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Sex Differences in Neural Circuit Mechanisms of Aggression

攻击性神经回路机制的性别差异

基本信息

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
项目类别：
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

项目摘要

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.

项目总结-攻击神经回路机制的性别差异