Sex Differences in Neural Circuit Mechanisms of Aggression

项目概要-攻击性神经系统机制的性别差异 攻击性是社会行为的一个必要的、适应性的组成部分;然而，它可能会升级， 威胁生命，增加受害者患精神疾病的风险，并造成巨大的经济损失。 社会的负担。尽管侵略行为会对我们的健康和福祉产生如此巨大的影响， 社会，我们有很少的治疗，由于我们仍然有限的了解神经回路机制 驾驶侵略性。在这个应用中，我们首先采取无偏的计算方法来识别新的电路 侵略的机制。使用iDISCO+组织清除方法，我们广泛评估了cFos表达- 一种由神经活动诱导的立即早期基因（IEG）-在整个大脑中识别大脑区域 在攻击性和非攻击性的社会互动后被不同地激活。我们评估了约500名 大脑区域-注册到艾伦大脑地图集-同时检查大脑之间的相互作用 通过加权相关网络分析（WCNA）生成共表达网络， 使用数据挖掘方法研究基于变量之间的成对相关性的生物网络。在 在这种情况下，我们检查了大脑区域中cFos表达之间的相关性，并根据相关性进行了排名。 依赖于相关性的强度和总连接的数量。世界上最紧密相连的 杏仁核是由一组高度异质的大脑区域和细胞组成的 这些类型执行从控制焦虑和恐惧到社会行为和奖励的各种功能。 使用先进的钙离子成像和化学遗传学，我们发现，在脑内的Esr 1受体能神经元的激活， 雄鼠攻击时COAp是攻击行为所必需的。化学发生抑制这些 细胞增加亲社会调查期间，居民入侵者（RI）测试，但是，它并没有闭塞亲， 社会奖励/强化行为。例如，我们发现，以前具有攻击性的老鼠会主动杠杆， 按下入侵者鼠标;不是攻击入侵者，而是与他们进行亲社会的互动。 相反，在女性中，我们发现COAp神经元的激活是亲社会接触所必需的。 RI测试因此，我们的数据表明，COAp可能是一个重要的开关，在两种性别，虽然在 性的二态性方式--控制参与亲社会行为和攻击性社会行为的动机。基于 根据我们强大的试点数据，我们设计了一系列研究，以更好地了解这一现象， 描述COAp回路在调节攻击和亲社会行为中的作用。我们将使用 化学遗传学/光遗传学、电生理学和体内Ca 2+成像，以剖析COAp和 下游电路在调解侵略和亲社会行为在雄性和雌性小鼠。我们认为 这些研究将提供一个重要的了解神经回路机制，支配社会 行为

PROJECT SUMMARY – SEX DIFFERENCES IN NEURAL CIRCUIT MECHANISMS OF AGGRESSION Aggression is a necessary, adaptive component of social behavior; however, it can become escalated and may threaten lives, increase the risk of developing psychiatric disease in victims, and incur tremendous economic burdens on society. Even though aggression can have such dramatic effects on the health and well-being of our society, we have very few treatments, owing to our still limited understanding of the neural circuit mechanisms driving aggression. In this application we first take an unbiased computational approach to identify novel circuit mechanisms of aggression. Using an iDISCO+ tissue clearing method, we broadly assessed cFos expression— an immediate early gene (IEG) induced by neural activity—across the entire brain to identify brain regions differentially activated following aggressive versus non-aggressive social interaction. We assessed cFos in ~500 brain regions—registered to the Allen brain atlas—simultaneously and examined interactions across brain regions by generating co-expression networks with weighted correlation network analysis (WCNA), a widely used data mining method for studying biological networks based on pairwise correlations between variables. In this case we examined correlations between cFos expression in brain regions and ranked the correlations based on the strength of the correlation and the number of total connections. One of the most strongly interconnected networks was within the amygdala, which is made up of a highly heterogenous cluster of brain regions and cell types that perform a diverse range of functions from controlling anxiety and fear to social behavior and reward. Using advanced Ca2+ imaging and chemogenetics, we found that activation of Esr1 glutamatergic neurons in the COAp of males during aggression was necessary for aggressive behavior. Chemogenetic inhibition of these cells increased pro-social investigation during the resident intruder (RI) test, however, it did not occlude pro- social reward/reinforcement behavior. For example, we found that previously aggressive mice will actively lever press for an intruder mouse; not to attack to the intruder, but to engage in pro-social interactions with them. Conversely, in females we find that activation of COAp neurons is necessary for pro-social encounters during the RI test. Thus, our data suggests that the COAp may serve as an important switch in both sexes—though in sexually dimorphic ways—to control the motivation to engage in pro- versus aggressive-social behavior. Based on our strong pilot data, we have designed a series of studies to better understand this phenomenon and fully characterize the role of COAp circuitry in mediating aggression and pro-social behavior. We will use chemogenetics/optogenetics, electrophysiology and in vivo Ca2+ imaging to dissect the role of COAp and downstream circuits in mediating aggression and pro-social behavior in both male and female mice. We believe that these studies will provide an important understanding of the neural circuit mechanisms governing social behavior.