Sex Differences in Neural Circuit Mechanisms of Aggression

攻击性神经回路机制的性别差异

• 批准号: 10822730
• 负责人: SCOTT JAMES RUSSO
• 金额: $ 63.77万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10822730
• 关键词: Adult; Affect; Aggressive behavior; Amygdaloid structure; Anxiety; Atlases; Automobile Driving; Behavior; Behavioral; Behavioral Model; Biological; Brain; Brain region; Cells; Complex; Data; Desire for food; ESR1 gene; Economic Burden; Electrophysiology (science); Ensure; Environment; Female; Fright; Genetic; Glutamates; Health; Histologic; Hypothalamic structure; Image; Immediate-Early Genes; Investigation; Maintenance; Maps; Mediating; Mental disorders; Methods; Modeling; Motivation; Mus; Nature; Network-based; Neurons; Pathway Analysis; Pattern; Personal Satisfaction; Population; Psychological reinforcement; Regulation; Resources; Rewards; Risk; Role; Series; Sex Differences; Social Behavior; Social Interaction; Societies; Surrogate Markers; Symptoms; Testing; Tissues; brain cell; cell type; conditioned place preference; data mining; design; in vivo; interest; male; neural; neural circuit; neuromechanism; novel; optogenetics; pre-clinical; sex; sexual dimorphism; social

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.

项目摘要 - 神经回路机制的性别差异 侵略是社会行为的必要组成部分；但是，它可能会升级，可能 威胁生命，增加在恐怖疾病中患精神病的风险，并产生巨大的经济 社会负担。即使积极进取可以对我们的健康和福祉产生如此巨大的影响 社会，由于我们对神经回路机制的理解仍然有限，我们几乎没有治疗 驾驶侵略性。在此应用中，我们首先采用公正的计算方法来识别新的电路 侵略性机制。使用IDISCO+组织清除方法，我们广泛评估了CFOS表达 - 神经活动引起的直接早期基因（IEG） - 整个大脑都可以识别大脑区域 在积极与非攻击性社会互动之后被差异激活。我们评估了〜500的CFO 大脑区域（已注册到艾伦大脑图书馆），并对脑部的相互作用进行了检查 通过使用加权相关网络分析（WCNA）生成共表达网络的区域，这是一个广泛的 使用的数据挖掘方法是基于变量之间的成对相关性研究生物网络的方法。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，并对基于相关的排名 关于相关的强度和总连接的数量。最紧密的互连之一 网络位于杏仁核内，该杏仁核由大脑区域和细胞的高度异源簇组成 从控制焦虑和恐惧到社会行为和奖励的潜水员功能的类型。 使用高级CA2+成像和化学遗传学，我们发现ESR1谷氨酸能神经元激活 在攻击行为过程中，男性的cuap对于侵略行为是必要的。化学抑制这些 细胞增加了居民入侵者（RI）检验期间的亲社会研究 社会奖励/加强行为。例如，我们发现以前侵略性小鼠会积极杠杆 按下入侵者鼠标；不是要攻击入侵者，而是要与他们进行亲社会互动。 相反，在女性中，我们发现圆盘神经元的激活对于亲社会遭遇是必要的 RI测试。这是，我们的数据表明，托管可能是两个性别的重要转换，尽管 性二态性的方式 - 控制参与亲社会行为的动机。基于 在我们强大的飞行员数据上，我们设计了一系列研究，以更好地了解这种现象并充分了解 表征托管电路在介导侵略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Ca2+成像，以剖析CoAP和 在男性和雌性小鼠中介导侵略性和亲社会行为的下游回路。我们相信 这些研究将为管理社会的神经电路机制提供重要的理解 行为。