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

美国每年有超过10%的人口患有抑郁症，据报道，女性患抑郁症的频率是男性的两倍。对社会应激源的生理反应在进化上是保守的，啮齿动物和人类都会经历会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丧失，对以前的奖励失去兴趣会激活，这是抑郁症的一个主要诊断特征。减少奖励可以减少蔗糖的消耗，减少参与社交活动的时间。这使得研究大脑的变化如何与这些行为的变化相关联。在常用的实验室大鼠和小鼠中，攻击性互动很少发生，这使得很难或不可能研究社会压力对雌性动物的影响。加州老鼠(Permyscus CalforNicus)的雄性和雌性都是地域性的，这使得它们适合研究性别差异。暴露在社会压力下的雌性加州小鼠，而不是雄性小鼠，参与社会互动的时间更少。催产素(OT)和精氨酸加压素(AVP)是在社会交往中发挥重要作用的相关神经蛋白。这两种蛋白质都已被确定为治疗抑郁症的潜在药物靶点。这项拟议的研究使用了三个实验来检验大脑中OT和AVP系统对社会压力的反应方式的性别差异。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、社会互动或控制条件下的小鼠获得的脑组织。这使得可以量化含有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。第二个实验将用实时定量聚合酶链式反应检测社会失败后4wk大鼠外侧隔核、中央杏仁核、室旁核和垂体区OT和AVP受体基因表达的变化。最后，在实验3中，我将在慢性社会应激前将OT或OT受体拮抗剂注入侧脑室，以确定操纵OT功能是否能在4wk后阻断或诱导社交厌恶的发展。综上所述，这些实验应该能够深入了解OT和AVP是否在社交退缩的发展和表达中发挥作用。

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.