The goal of our grant application is a functional and anatomic dissection of the mouse bed nucleus of the stria terminalis (BNST). This nucleus regulates many behaviors, including social approach and interactions, response to predators, coping with physiological and behavioral stressors, and reward responses. The BNST is heterogeneous and contains many neuronal pools with distinct identities. One hypothesis to account for the functional diversity of the BNST is that different BNST neuronal pools serve distinct functions. Our previous work (funded by prior grant periods) and that of others has identified a population of aromatase expressing neurons located in the medial division posteromedial component of the BNST (BNSTmpm). Both aromatase and the BNST are critical for social interactions in males and females. Intriguingly, our work shows that there are more aromatase+ neurons in the BNSTmpm in males compared to females. We therefore hypothesize that aromatase+ BNSTmpm neurons influence the distinct social interactions displayed by the two sexes.
In Aim 1, we will use genetically targeted tools to map the connectivity and stimulus responsivity of BNSTmpm neurons in males and females.
In Aim 2, we will use genetic approaches to determine the necessity and sufficiency of BNSTmpm aromatase neurons for social interactions in males and females.
In Aim 3, we will use genetically modified mice we have developed to determine the role of aromatase in adult BNSTmpm neurons in the regulation of social interactions. In summary, our proposed studies will provide insight into the neural pathways emanating from aromatase BNSTmpm neurons and their functional relevance in vivo. Health Relatedness: Neurodegenerative and psychiatric conditions often reflect dysfunction of neural circuitry at a gross or microscopic level, and these remain poorly understood and therapeutically intractable. The BNST is a critical node linking amygdalar, hypothalamic, and cortical networks in the regulation of social interactions, response to various stressors, and reward pathways. Our proposed studies will shed light on the connectivity and functions of a subset of BNST neurons in the two sexes, thereby leading to an advance in basic scientific understanding of this region and the neural circuits within which it functions in health, and it may ultimately provide insights into future therapeutic or diagnostic applications for mental illness and common neurodegenerative conditions.

Public Health Relevance

Dysfunction of neural circuits underlies many devastating neurological and psychiatric conditions. Our basic research is focused on elucidating the connections and functions of the bed nucleus of stria terminalis, a brain region that is a critical hub in the brain for coping with social interactions, stress, reward pathways, and other physiological functions. Our work will shed light on how this brain region functions in health, and ultimately may help guide future therapeutic and diagnostic applications for neural circuit dysfunction in diverse disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS049488-11A1
Application #
9246958
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Gnadt, James W
Project Start
2005-05-01
Project End
2022-11-30
Budget Start
2017-05-15
Budget End
2018-11-30
Support Year
11
Fiscal Year
2017
Total Cost
$520,159
Indirect Cost
$196,397
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Yang, Taehong; Yang, Cindy F; Chizari, M Delara et al. (2017) Social Control of Hypothalamus-Mediated Male Aggression. Neuron 95:955-970.e4
Roberts, Todd F; Hisey, Erin; Tanaka, Masashi et al. (2017) Identification of a motor-to-auditory pathway important for vocal learning. Nat Neurosci 20:978-986
Delwig, Anton; Larsen, DeLaine D; Yasumura, Douglas et al. (2016) Retinofugal Projections from Melanopsin-Expressing Retinal Ganglion Cells Revealed by Intraocular Injections of Cre-Dependent Virus. PLoS One 11:e0149501
Bayless, Daniel W; Shah, Nirao M (2016) Genetic dissection of neural circuits underlying sexually dimorphic social behaviours. Philos Trans R Soc Lond B Biol Sci 371:20150109
Yang, Taehong; Shah, Nirao M (2016) Molecular and neural control of sexually dimorphic social behaviors. Curr Opin Neurobiol 38:89-95
Sokolowski, Katie; Esumi, Shigeyuki; Hirata, Tsutomu et al. (2015) Specification of select hypothalamic circuits and innate behaviors by the embryonic patterning gene dbx1. Neuron 86:403-16
Unger, Elizabeth K; Burke Jr, Kenneth J; Yang, Cindy F et al. (2015) Medial amygdalar aromatase neurons regulate aggression in both sexes. Cell Rep 10:453-62
Cheung, Clement C; Krause, William C; Edwards, Robert H et al. (2015) Sex-dependent changes in metabolism and behavior, as well as reduced anxiety after eliminating ventromedial hypothalamus excitatory output. Mol Metab 4:857-66
Fraser, Eleanor J; Shah, Nirao M (2014) Complex chemosensory control of female reproductive behaviors. PLoS One 9:e90368
Morgan, Charles W; Julien, Olivier; Unger, Elizabeth K et al. (2014) Turning on caspases with genetics and small molecules. Methods Enzymol 544:179-213

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