Sex differences in the cellular differentiation of the developing brain when paired with altered development can lead to abnormal circuitries that may be associated with sex differences in susceptibility to major mental disorders. The goal of our studies is to determine where and how genetic and hormonal factors interact to result in sexual differentiation of the brain. This proposal concentrates on the formation of the preoptic area/ anterior hypothalamus (POA/AH) as a key target for studying this process. The POA/AH is important for regulating homeostatic, neuroendocrine, and behavioral functions. It is a region where hormones dramatically influence development and where hormone-concentrating cells regulate physiology and behavior. We hypothesize that gonadal steroid hormones may """"""""overwrite"""""""" direct genetic instructions, and a hormone-free development allows evaluation of the underlying genetic instructions. Mice with a disrupted steroidogenic factor-1 (SF-1) gene never develop a gonad and provide a model to test the hormone- dependence versus independence of selected characteristics of brain sexual differentiation. Our methods render developmental processes accessible to live observation, and direct manipulation in vitro. We can raise SF-1 knockout (KO) mice to adulthood to assess adult consequences of brain sexual differentiation without endogenous gonadal steroids. Three major questions will be addressed: 1) How are sex differences in the positioning of cells in the embryonic POA/AH regulated by gonadal steroids at different ages? 2) Does nitric oxide generation contribute to the development of the POA/AH by influencing the characteristics of cell migration, cell death, or the phenotypic differentiation of cells? 3) What are the functional consequences of developing in the absence of exposure to gonadal steroids? These questions will be addressed using unique transgenic and gene disrupted models that mark specific cell populations for fluorescence and prevent endogenous gonadal steroid hormone synthesis or prevent neural generation of nitric oxide. The proposed studies will bring us closer to determining the hormone-dependent and independent steps involved in the establishment of sex differences in brain structure and function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH061376-09
Application #
7588077
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Panchision, David M
Project Start
2000-05-10
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
9
Fiscal Year
2009
Total Cost
$295,800
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Büdefeld, Tomaz; Tobet, Stuart A; Majdic, Gregor (2016) The Influence of Gonadal Steroid Hormones on Immunoreactive Kisspeptin in the Preoptic Area and Arcuate Nucleus of Developing Agonadal Mice with a Genetic Disruption of Steroidogenic Factor 1. Neuroendocrinology 103:248-58
Spanic, Tanja; Fabjan, Teja; Majdic, Gregor (2015) Expression levels of mRNA for neurosteroidogenic enzymes 17?-HSD, 5?-reductase, 3?-HSD and cytochrome P450 aromatase in the fetal wild type and SF-1 knockout mouse brain. Endocr Res 40:44-8
Babwah, Andy V; Navarro, Víctor M; Ahow, Maryse et al. (2015) GnRH Neuron-Specific Ablation of G?q/11 Results in Only Partial Inactivation of the Neuroendocrine-Reproductive Axis in Both Male and Female Mice: In Vivo Evidence for Kiss1r-Coupled G?q/11-Independent GnRH Secretion. J Neurosci 35:12903-16
Kercmar, Jasmina; Tobet, Stuart A; Majdic, Gregor (2014) Social isolation during puberty affects female sexual behavior in mice. Front Behav Neurosci 8:337
Ahow, Maryse; Min, Le; Pampillo, Macarena et al. (2014) KISS1R signals independently of G?q/11 and triggers LH secretion via the ?-arrestin pathway in the male mouse. Endocrinology 155:4433-46
Kercmar, Jasmina; Snoj, Tomaz; Tobet, Stuart A et al. (2014) Gonadectomy prior to puberty decreases normal parental behavior in adult mice. Horm Behav 66:667-73
Knoll, John Gabriel; Clay, Colin M; Bouma, Gerrit J et al. (2013) Developmental profile and sexually dimorphic expression of kiss1 and kiss1r in the fetal mouse brain. Front Endocrinol (Lausanne) 4:140
Grgurevic, Neza; Budefeld, Tomaz; Spanic, Tanja et al. (2012) Evidence that sex chromosome genes affect sexual differentiation of female sexual behavior. Horm Behav 61:719-24
Nugent, B M; Tobet, S A; Lara, H E et al. (2012) Hormonal programming across the lifespan. Horm Metab Res 44:577-86
Majdic, Gregor; Tobet, Stuart (2011) Cooperation of sex chromosomal genes and endocrine influences for hypothalamic sexual differentiation. Front Neuroendocrinol 32:137-45

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