Project description:Gender differences in brain development and in the prevalence of neuropsychiatric disorders such as depression have been reported. Gender differences in human brain might be related to patterns of gene expression. Microarray technology is one useful method for investigation of gene expression in brain. We investigated gene expression, cell types, and regional expression patterns of differentially expressed sex chromosome genes in brain. We profiled gene expression in male and female dorsolateral prefrontal cortex, anterior cingulate cortex, and cerebellum using the Affymetrix oligonucleotide microarray platform. Differentially expressed genes between males and females on the Y chromosome (DBY, SMCY, UTY, RPS4Y, and USP9Y) and X chromosome (XIST) were confirmed using real-time PCR measurements. In situ hybridization confirmed the differential expression of gender-specific genes and neuronal expression of XIST, RPS4Y, SMCY, and UTY in three brain regions examined. The XIST gene, which silences gene expression on regions of the X chromosome, is expressed in a subset of neurons. Since a subset of neurons express gender-specific genes, neural subpopulations may exhibit a subtle sexual dimorphism at the level of differences in gene regulation and function. The distinctive pattern of neuronal expression of XIST, RPS4Y, SMCY, and UTY and other sex chromosome genes in neuronal subpopulations may possibly contribute to gender differences in prevalence noted for some neuropsychiatric disorders. Studies of the protein expression of these sex-chromosome-linked genes in brain tissue are required to address the functional consequences of the observed gene expression differences. Experimental design: Two groups of male control subjects and female control subjects were selected that had no history of psychiatric disorder. Each subject was analyzed by microarray in 3 brain regions: AnCg (anterior cingulate cortex), DLPFC (dorsalateral prefrontal cortex), and CB (cerebellum). Total RNA aliquots for some subjects were analyzed at either 1 site, 2 sites, or 3 sites (UM , University of Michigan); UCD (University of California, Davis); or UCI (University of California, Irvine). The data was analyzed by looking at each Male vs Female comparison separately at each site by a t-test for gender differences. Thus for one brain region, a Male vs Female comparison was run at 3 sites, and the overlapping significant genes from the three comparisons were reported. We appreciate the assistance of Richard Stein, Ph.D. and Preston Cartagena, Psy.D. for their contributions to postmortem clinical characterization of subjects. We acknowledge Kathleen Burke as well as Jacque Berndt and the investigators and medical examiners at the Orange County Coroners Office for procurement of brain tissue. We also appreciate the technical contributions of Kevin Overman, Sharon Burke, and Phong Nguyen. F. Warren Lovell, M.D, performed a neuropathological evaluation of the postmortem brains. Tissue specimens were processed and stored at the Human Brain and Spinal Fluid Resource Center, Veteran's Medical Center, Los Angeles under the direction of Wallace W. Tourtellotte, M.D., Ph.D. This project is supported by the NIMH Conte Center Grant P50 MH60398, Pritzker Neuropsychiatric Disorders Research Consortium, William Lion Penzner Foundation (UCI), Della Martin Foundation (UCI), NIMH Grant #MH54844 (EGJ), W.M. Keck Foundation (EGJ), and the NIMH Program Project MH42251 (SJW and HA). The authors are members of of a Conte Center supported by the NIMH and the Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by the Pritzker Neuropsychiatric Disorders Research Fund L.L.C. A shared intellectual property agreement exists between this philanthropic fund and the University of Michigan, the University of California, and Stanford University to encourage the development of appropriate findings for research and clinical applications. Keywords: other

Project description:Gender differences in brain development and in the prevalence of neuropsychiatric disorders such as depression have been reported. Gender differences in human brain might be related to patterns of gene expression. Microarray technology is one useful method for investigation of gene expression in brain. We investigated gene expression, cell types, and regional expression patterns of differentially expressed sex chromosome genes in brain. We profiled gene expression in male and female dorsolateral prefrontal cortex, anterior cingulate cortex, and cerebellum using the Affymetrix oligonucleotide microarray platform. Differentially expressed genes between males and females on the Y chromosome (DBY, SMCY, UTY, RPS4Y, and USP9Y) and X chromosome (XIST) were confirmed using real-time PCR measurements. In situ hybridization confirmed the differential expression of gender-specific genes and neuronal expression of XIST, RPS4Y, SMCY, and UTY in three brain regions examined. The XIST gene, which silences gene expression on regions of the X chromosome, is expressed in a subset of neurons. Since a subset of neurons express gender-specific genes, neural subpopulations may exhibit a subtle sexual dimorphism at the level of differences in gene regulation and function. The distinctive pattern of neuronal expression of XIST, RPS4Y, SMCY, and UTY and other sex chromosome genes in neuronal subpopulations may possibly contribute to gender differences in prevalence noted for some neuropsychiatric disorders. Studies of the protein expression of these sex-chromosome-linked genes in brain tissue are required to address the functional consequences of the observed gene expression differences. Experimental design: Two groups of male control subjects and female control subjects were selected that had no history of psychiatric disorder. Each subject was analyzed by microarray in 3 brain regions: AnCg (anterior cingulate cortex), DLPFC (dorsalateral prefrontal cortex), and CB (cerebellum). Total RNA aliquots for some subjects were analyzed at either 1 site, 2 sites, or 3 sites (UM , University of Michigan); UCD (University of California, Davis); or UCI (University of California, Irvine). The data was analyzed by looking at each Male vs Female comparison separately at each site by a t-test for gender differences. Thus for one brain region, a Male vs Female comparison was run at 3 sites, and the overlapping significant genes from the three comparisons were reported. We appreciate the assistance of Richard Stein, Ph.D. and Preston Cartagena, Psy.D. for their contributions to postmortem clinical characterization of subjects. We acknowledge Kathleen Burke as well as Jacque Berndt and the investigators and medical examiners at the Orange County Coroners Office for procurement of brain tissue. We also appreciate the technical contributions of Kevin Overman, Sharon Burke, and Phong Nguyen. F. Warren Lovell, M.D, performed a neuropathological evaluation of the postmortem brains. Tissue specimens were processed and stored at the Human Brain and Spinal Fluid Resource Center, Veteran's Medical Center, Los Angeles under the direction of Wallace W. Tourtellotte, M.D., Ph.D. This project is supported by the NIMH Conte Center Grant P50 MH60398, Pritzker Neuropsychiatric Disorders Research Consortium, William Lion Penzner Foundation (UCI), Della Martin Foundation (UCI), NIMH Grant #MH54844 (EGJ), W.M. Keck Foundation (EGJ), and the NIMH Program Project MH42251 (SJW and HA). The authors are members of of a Conte Center supported by the NIMH and the Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by the Pritzker Neuropsychiatric Disorders Research Fund L.L.C. A shared intellectual property agreement exists between this philanthropic fund and the University of Michigan, the University of California, and Stanford University to encourage the development of appropriate findings for research and clinical applications.

Project description:Brain structure and function are sexually dimorphic. As neuroscience research has largely focused on the male brain and behavior, the female brain and, in particular, its inherent dynamics have been left underexplored. During the mammalian reproductive period, the female brain is exposed to fluctuating hormone levels over the cycles known as menstrual (in humans) or estrous (in rodents). Variation in estradiol levels has been shown to affect synaptic plasticity in the female brain, including changes in dendritic spine density systematically across the estrous cycle. Female emotionality and cognitive function vary with physiologically fluctuating sex hormone levels. However, the molecular mechanisms underlying the dynamic nature of the female brain structure and function are currently unknown. Here we show that neuronal chromatin organization in the female ventral hippocampus of mouse is dynamic and fluctuates across the estrous cycle. We find changes in chromatin organization associated with the transcriptional activity of nearby genes important for neuronal function, neurotransmission, synapse formation, and behavior. We also link these chromatin dynamics to variation in anxiety-like behavior and to fluctuations in dendritic spine and synaptic density in the ventral hippocampus. In terms of chromatin structure, within-female and between-sex variation are of similar magnitudes, emphasizing the importance of accounting for fluctuating sex-hormone levels in females in the studies of the brain epigenome and behavior. These results provide critical insights into the mechanisms underlying sex-hormone and sex-dependent variation in adult brain structure and function. The study also has implications for better understanding of sex-biased disorders such as depression and anxiety which are strongly associated with sex-hormone status in females and are twice as prevalent in women than in men. This study establishes a foundation for the development of sex-specific approaches to treat sex-biased neuropsychiatric disorders including depression and anxiety disorders.

Dataset Information

Proteomic analysis of brain region and gender-specific synaptic protein expression in the adult mouse brain

Publications

Proteomic Analysis of Brain Region and Sex-Specific Synaptic Protein Expression in the Adult Mouse Brain.

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