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.

项目概要/摘要 长期剥夺社交接触会对大脑和行为产生有害影响。社交隔离 (SI) 或其感知（孤独感）与吸烟或肥胖一样，是导致不良健康结果的危险因素。 许多因素导致了现代孤独感的流行：人口老龄化、巨大的变化 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间的攻击和针对他人的暴力行为 – 事实上，与 SI 相关的家庭暴力上升了 20%，自杀率激增，校园枪击事件 继续撕裂社会结构。尽管如此，我们对基因定义的了解还很有限， 引起隔离引起的攻击的电路机制，代表了一个关键的障碍 开发有针对性的干预措施和认知疗法来治疗病理形式的攻击行为。一键 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 前额皮质（mPFC）。然而，mPFC 在调节 SI 诱发的攻击行为中的作用是 未知。在这里提出的项目中，我们将询问不同的、基因定义的细胞的功能 mPFC 调节 SI 诱发的攻击行为。为了支持这一点，我们最近发现了神经肽速激肽 2 (Tac2)/神经激肽 B (NkB) 作为 SI 的关键皮层下调节因子。在这里，我们将测试 Tac2 信号是否在 mPFC 对 SI 攻击发挥皮质控制。在初步研究中，我们发现 Tac2+ mPFC 神经元由一类独特的、未经探索的 GABA 能中间神经元 (IN) 组成。这些发现导致 Tac2+ INs 对兴奋性锥体神经元 (PNs) 施加前馈抑制以介导的具体假设 SI-侵略。为了测试这一点，我们将结合行为、机器学习、分子遗传损失和增益 功能操作和体内 Ca2+ 成像，以实现对如何进行电路级、机制的理解 mPFC 中不同的基因定义的神经元群对 SI-发挥协调的皮质控制 侵略。我们将确定 mPFC Tac2+ 神经元是否需要 SI 攻击（目标 1），是否 mPFC PN 足以抑制 SI 攻击（目标 2），以及 Tac2+ IN 是否直接调节 PN 活性 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、基因定义的 mPFC 用于自上而下的皮层控制隔离引起的攻击的微电路​​。这些发现将改变 通过扩展我们对病理性攻击形式如何编码和控制的理解 大脑中的前额叶回路。重要的是，这项研究将对社会问题的治疗产生深远的影响。 与隔离相关的精神健康障碍，特别是那些导致暴力的疾病。