Sex differences in microglia-neuron-circuit interactions in adolescence

青春期小胶质细胞-神经元-回路相互作用的性别差异

• 批准号: 10334801
• 负责人: Jordan P Hamm
• 金额: $ 34.52万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-20 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334801
• 关键词: 3-Dimensional; Address; Adolescence; Adolescent; Adolescent Development; Adult; Anatomy; Animals; Attention; Basic Science; Brain; Brain region; CSF1R gene; Calcium; Cell physiology; Cells; Cerebral cortex; Cognition; Cognitive; Coupling; Dependence; Development; Disease; Electronic Medical Records and Genomics Network; Female; Female Adolescents; Foundations; Functional disorder; Future; Goals; Homeostasis; Human; Image; Immune; Inflammatory; Link; Measures; Medial; Mediator of activation protein; Mental disorders; Microglia; Morphology; Mus; Neuroglia; Neuroimmune; Neurons; Odors; Optics; PTPNS1 gene; Pattern; Pharmacology; Phase; Physiological; Population; Prefrontal Cortex; Prevalence; Process; Regulation; Rodent; Role; Schizophrenia; Sex Differences; Shapes; Surveys; Synapses; Synaptic plasticity; Techniques; Testing; Time; Training; Vertebral column; Visual; Work; awake; base; cell motility; cognitive ability; cognitive development; cognitive function; cognitive reappraisal; critical period; density; emerging adult; immune function; in vivo imaging; inhibitor; insight; male; neural circuit; neural network; neuronal circuitry; neuroregulation; novel; optogenetics; preadolescence; psychosocial stressors; relating to nervous system; response; sex; sexual dimorphism; spatiotemporal; two photon microscopy; two-photon

A basic understanding of neuron-glia interactions is key to linking altered immune function to disrupted neural circuitry and cognition present in major psychiatric diseases. Microglia are a resident immune cell in the cerebral cortex, and one of their main functions under physiological conditions is to modify synaptic connections among neurons. How these activities extend to influence higher-order functional networks in cortical circuits is not clear, particularly in brain regions crucial for cognitive function, such as the prefrontal cortex (PFC). A key may lie in how neural circuit synchrony stimulates nearby microglial cell motility – i.e. active extension and retraction of fine cellular processes – and, specifically, in how this relationship changes throughout adolescence, a critical period for the development of PFC and higher cognition. Further, sex differences have been established in some aspects of microglial function. Clarifying how sex modulates the role of microglia in PFC circuit development is essential, especially given the dramatic sex differences in vulnerability to adolescent onset of psychiatric diseases such as schizophrenia. The goal of the current project is to obtain a basic understanding of glial-neuronal-circuit interactions in the mammalian prefrontal cortex. The planned approach (Aim 1) employs three-dimensional two-photon microscopy and single neuron optogenetics in awake mouse medial prefrontal cortex (mPFC) to elucidate how the structural dynamics of microglial cells are driven by neuronal activity and oscillatory synchrony in local circuits. This will be examined at distinct time windows from pre-adolescence into early adulthood and compared between males and females. (Aim 2,3) To test whether, how, and when microglia activity is necessary for the establishment of adult mPFC function, microglia will be selectively eliminated during restricted windows during adolescence and early adulthood using a pharmacological strategy. Then in adulthood, sex- and adolescent-period specific effects on the development of i) (Aim 2) spatiotemporal circuit dynamics in mPFC (functional network clustering, gamma oscillations, theta-gamma coupling) will be measured using two-photon calcium imaging and dense electrical recordings and ii) (Aim 3) PFC-dependent cognition will be assessed with an established odor-based attentional set-shifting task. This project employs state-of-the-art optical techniques to study brain function of behaving animals with cell- level precision. Results will identify when and how microglia interact with developing neuronal circuits to support adult-level cognitive function under physiological conditions. Since microglia may be a key mediator of psychiatric disease-relevant neuroimmune dysfunction, the basic science insights from this project, particularly afforded by a sex- and developmental-period stratified approach, could transform the search for core pathophysiological mechanisms and circuit-based treatments.

对神经元-胶质细胞相互作用的基本了解是将免疫功能改变与神经元破坏联系起来的关键 主要精神疾病中存在的电路和认知小胶质细胞是大脑中的常驻免疫细胞。 皮层，其在生理条件下的主要功能之一是改变突触连接 这些活动如何影响皮质回路中的高阶功能网络尚不清楚。 特别是对于认知功能至关重要的大脑区域，例如前额皮质（PFC）。 关键可能在于神经回路同步如何刺激附近的小胶质细胞运动——即主动延伸 以及细小细胞过程的收缩——特别是这种关系在整个过程中如何变化 青春期是 PFC 和高级认知发展的关键时期。 此外，性别差异也存在。 阐明了性别如何调节小胶质细胞的作用。 PFC 电路的开发至关重要，特别是考虑到青少年易受伤害的性别差异巨大 精神分裂症等精神疾病的发作。 当前项目的目标是获得对神经胶质-神经元-电路相互作用的基本了解 计划的方法（目标 1）采用三维双光子显微镜。 和清醒小鼠内侧前额叶皮层（mPFC）中的单神经元光遗传学，以阐明结构如何 小胶质细胞的动力学是由局部回路中的神经元活动和振荡同步驱动的。 在从青春期前到成年早期的不同时间窗口进行检查，并在男性和女性之间进行比较 （目标 2,3）测试小胶质细胞活动是否、如何以及何时对于成年的建立是必要的。 mPFC 功能，小胶质细胞将在青春期和早期的受限窗口内被选择性消除 成年期使用药理学策略对成年期、性和青少年时期的具体影响。 i)（目标 2）mPFC 中时空电路动力学的发展（功能网络聚类、伽玛 振荡，θ-伽马耦合）将使用双光子钙成像和密集电测量 记录和 ii)（目标 3）将使用既定的基于气味的注意力来评估 PFC 依赖性认知 设定转移任务。 该项目采用最先进的光学技术来研究具有细胞行为的动物的大脑功能 结果将确定小胶质细胞何时以及如何与发育中的神经回路相互作用以支持 生理条件下的成人认知功能，因为小胶质细胞可能是精神疾病的关键介质。 与疾病相关的神经免疫功能障碍，该项目的基础科学见解，特别是由 性别和发育时期的分层方法可以改变对核心病理生理学的探索 机制和基于电路的治疗。