Men and women differ in their behavior and susceptibility to disease. This project aims to understand the biological origins of sex differences in the brain and behavior, in health and disease. The novel mouse model, the """"""""four core genotypes"""""""" (FCG), offers significant advantages for discriminating among several classes of biological factors that lead to sex differences in the brain, including organizational and activational effects of gonadal hormones, and direct effects of X and Y genes that are present in different numbers in the XX and XY genome. We propose to use the FCG model to investigate further sex differences in nociception and analgesia and in stress- induced changes in gastrointestinal motor function. A major goal is to develop a better understanding of direct actions of sex chromosome genes that lead to sex differences. We will investigate whether direct sex chromosome effects cause sex differences in stress-induced analgesia, in the effectiveness of kappa opioid analgesic drugs and their modulation by glutaminergic systems, in the effects of neuropathic nociception, and in effects of morphine. We will also investigate the sites and mechanisms by which sex chromosome genes lead to sex differences in neurovisceral changes underlying colonic motor responses induced by stress. The interaction of sex chromosome effects and gonadal hormone effects will be studied. We propose to identify X and Y genes that are directly responsible for the sex differences in these systems. The results will shed light on fundamental sex differences in nociception, stress, and neurovisceral responses to stress, leading to great understanding of sex-specific factors that ameliorate or exacerbate disease.

Public Health Relevance

Men and women show significant differences in behavior and in their susceptibility to diseases of the brain. The proposed research aims to understand the biological origins of such sex differences, especially those differences that are caused by the sex differences in genomic representation of X and Y genes. Understanding the molecular basis of sex differences will shed light on factors that protect the brain from disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
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Gnadt, James W
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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Arnold, Arthur P (2017) A general theory of sexual differentiation. J Neurosci Res 95:291-300
Arnold, Arthur P; Reue, Karen; Eghbali, Mansoureh et al. (2016) The importance of having two X chromosomes. Philos Trans R Soc Lond B Biol Sci 371:20150113
Burgoyne, Paul S; Arnold, Arthur P (2016) A primer on the use of mouse models for identifying direct sex chromosome effects that cause sex differences in non-gonadal tissues. Biol Sex Differ 7:68
Manwani, Bharti; Bentivegna, Kathryn; Benashski, Sharon E et al. (2015) Sex differences in ischemic stroke sensitivity are influenced by gonadal hormones, not by sex chromosome complement. J Cereb Blood Flow Metab 35:221-9
Itoh, Yuichiro; Mackie, Ryan; Kampf, Kathy et al. (2015) Four core genotypes mouse model: localization of the Sry transgene and bioassay for testicular hormone levels. BMC Res Notes 8:69
Chen, Xuqi; Wang, Lixin; Loh, Dawn H et al. (2015) Sex differences in diurnal rhythms of food intake in mice caused by gonadal hormones and complement of sex chromosomes. Horm Behav 75:55-63
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
Li, Jingyuan; Chen, Xuqi; McClusky, Rebecca et al. (2014) The number of X chromosomes influences protection from cardiac ischaemia/reperfusion injury in mice: one X is better than two. Cardiovasc Res 102:375-84
Itoh, Yuichiro; Arnold, Arthur P (2014) X chromosome regulation of autosomal gene expression in bovine blastocysts. Chromosoma 123:481-9
Arnold, Arthur P (2014) Conceptual frameworks and mouse models for studying sex differences in physiology and disease: why compensation changes the game. Exp Neurol 259:2-9

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