Sex Differences in Neural Circuit Mechanisms of Aggression

攻击性神经回路机制的性别差异 攻击性是社会行为的一个必要的、适应性的组成部分；然而，它可能会升级并可能 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 给社会带来的负担。尽管攻击性会对我们的健康和福祉产生如此戏剧性的影响 社会上，由于我们对神经回路机制的了解仍然有限，我们有很少的治疗方法 驱使攻击性。在这个应用中，我们首先采用一种无偏计算方法来识别新电路 攻击性机制。使用iDISCO+组织清除方法，我们广泛评估了CFO的表达- 由神经活动诱导的即刻早期基因(IEG)--横跨整个大脑，以识别大脑区域 在攻击性和非攻击性社交互动后被不同地激活。我们对大约500名CFO进行了评估 大脑区域--登记在艾伦大脑图谱上--同时研究了大脑之间的相互作用 通过使用加权相关网络分析(WCNA)生成共表达网络来生成区域，这是一种广泛的 将数据挖掘方法应用于基于变量间成对相关性的生物网络研究。在……里面 在这个案例中，我们检查了大脑区域CFO表达之间的相关性，并基于 基于相关性的强度和总连接的数量。最紧密的互联之一 网络位于杏仁核内，杏仁核由高度异质的大脑区域和细胞组成。 执行各种功能的类型，从控制焦虑和恐惧到社交行为和奖励。 利用先进的钙离子成像和化学遗传学，我们发现ESR1谷氨酸能神经元的激活 男性攻击时的COAP是攻击行为所必需的。这些化合物的化学发生抑制作用 在居民入侵者(RI)测试中，细胞增加了亲社会调查，但它并没有阻止亲社会调查 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利用杠杆 按下一个入侵者鼠标；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 国际扶轮测试。因此，我们的数据表明，COAP可能是两性之间的一个重要转换--尽管在 性两面性方式-控制从事亲社会行为与攻击性社会行为的动机。基座 根据我们强大的试点数据，我们设计了一系列研究，以更好地理解这一现象并充分 描述COAP回路在调节攻击性和亲社会行为中的作用。我们将使用 化学遗传学/光遗传学、电生理学和体内钙成像剖析COAP和 调节雄性和雌性小鼠攻击性和亲社会行为的下游回路。我们相信 这些研究将提供对支配社会的神经回路机制的重要理解 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.