Sex Differences in the Roles of Oxytocin and Vasopressin in Social Withdrawal

催产素和加压素在社交退缩中的作用的性别差异

• 批准号: 8401976
• 负责人: Michael Q. Steinman
• 金额: $ 3.4万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401976
• 关键词: Adrenal Glands; Adverse effects; Affect; Aggressive behavior; Amygdaloid structure; Anhedonia; Animal Model; Animals; Appearance; Argipressin; Beds; Behavior; Behavioral Model; Behavioral Symptoms; Biological; Brain; California; Cell Nucleus; Cells; Chronic; Citalopram; Conflict (Psychology); Consumption; Corticosterone; Development; Diagnostic; Drug Targeting; Exposure to; FOS gene; Female; Future; Growth; Human; Hypothalamic structure; Immunohistochemistry; Individual; Infusion procedures; Intranasal Administration; Investigation; Label; Laboratory Rat; Laboratory mice; Lateral; Maintenance; Major Depressive Disorder; Mediating; Mental Depression; Microtus; Modeling; Mood Disorders; Mus; Neurons; Neuropeptides; Outcome; Oxytocin; Oxytocin Receptor; Peromyscus; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Pituitary Gland; Plasma; Play; Population; Predisposition; Proteins; Rattus; Regulation; Reporting; Rewards; Rodent; Role; Sex Characteristics; Sexual Dysfunction; Sleep Disorders; Social Behavior; Social Development; Social Interaction; Sucrose; Syndrome; System; Testing; Therapeutic; Time; Vasopressins; Weight Gain; Withdrawal; Woman; argipressin receptor; biological adaptation to stress; brain tissue; coping; depressive symptoms; experience; human subject; hypothalamic-pituitary-adrenal axis; improved; insight; interest; lateral ventricle; mRNA Expression; male; men; monoamine; novel; paraventricular nucleus; receptor; research study; response; sex; social; social stress; stressor; supraoptic nucleus; treatment strategy

Depression occurs in over 10% of the US population each year, and women are reported to experience depression twice as frequently as men. Physiological reactivity to social stressors is evolutionarily conserved and both rodents and humans experience social conflicts that can alter affect and behavior. In animal models social stress induces anhedonia, a loss of interest in previously rewarding activates, which is a major diagnostic feature of depression. Diminished reward can result in reduced consumption of sucrose and reduced time engaging in social interaction. This allows for the study of how changes in the brain are associated with these changes in behavior. Aggressive interactions are infrequent in commonly used laboratory rats and mice, making it difficult or impossible to study effects of social stress on females. California mouse (Peromyscus californicus) males and females are territorial, making them suitable for studying sex differences. Female but not male California mice exposed to social stress spend less time engaging in social interactions. Oxytocin (OT) and arginine vasopressin (AVP) are related neuroproteins that play important roles in social interactions. Both proteins have been identified as potential targets for drugs in the treatment of depression. The proposed study uses three experiments to examine sex differences in how OT and AVP systems in the brain respond to social stress. In the first experiment, triple-label immunohistochemistry will be used on brain tissue acquired from mice exposed to social stress, social interaction, or control conditions. This allows for quantifying the number of OT and AVP neurons that contain c-fos, a protein whose presence suggests that the cells were recently activated. The second experiment will use real time PCR to examine how OT and AVP receptor mRNA expression in the lateral septum, central amygdala, paraventricular nucleus and pituitary is changes 4 wk after social defeat. Finally, in experiment 3, I will infuse OT or OT receptor antagonist into the lateral ventricles just before chronic social stress to determine whether manipulating OT function can block or induce the development of social aversion 4 wk later. Together these experiments should provide insight into whether OT and AVP play a role in the development and expression of social withdrawal.

每年有超过10%的美国人患有抑郁症，据报道，女性患抑郁症的频率是男性的两倍。对社会压力的生理反应在进化上是保守的，啮齿动物和人类都经历了可以改变情感和行为的社会冲突。在动物模型中，社会压力会导致快感缺失，即对以前的奖励活动失去兴趣，这是抑郁症的主要诊断特征。奖励减少会导致蔗糖消耗减少，参与社会互动的时间减少。这使得研究大脑的变化如何与这些行为变化相关联。在常用的实验室大鼠和小鼠中，攻击性互动并不常见，因此很难或不可能研究社会压力对女性的影响。加州小鼠（Peromyscus californicus）的雄性和雌性都具有领地性，这使得它们适合研究性别差异。雌性而非雄性的加州老鼠在社会压力下花在社交互动上的时间更少。催产素（OT）和精氨酸加压素（AVP）是在社会互动中起重要作用的相关神经蛋白。这两种蛋白质已被确定为治疗抑郁症的药物的潜在靶点。这项研究使用了三个实验来研究大脑中OT和AVP系统如何对社会压力做出反应的性别差异。在第一个实验中，三重标记免疫组织化学将用于从暴露于社会压力、社会互动或对照条件的小鼠获得的脑组织。这允许量化含有c-fos的OT和AVP神经元的数量，c-fos是一种蛋白质，其存在表明细胞最近被激活。实验二采用真实的时间PCR检测社交失败后4 wk大鼠外侧隔、中央杏仁核、室旁核和垂体OT和AVP受体mRNA表达的变化。最后，在实验3中，我将在慢性社会应激前向侧脑室注射OT或OT受体拮抗剂，以确定操纵OT功能是否可以阻断或诱导4周后社会厌恶的发展。总之，这些实验应该提供洞察OT和AVP是否在社会退缩的发展和表达中发挥作用。