Prefrontal-Accumbens Neurocircuits Mediating Response to Social Stress

前额叶伏隔神经回路调节对社会压力的反应

基本信息

批准号：
10624234
负责人：
Deveroux Ferguson
金额：
$ 59.7万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624234
关键词：
Acute Adopted Affect Behavior Binding Bioinformatics Brain Brain region Chronic Chronic stress Cognitive Data Development Electrophysiology (science)Environmental Risk Factor Etiology Exposure to Female Gene Expression Genes Genetic Glutamates Goals Homeostasis Human Human Genetics Immunoprecipitation Impairment Intervention Investigation Label Laboratories Lasers Lead Link LoxP-flanked allele Maps Medial Mediating Medical Mental Depression Mental disorders Messenger RNA Modeling Molecular Molecular Biology Morphology Mus Neuroanatomy Neurons Nucleus Accumbens Opsin Pathology Play Population Population Projection Predisposition Prefrontal Cortex Psychological Stress Public Health Reporter Research Research Personnel Resistance RiboTag Ribosomes Risk Factors Role SIRT1 gene Scanning Shapes Slice Social Behavior Stress Stress and Coping Synapses Tamoxifen Testing Therapeutic Tissue-Specific Gene Expression Translating Viral behavioral impairment behavioral outcome brain circuitry cell type combat cortico-limbic circuits depressive symptoms emotional stimulus executive function gene network gene regulatory network genetic risk factor genome wide association study innovation male neural neural circuit neurophysiology neuropsychiatric disorder neuropsychiatry novel novel therapeutic intervention optogenetics patch clamp prevent psychiatric symptom recruit resilience response selective expression sex social social defeat social deficits social stress stressor synaptic function transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT (revised) Mal-adaptations to stress often leads to impaired social behavior, a shared domain across many neuropsychiatric conditions. While it is well-established that environmental factors, such as stress, play an etiology role, the brain mechanisms, particularly the role of specific neural circuits mediating the maladaptive responses, remain to be elucidated. Chronic social defeat stress (cSDS) in mice is a highly relevant, validated model to study brain circuit mechanisms related to stress. cSDS has been shown to induce morphological and functional changes in multiple brain regions including the medial prefrontal cortex (mPFC), which contains heterogeneous cell types and is interconnected with other limbic brain regions. Using recently developed neuronal activity reporter mouse lines, termed fosTRAP and TRAP2, the applicants’ laboratories have determined that acute (aSDS) and chronic (cSDS) social defeat stress activate distinct populations of projection neurons in the mPFC. The goal of this study is to determine whether specific circuit connectivity is pertinent to stress-induced social impairment and if novel therapeutic intervention strategies could be devised to selectively target the relevant circuits to combat the social deficits and alleviate off target effects. The expertise of two laboratories (Ferguson- mouse behavior, molecular biology and bioinformatics; Qiu-neurophysiology and functional circuit mapping, optogenetics) will be combined to test the hypothesis that cSDS-induced, impaired social behaviors are encoded within a specific neural circuit in the mPFC. The PIs will employ a TRAP2 reporter mouse line to gain genetic access to the mPFC neurons that are activated by cSDS, followed by investigation of: Aim 1) whether disrupted synaptic homeostasis selectively occurs in NAc-projecting mPFC neuronal populations that are activated by the cSDS, and whether disrupted synaptic homeostasis occurs selectively in the mice susceptible to social impairment. In Aim 2, this team will use targeted optogenetic manipulation of neural activity in the cSDS-activated mPFC projection neurons that also selectively express excitatory or inhibitory opsins. The investigators will test the novel hypothesis that optogenetic inhibition of this specific neuron ensemble during the cSDS confers resilience, while repeated activation of these neurons leads to susceptibility to social impairments. Aim 3 will investigate potential dysregulated gene networks in cSDS-activated mPFC neurons and to what extent such changes depend on SIRT1, a major human genetic risk factor for depression, through an innovative combination of cSDS in TRAP2 and RiboTag mice and bioinformatics analyses on RNAseq data collected from both male and female mice. Impact: Successful completion of these aims could reveal a paradigm-shifting practice in circuit-based therapeutics aimed at restoring prefrontal synaptic homeostasis and could establish a specific corticolimbic circuit as a lead intervention target for preventing the development of stress induced circuit pathology, which is otherwise not possible by previous studies examining an indiscriminate wholesale population of PFC neurons.

项目概要/摘要（修订）对压力的适应不良常常会导致社会行为受损，这是许多神经精神疾病的共同领域。虽然众所周知，压力等环境因素在病因学中发挥着作用，但大脑机制，特别是特定神经回路的作用。小鼠的慢性社交挫败应激 (cSDS) 是一种高度相关且经过验证的模型，可用于研究与应激相关的脑回路机制。申请人的实验室使用最近开发的神经元活动报告小鼠系（称为 fosTRAP 和 TRAP2）确定了多个大脑区域的功能变化，包括内侧前额叶皮层（mPFC），该区域包含异质细胞类型并与其他边缘脑区域相互连接。急性 (aSDS) 和慢性 (cSDS) 社交失败压力会激活 mPFC 中不同的投射神经元群。本研究的目的是确定特定的回路连接是否与压力引起的社交相关。以及是否可以设计新的干预策略来选择性地针对相关回路来对抗社交缺陷并减轻治疗脱靶效应（Ferguson-小鼠行为、分子生物学和生物信息学；Qiu-神经生理学和功能回路映射）。，光遗传学）将被结合起来，以测试 cSDS 诱导的社会行为受损是在 mPFC 中的特定神经回路中编码的假设，PI 将使用 TRAP2 报告小鼠。线以获得对 cSDS 激活的 mPFC 神经元的遗传访问，然后调查：目标 1) 突触稳态是否被破坏选择性地发生在由 cSDS 激活的 NAc 投射 mPFC 神经元群体中，以及突触稳态是否被破坏选择性地发生在目标 2 中，该团队将在 cSDS 激活的 mPFC 投射神经元中使用有针对性的光遗传学操作。研究人员将测试新的假设，即 cSDS 期间这种特定神经元群的光遗传学抑制会赋予弹性，而这些神经元的重复激活会导致对社交障碍的易感性。目标 3 将研究潜在的失调基因网络。 cSDS 激活的 mPFC 神经元以及这些变化在多大程度上依赖于 SIRT1（人类抑郁症的主要遗传风险因素），通过 TRAP2 和 RiboTag 中 cSDS 的创新组合小鼠和对从雄性和雌性小鼠收集的 RNAseq 数据进行的生物信息学分析：成功完成这些目标可以揭示旨在恢复前额突触稳态的基于回路的治疗的范式转变实践，并可以建立一个特定的皮质边缘回路作为主导。预防应激诱发的环路病理学发展的干预目标，否则通过先前研究不加区别的大规模 PFC 神经元的研究是不可能实现的。