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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

基本信息

批准号：
10542428
负责人：
Jordan P Hamm
金额：
$ 38.61万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10542428
关键词：
3-Dimensional Adolescence Adolescent Adolescent Development Adult Anatomy Animals Attention Basic Science Brain Brain region CSF1R gene Calcium Cell physiology Cells Cerebral cortex Cognition 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 Mental disorders Microglia Morphology Mus Neuroglia Neuroimmune Neurons Odors Optics PTPNS1 gene Pattern Phase Physiological Population Prefrontal Cortex Prevalence Process Regulation Rodent Role Schizophrenia Sex Differences Shapes Surveys Synapses Synaptic plasticity Techniques Testing Time Traction Training Vertebral column Visual Cortex Work awake cell motility cognitive ability cognitive development cognitive function cognitive reappraisal critical period density emerging adult immune function in vivo imaging inhibitor insight male neural neural circuit neural network neuronal circuitry neuroregulation novel optogenetics pharmacologic preadolescence psychosocial stressors response sex sexual dimorphism spatiotemporal two photon microscopy two-photon

项目摘要

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-神经胶质相互作用的基本理解是将免疫功能改变与神经系统紊乱联系起来的关键