD