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

• 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
• 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

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（修订版） 对压力的不良适应通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。虽然它是公认的环境因素，如压力，发挥病因学的作用，大脑机制，特别是特定的神经回路介导的适应不良反应的作用，仍有待阐明。小鼠的慢性社会失败应激（cSDS）是研究与应激相关的脑回路机制的高度相关的、经验证的模型。cSDS已被证明可诱导多个脑区的形态和功能变化，包括内侧前额叶皮质（mPFC），其中包含异质细胞类型，并与其他边缘脑区相互连接。使用最近开发的称为fosTRAP和TRAP 2的神经元活动报告小鼠系，申请人的实验室已经确定急性（aSDS）和慢性（cSDS）社交失败应激激活mPFC中投射神经元的不同群体。本研究的目的是确定特定的电路连接是否与压力引起的社会障碍有关，以及是否可以设计新的治疗干预策略来选择性地针对相关电路来对抗社会缺陷并减轻脱靶效应。两个实验室（Ferguson-小鼠行为，分子生物学和生物信息学; Qiu-神经生理学和功能电路映射，光遗传学）的专业知识将被结合起来，以测试cSDS诱导的，受损的社会行为在mPFC中的特定神经回路中编码的假设。PI将采用TRAP 2报告小鼠系获得对cSDS激活的mPFC神经元的遗传访问，然后研究：目的1）在cSDS激活的NAC投射mPFC神经元群体中是否选择性发生突触稳态破坏，以及在易受社会损害的小鼠中是否选择性发生突触稳态破坏。在目标2中，该团队将使用cSDS激活的mPFC投射神经元中的神经活动的靶向光遗传学操纵，这些神经元也选择性地表达兴奋性或抑制性视蛋白。研究人员将测试新的假设，即在cSDS期间这种特定神经元集合的光遗传学抑制赋予弹性，而这些神经元的重复激活导致对社会障碍的易感性。目的3将研究cSDS激活的mPFC神经元中潜在的失调基因网络，以及这种变化在多大程度上依赖于SIRT 1，SIRT 1是抑郁症的主要人类遗传风险因素，通过TRAP 2和RiboTag小鼠中cSDS的创新组合以及对从雄性和雌性小鼠中收集的RNAseq数据的生物信息学分析。影响：这些目标的成功完成可能会揭示一个基于回路的治疗方法，旨在恢复前额叶突触稳态的范式转变的做法，并可以建立一个特定的皮质边缘回路作为一个铅干预目标，以防止发展的压力诱导的电路病理，这是不可能的，否则由以前的研究检查一个不加选择的批发人口的PFC神经元。