Prefrontal Circuit Control of Isolation-Induced Aggression

孤立诱发攻击的前额叶回路控制

• 批准号: 10638671
• 负责人: Moriel Zelikowsky
• 金额: $ 67.24万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-06 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638671
• 关键词: Aggressive behavior; Behavior; Biological Assay; Brain; Brain region; COVID-19 pandemic; Cells; Cognitive Therapy; Color; Coupled; Data; Development; Domestic Violence; Endoscopy; Epidemic; House mice; Housing; Hypothalamic structure; Image; Interneurons; Lead; Loneliness; Machine Learning; Medial; Mediating; Mediator; Mental disorders; Modernization; Molecular Genetics; Mus; Neurokinin B; Neuromedin K Receptor; Neurons; Neuropeptides; Obesity; Pathologic; Perception; Population; Prefrontal Cortex; Public Health; Research; Risk Factors; Role; Signal Transduction; Smoking; Social Controls; Social isolation; Socialization; Societies; System; Tachykinin; Technology; Testing; Textiles; Therapeutic Intervention; Violence; aging population; attenuation; behavior test; cognitive control; gain of function; gamma-Aminobutyric Acid; gene function; hippocampal pyramidal neuron; in vivo; loss of function; neural; neural patterning; opioid epidemic; optogenetics; poor health outcome; school shooting; social; social contact; social deprivation; social group; social media; social structure; suicide rate

PROJECT SUMMARY/ ABSTRACT Extended deprivation of social contact can produce deleterious effects on the brain and behavior. Social isolation (SI), or its perception (loneliness), is as predictive a risk factor for poor health outcomes as smoking or obesity. Many factors have contributed to a modern epidemic of loneliness: a growing aging population, dramatic changes to our social structure (technology, social media), the opioid crisis, and, most recently, the COVID-19 pandemic. One of the most damaging impacts of SI is the promotion of interpersonal aggression and violence against others – indeed, SI-associated domestic violence has risen by 20%, rates of suicide have surged, and school shootings continue to rip at the fabric of society. Despite this, we have a poor understanding of the genetically-defined, circuit mechanisms that give rise to isolation-induced aggression, representing a critical barrier for the development of targeted interventions and cognitive therapies to treat pathological forms of aggression. One key brain region known to exert top-down, cognitive control over behavior, including aggression, is the medial prefrontal cortex (mPFC). However, the role of the mPFC in modulating the effects of SI-induced aggression is unknown. In the project proposed here, we will interrogate the function of distinct, genetically-defined cells in the mPFC to modulate SI-induced aggression. In support of this, we recently identified the neuropeptide Tachykinin 2 (Tac2)/Neurokinin B (NkB) as a key, subcortical mediator of SI. Here, we will test whether Tac2 signaling in the mPFC exerts cortical control of SI-aggression. In preliminary studies, we have discovered that Tac2+ mPFC neurons comprise a unique, unexplored class of GABAergic interneurons (INs). These findings lead to the specific hypothesis that Tac2+ INs exert feed-forward inhibition of excitatory pyramidal neurons (PNs) to mediate SI-aggression. To test this, we will combine behavior, machine learning, molecular-genetic loss- and gain-of function manipulations, and in vivo Ca2+ imaging to achieve a circuit-level, mechanistic understanding of how distinct populations of genetically-defined neurons in the mPFC exert coordinated, cortical control of SI- aggression. We will determine whether mPFC Tac2+ neurons are required for SI-aggression (Aim 1), whether mPFC PNs are sufficient to inhibit SI-aggression (Aim 2), and whether Tac2+ INs directly regulate PN activity during SI-aggression (Aim 3). Collectively, we aim to uncover a conserved, genetically-defined mPFC microcircuit for the top-down, cortical control of isolation-induced aggression. These findings will transform the field by expanding our understanding of how pathological forms of aggression are encoded and controlled by prefrontal circuits in the brain. Importantly, this research will have profound implications for the treatment of social isolation-related mental health disorders, particularly those that result in violence.

项目摘要/摘要 扩大社会接触的剥夺会对大脑和行为产生有害影响。社交隔离 （SI）或其感知（孤独）是预测健康结果的危险因素，例如吸烟或肥胖。 许多因素导致了现代的孤独感：人口衰老，急剧变化 到我们的社会结构（技术，社交媒体），阿片类药物危机以及最近的COVID-19大流行。 SI最具破坏性的影响之一是促进人际交往和暴力对他人 - 的确，SI-SI相关的家庭暴力已上升20％，自杀率飙升，学校枪击事件 继续撕裂社会的结构。尽管如此，我们对普遍定义的，不良的了解 产生隔离引起的侵略性的电路机制，代表 开发有针对性的干预措施和认知疗法，以治疗侵略性的病理形式。一个钥匙 媒体已知可以执行自上而下的大脑区域对行为的认知控制，包括侵略性 前额叶皮层（MPFC）。但是，MPFC在调节Si引起的侵略性的影响中的作用是 未知。在此处提出的项目中，我们将询问不同，一般定义的单元的功能 MPFC调节SI引起的侵略性。为了支持这一点，我们最近确定了神经肽速肽 2（TAC2）/Neurokinin B（NKB）作为Si的钥匙，皮质下介质。在这里，我们将测试TAC2是否发出信号 MPFC对Si-gression施加皮质控制。在初步研究中，我们发现TAC2+ MPFC 神经元包括一类独特的，意外的GABA能中间神经元（INS）。这些发现导致 特定的假设是TAC2+ INS对兴奋性锥体神经元（PNS）的进食前向前抑制以介导 si侵略。为了测试这一点，我们将结合行为，机器学习，分子遗传损失和获取 功能操作和体内Ca2+成像，以实现电路级别的机械理解 MPFC中遗传定义的神经元的不同种群施加了协调的皮质控制。 挑衅的。我们将确定MPFC TAC2+神经元是否需要Si-gymession（AIM 1），是否需要 MPFC PN足以抑制Si-gression（AIM 2），以及TAC2+ INS是否直接调节PN活性 在Si-gression期间（AIM 3）。总的来说，我们旨在揭示构成的，遗传定义的MPFC 微电路，用于自上而下的隔离诱导攻击性的皮质控制。这些发现将改变 通过扩展我们对病理形式侵略性形式如何被编码和控制的领域 大脑的前额叶电路。重要的是，这项研究将对社会的治疗产生深远的影响 与孤立有关的心理健康障碍，尤其是导致暴力的疾病。