Top‐Down Control of Isolation‐Induced Aggression Through mPFC Tac2+ Interneurons

上-下隔离控制-通过 mPFC Tac2 中间神经元诱导攻击

• 批准号: 10674483
• 负责人: Rachel Gatlin
• 金额: $ 3.78万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674483
• 关键词: Adolescent; Aggressive behavior; Anxiety; Behavior; Behavioral; Biological Assay; Brain; Brain region; COVID-19 pandemic; Calcium; Chronic; Color; Computer Analysis; Confocal Microscopy; Data; Data Analyses; Development; Endoscopy; Equilibrium; Exhibits; Feeling; Fellowship; Female; Genes; Genetic; Genetic Identity; Goals; Health; House mice; Image; In Situ Hybridization; Institution; Interneurons; Knowledge; Lead; Link; Measures; Medial; Mediating; Mental Depression; Mental Health; Modeling; Mus; Neurobiology; Neurokinin B; Neuromedin K Receptor; Neurons; Neuropeptides; Neurosciences; Operative Surgical Procedures; Outcome; Pattern; Population; Positioning Attribute; Postdoctoral Fellow; Prefrontal Cortex; Process; Public Health; Research; Rodent; Role; Signal Transduction; Social Behavior; Social Environment; Social Interaction; Social isolation; Stress; System; Tachykinin; Technical Expertise; Testing; Training; Violence; Viral; Work; calcium indicator; career; cell type; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; imaging approach; implantation; in vivo; in vivo imaging; insight; knock-down; lens; loss of function; male; microendoscopy; neural correlate; novel; professor; skills; social; social separation; stressor

Project Summary/Abstract As social creatures, social interaction is vital for mammalian health. Prolonged separation from social environments can result in social isolation stress, which is linked to poor mental health outcomes, including anxiety, depression, and violence. Despite this, relatively little is known about the neurobiology underlying these changes induced by social isolation, representing a critical gap in the field. In this proposal, I will investigate the role of Tachykinin 2-expressing (Tac2+) interneurons in the medial prefrontal cortex (mPFC) in regulating isolation-induced aggression, through a combination of genetic characterization, cell-type specific functional manipulations, and in vivo imaging approaches. My preliminary work establishes mPFC Tac2+ neurons as interneurons and finds isolation-induced aggression in both male and female mice. In Aim 1 I will use an in situ hybridization assay to investigate the extent to which neuropeptide-encoding genes are expressed in mPFC Tac2+ interneurons to understand whether these neurons are a homogenous population or can be subdivided into subpopulations. Then, in Aim 2 I will examine whether the activity of mPFC Tac2+ interneurons or Tac2/Neurokinin B signaling is necessary for isolation-aggression and will investigate the role of neurokinin B in this process. Lastly in Aim 3, I will use dual-color in vivo microendoscopic imaging of different colored calcium indicators expressed in mPFC Tac2+ interneurons and mPFC pyramidal neurons, respectively, to understand the activity of these neuronal populations during isolation-induced aggression. This project builds off my strong background in rodent behavior and allows me to gain computational skills for the analysis of behavior and calcium imaging data. Under the training provided by this fellowship, I will gain the necessary technical skills, knowledge of my field, and data analysis skills to assist in my transition to a postdoctoral position in systems neuroscience and achieve my career goal of becoming a professor at a research-intensive institution. Through understanding the contribution of mPFC Tac2+ interneurons to isolation-induced aggression, this project will further our understanding of the circuit-level mechanisms that contribute to mental health issues resulting from prolonged social isolation.

项目总结/摘要 作为社会性动物，社会互动对哺乳动物的健康至关重要。长期脱离社会 环境可能导致社会孤立压力，这与不良的心理健康结果有关，包括 焦虑抑郁和暴力尽管如此，人们对这些疾病背后的神经生物学知之甚少。 社会孤立引起的变化，这是该领域的一个关键差距。在这个建议中，我将调查 内侧前额叶皮层（mPFC）中表达Tac 2+的中间神经元在调节 隔离诱导的攻击，通过遗传特征，细胞类型特异性功能， 操作和体内成像方法。我的初步工作建立了mPFC Tac 2+神经元， 在雄性和雌性小鼠中发现了隔离诱导的攻击性。在目标1中，我将使用一个原位 杂交试验以研究神经肽编码基因在mPFC中表达的程度 Tac 2+中间神经元，以了解这些神经元是否是同质群体或可以细分 分成亚群。然后，在目标2中，我将检查mPFC Tac 2+中间神经元或 Tac 2/神经激肽B信号传导对于孤立攻击是必需的，并且将研究神经激肽B在 这个过程最后，在目标3中，我将使用不同颜色钙的双色体内显微内窥镜成像 分别在mPFC Tac 2+中间神经元和mPFC锥体神经元中表达的指标，以了解 这些神经元群体在隔离诱导的攻击过程中的活动。这个项目建立在我强大的 啮齿动物行为的背景，使我能够获得分析行为和钙的计算技能， 成像数据。在这个奖学金提供的培训下，我将获得必要的技术技能，知识， 我的领域，和数据分析技能，以协助我过渡到博士后的立场，在系统神经科学 并实现我的职业目标，成为一个研究密集型机构的教授。通过了解 mPFC Tac 2+中间神经元对隔离诱导的攻击的贡献，这个项目将进一步我们 了解电路水平的机制，有助于心理健康问题所造成的长期 社会孤立