Males and females differ in most phenotypic measures, including the brain. Substantial advances continue to be made in describing the magnitude and variety of sex differences in the brain which occur at the macro, micro and molecular level. This data combined with a broad based knowledge of the temporal profile and hormonal parameters that constrain the developmental establishment of sex differences, now allow for advancement of mechanistic questions. The rat provides an excellent model for elucidating these basic cellular mechanisms. There are sex differences in a multitude of behaviors, which include cognitive, appetitive, social and reproductive behaviors, and the associated brain regions which include the cortex, hippocampus, preoptic area and hypothalamus. Sexually dimorphic copulatory behavior in the adult provides highly quantitative outcome measures for mechanistic developmental studies. Behavioral studies have defined 3 distinct developmental processes that can be operationally defined as 1) masculinization = capacity for expression of male sexual behavior, 2) defeminization = loss of the capacity to express female sexual behavior and 3) feminization = capacity for expression of female sexual behavior. The first 2, masculinization and defeminization, are required for the development of the complete male sexual behavior phenotype. These are both active hormonally-induced processes that are induced consequent to testosterone secretion from the perinatal testis. The third, feminization, is the default processes that occurs in the absence of a hormonal trigger. We will use these historical constructs for exploration into the cellular and molecular mechanisms that establish sex differences in the brain.
Specific Aim #1 focuses on the circuitry of masculinization at the systems and cellular level and explores further the role of PGE2.
Aim #2 will exploit a novel tool for masculinizing but not defeminizing the brain and use the Agilent Rat Oligo Microarray to examine profiles of gene expression.
Aim #3 explores new endpoints of potential significance to the previously unexplored process of feminization based on pilot data generated using a PowerBlot Phosphospecific Array for protein expression. Disorders and diseases of mental health are profoundly influenced by gender. Understanding at the mechanistic level how sex differences are determined provides an entry point into investigating why sex or gender impacts on the eitology of mental illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH052716-11
Application #
6930309
Study Section
Special Emphasis Panel (ZRG1-IFCN-D (02))
Program Officer
Sieber, Beth-Anne
Project Start
1995-04-01
Project End
2010-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
11
Fiscal Year
2005
Total Cost
$297,000
Indirect Cost
Name
University of Maryland Baltimore
Department
Physiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Lenz, Kathryn M; Pickett, Lindsay A; Wright, Christopher L et al. (2018) Mast Cells in the Developing Brain Determine Adult Sexual Behavior. J Neurosci 38:8044-8059
VanRyzin, Jonathan W; Pickett, Lindsay A; McCarthy, Margaret M (2018) Microglia: Driving critical periods and sexual differentiation of the brain. Dev Neurobiol 78:580-592
McCarthy, Margaret M; Herold, Kevin; Stockman, Sara L (2018) Fast, furious and enduring: Sensitive versus critical periods in sexual differentiation of the brain. Physiol Behav 187:13-19
McCarthy, Margaret M; Wright, Christopher L (2017) Convergence of Sex Differences and the Neuroimmune System in Autism Spectrum Disorder. Biol Psychiatry 81:402-410
McCarthy, Margaret M; Nugent, Bridget M; Lenz, Kathryn M (2017) Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain. Nat Rev Neurosci 18:471-484
Argue, Kathryn J; VanRyzin, Jonathan W; Falvo, David J et al. (2017) Activation of Both CB1 and CB2 Endocannabinoid Receptors Is Critical for Masculinization of the Developing Medial Amygdala and Juvenile Social Play Behavior. eNeuro 4:
Stockman, Sara L; McCarthy, Margaret M (2017) Predator odor exposure of rat pups has opposite effects on play by juvenile males and females. Pharmacol Biochem Behav 152:20-29
McCarthy, Margaret M; Nugent, Bridget M (2015) At the frontier of epigenetics of brain sex differences. Front Behav Neurosci 9:221
Argue, Kathryn J; McCarthy, Margaret M (2015) Utilization of same- vs. mixed-sex dyads impacts the observation of sex differences in juvenile social play behavior. Curr Neurobiol 6:17-23
Nugent, Bridget M; Wright, Christopher L; Shetty, Amol C et al. (2015) Brain feminization requires active repression of masculinization via DNA methylation. Nat Neurosci 18:690-7

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