Male and female brains are different. The overarching goal of the proposed studies is to understand the molecular mechanisms of sex differences in the brain, focusing on the substantia nigra (SN) as a model. It is well established that testosterone, secreted by the testes, before or after birth, acts on the male brain to masculinize specific neural networks, which results in specific masculine behaviors. The classical view is that gonadal androgens are the only factors involved in the masculinization of the brain. Discovery of differential gene expression in the mammalian brain before the gonads start producing androgens led us to propose an alternative hypothesis. We propose to explore that sex differences in brain function and behavior may be caused in part by genetic factors not produced by the gonads. We have demonstrated specific expression of the Y-linked, testis-determining factor Sry, in two regions of the adult brain: the substantia nigra (SN) and the mammillary bodies. Reduction of Sry expression in the SN resulted in a strong decrease of tyrosine hydroxylase as well as in sensorimotor impairment. In order to understand the role of Sry in sex differences in SN function, we will investigate the expression profile of Sry in the adult brain, identify the cell types in which Sry is expressed, measure the level of expression of Sry and test whether it correlates with TH expression (Specific Aim 1). We will explore the consequences of down-regulating and upregulating Sry in the SN on TH-positive neurons and the sensorimotor behaviors they control, and whether Sry action in males compensates for the lack (or lower levels) of a female-specific factor. Specifically, we will test if this female factor could be estradiol, or dosage of the X chromosome (Specific Aim 2). Finally, we will elucidate the molecular mechanisms of action of Sry on dopaminergic neurons using NT2N cells as a model of dopaminergic neurons (Specific Aim 3). This proposal intends to improve our general understanding of sex differences in brain function. The characterization of the molecular mechanisms by which male and female brains differ impacts our understanding of sex differences in psychiatric and neurological disorders such as Parkinson's disease, attention deficit disorder, or depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH075046-04
Application #
7911767
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2007-08-31
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$363,308
Indirect Cost
Name
University of California Los Angeles
Department
Genetics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Ngun, Tuck C; Ghahramani, Negar M; Creek, Michelle M et al. (2014) Feminized behavior and brain gene expression in a novel mouse model of Klinefelter Syndrome. Arch Sex Behav 43:1043-57
Czech, Daniel P; Lee, Joohyung; Sim, Helena et al. (2012) The human testis-determining factor SRY localizes in midbrain dopamine neurons and regulates multiple components of catecholamine synthesis and metabolism. J Neurochem 122:260-71
Sutton, Edwina; Hughes, James; White, Stefan et al. (2011) Identification of SOX3 as an XX male sex reversal gene in mice and humans. J Clin Invest 121:328-41
Ngun, Tuck C; Ghahramani, Negar; Sánchez, Francisco J et al. (2011) The genetics of sex differences in brain and behavior. Front Neuroendocrinol 32:227-46
Bernard, Pascal; Harley, Vincent R (2010) Acquisition of SOX transcription factor specificity through protein-protein interaction, modulation of Wnt signalling and post-translational modification. Int J Biochem Cell Biol 42:400-10
Sánchez, Francisco J; Westefeld, John S; Liu, William Ming et al. (2010) Masculine Gender Role Conflict and Negative Feelings about Being Gay. Prof Psychol Res Pr 41:104-111
Bernard, Pascal; Sim, Helena; Knower, Kevin et al. (2008) Human SRY inhibits beta-catenin-mediated transcription. Int J Biochem Cell Biol 40:2889-900