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——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 给社会带来负担。尽管攻击行为会对我们的健康和福祉产生如此巨大的影响 社会上，由于我们对神经回路机制的了解仍然有限，我们的治疗方法非常少 驾驶攻击性。在此应用中，我们首先采用无偏计算方法来识别新颖的电路 攻击机制。使用 iDISCO+ 组织透明化方法，我们广泛评估了 cFos 表达—— 由神经活动诱导的即早基因（IEG）——遍及整个大脑以识别大脑区域 攻击性与非攻击性社交互动后的激活差异。我们评估了 ~500 的 cFos 大脑区域——注册到艾伦大脑图谱——同时检查整个大脑的相互作用 通过加权相关网络分析（WCNA）生成共表达网络来区域 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 相关性的强度和总连接数。相互联系最紧密的国家之一 网络位于杏仁核内，杏仁核由高度异质的大脑区域和细胞簇组成 执行多种功能的类型，从控制焦虑和恐惧到社会行为和奖励。 使用先进的 Ca2+ 成像和化学遗传学，我们发现 Esr1 谷氨酸能神经元的激活 攻击期间雄性的 COAp 对于攻击行为是必要的。这些的化学遗传学抑制 在常驻入侵者（RI）测试期间，细胞增加了亲社会调查，但是，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小鼠会主动利用杠杆 按下鼠标即可入侵；不是攻击入侵者，而是与他们进行亲社会互动。 相反，在女性中，我们发现 COAp 神经元的激活对于亲社会接触是必要的。 RI 测试。因此，我们的数据表明，COAp 可能是两性中的一个重要转变——尽管在男女中 性别二态性方式——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 Ca2+ 成像来剖析 COAp 和 调节雄性和雌性小鼠的攻击性和亲社会行为的下游回路。我们相信 这些研究将为控制社会的神经回路机制提供重要的理解 行为。