The long term goal of this research program is to identify the genes and signaling pathways that control sexual differentiation of social behavior. Sex differences in neurological diseases, normal and abnormal behaviors are well documented, but the mechanisms underlying the differences are not. Many behavioral disorders (i.e. schizophrenia, depression, autism etc.) have one universal symptom;atypical social interactions. Our goal is to understand development of normal social behavior and use this information to reveal novel genetic mutations in patients with behavioral disorders. In the past few years we have established that the androgen receptor (AR) is a major component in the sexual differentiation of social affiliative behaviors in the mouse. This is exciting because the AR has been implicated in sexual differentiation of primates, including humans. We will advance this finding by studying the genetic regulation of sexual differentiation downstream of AR, and we will discover the essential AR target genes.
In Aims 1 -3 we will validate one potential AR target gene, Calbindin D28k. Calbindin defines a sexually dimorphic cell cluster in the medial preoptic area. In addition, this calcium binding protein has well characterized anti-apoptotic actions in brain, and for these reasons it is very likely a contributor to the sexual differentiation pathway. We will use a number of genetically engineered mice, molecular, genetic and behavioral methods to characterize the relationship between the AR and Calbindin at the level of mRNA and protein. We will also use Calbindin knockout mice to assess the behavioral ramification of the loss of function of this gene. Finally we will conduct Microarray experiments to uncover novel candidate genes that are androgen responsive. The strategy we will pursue delineates the role AR plays in regulation of a gene that is part of a neuroprotection pathway and is likely involved in sexual differentiation. This same strategy can be recycled to identify other AR target genes.

Public Health Relevance

Understanding the genes and signaling pathways that control sexual differentiation of behavior is essential for eventual treatment of sex-biased mental illnesses, which include abnormal social behavior as a major symptom. Further, sexual differentiation is an exemplar of neural development, and understanding the molecular mechanisms directing these processes informs us about neural development, neuroprotection and repair generally.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH057759-14
Application #
8463615
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Panchision, David M
Project Start
1999-04-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
14
Fiscal Year
2013
Total Cost
$357,678
Indirect Cost
$120,078
Name
University of Virginia
Department
Biochemistry
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Stolzenberg, Danielle S; Stevens, Jacqueline S; Rissman, Emilie F (2014) Histone deacetylase inhibition induces long-lasting changes in maternal behavior and gene expression in female mice. Endocrinology 155:3674-83
Cox, Kimberly H; Bonthuis, Paul J; Rissman, Emilie F (2014) Mouse model systems to study sex chromosome genes and behavior: relevance to humans. Front Neuroendocrinol 35:405-19
Wolstenholme, Jennifer T; Goldsby, Jessica A; Rissman, Emilie F (2013) Transgenerational effects of prenatal bisphenol A on social recognition. Horm Behav 64:833-9
Wolstenholme, J T; Rissman, E F; Bekiranov, S (2013) Sexual differentiation in the developing mouse brain: contributions of sex chromosome genes. Genes Brain Behav 12:166-80
Bonthuis, Paul J; Rissman, Emilie F (2013) Neural growth hormone implicated in body weight sex differences. Endocrinology 154:3826-35
Bharadwaj, Pranay; McInnis, Christine; Madden, Amanda M K et al. (2013) Increased dendritic spine density and tau expression are associated with individual differences in steroidal regulation of male sexual behavior. PLoS One 8:e69672
Cox, Kimberly H; So, Nina L T; Rissman, Emilie F (2013) Foster dams rear fighters: strain-specific effects of within-strain fostering on aggressive behavior in male mice. PLoS One 8:e75037
Addison, Melisande L; Rissman, Emilie F (2012) Sexual dimorphism of growth hormone in the hypothalamus: regulation by estradiol. Endocrinology 153:1898-907
Stolzenberg, D S; Rissman, E F (2011) Oestrogen-independent, experience-induced maternal behaviour in female mice. J Neuroendocrinol 23:345-54
Bonthuis, Paul J; Patteson, James K; Rissman, Emilie F (2011) Acquisition of sexual receptivity: roles of chromatin acetylation, estrogen receptor-alpha, and ovarian hormones. Endocrinology 152:3172-81

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