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.

项目总结/摘要 长期剥夺社会接触会对大脑和行为产生有害影响。社会孤立 (SI)，或其感知（孤独），是预测健康结果不佳的风险因素，如吸烟或肥胖。 许多因素导致了现代孤独症的流行：人口老龄化的加剧， 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攻击和暴力侵害他人 - 事实上，与特种部队有关的家庭暴力上升了20%，自杀率激增，校园枪击事件 继续破坏社会结构尽管如此，我们对基因定义的， 电路机制，引起孤立引起的侵略，代表了一个关键的障碍， 发展有针对性的干预措施和认知疗法，以治疗病理性攻击。一个关键 已知对行为（包括攻击性）施加自上而下的认知控制的大脑区域是内侧区， 前额叶皮层（mPFC）。然而，mPFC在调节SI诱导的攻击效应中的作用是 未知在这里提出的项目中，我们将询问不同的，遗传定义的细胞在细胞中的功能。 mPFC调节SI诱导的攻击。为了支持这一点，我们最近发现了神经肽速激肽 2（Tac 2）/神经激肽B（Nk B）作为SI的关键皮层下介质。在这里，我们将测试Tac 2信号是否在 mPFC发挥对SI-攻击的皮质控制。在初步研究中，我们发现Tac 2 + mPFC 神经元包括一类独特的、未探索的GABA能中间神经元（IN）。这些发现导致了 Tac 2 + INs对兴奋性锥体神经元（PNs）产生前馈抑制， SI-侵略。为了测试这一点，我们将结合联合收割机行为，机器学习，分子遗传的损失和获得， 功能操作和体内Ca 2+成像，以实现电路水平，机械理解如何 mPFC中不同的遗传定义的神经元群体对SI发挥协调的皮质控制， 侵略我们将确定是否mPFC Tac 2+神经元需要SI-侵略（目的1）， mPFC PN足以抑制SI攻击（目的2），以及Tac 2 + IN是否直接调节PN活性 在SI攻击期间（目标3）。总的来说，我们的目标是发现一个保守的，遗传定义的mPFC 大脑皮层自上而下控制隔离引发的攻击的微电路。这些发现将改变 通过扩大我们对病理形式的侵略是如何编码和控制的理解， 大脑中的前额叶回路重要的是，这项研究将对治疗社会问题产生深远的影响。 与孤立有关的精神健康障碍，特别是导致暴力的精神健康障碍。