Cortical mechanisms of stress-induced cognitive impairment

压力引起的认知障碍的皮质机制

基本信息

批准号：
10381350
负责人：
Gyorgy Lur
金额：
$ 9.57万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10381350
关键词：
Acoustic Stimulation Action Potentials Acute Address Affect Anterior Area Attention Auditory Axon Behavior Behavioral Blindness Brain Brain region Calcium Cells Characteristics Chronic stress Cognition Color Data Decision Making Development Discrimination Economics Elements Environment Excitatory Synapse Exposure to Future Guidelines Health Care Costs Human Image Impaired cognition Impairment Intervention Knowledge Life Expectancy Link Measures Mediating Memory Mental Health Modality Mus National Institute of Mental Health Neocortex Neurons Output Parietal Parietal Lobe Physical Restraint Play Poverty Prevention strategy Productivity Publishing Pyramidal Cells Research Risk Role Sensory Signal Detection Analysis Slice Stimulus Stream Stress Synapses System Testing Visual War area striata base behavior test cingulate cortex cognitive function cognitive performance design designer receptors exclusively activated by designer drugs disability experimental study in vivo calcium imaging in vivo two-photon imaging innovation insight multimodality neuropsychiatric disorder novel novel strategies operation optogenetics outcome prediction patch clamp preservation preventive intervention response sensory discrimination sensory input sensory integration stress related disorder stressor therapy development two-photon visual stimulus

项目摘要

PROJECT SUMMARY / ABSTRACT Stress profoundly impacts mental health via impaired cognitive function and increased risk of neuropsychiatric disorders, resulting in loss of lives, tremendous healthcare costs and reduced economic productivity. Central to the mechanism of stress-induced cognitive impairment is loss of excitatory synapses and consequently, disrupted connectivity of key brain areas, including those involved in decision-making. Decisions rely on this connectivity to combine sensory clues with internal factors like attention, memories and outcome predictions. In the neocortex, sensory information is provided by bottom-up inputs while internal factors are conveyed via top- down systems. The capacity of the posterior parietal cortex (PPC) to integrate these various information streams is fundamental to decision-making. There is emerging evidence from human studies that the parietal circuit is affected by chronic stress. Yet, there is a critical gap in our knowledge regarding the mechanistic role the PPC circuit may play in mediating the link between stress and impaired decision-making. Our preliminary findings indicate that repeated exposure to multiple concurrent stressors (combining physical, visual and auditory stresses, RMS for short) destroys excitatory synapses in the PPC. Specifically, synaptic inputs corresponding to the sensory modalities (visual and auditory) conveying the stress are lost while top- down inputs from frontal brain regions are preserved. These findings motivate our central hypothesis that stress impedes decision-making by disrupting the integration of sensory and top-down information streams in the PPC circuit. We will test this hypothesis at the behavioral, circuit and synaptic level. First, utilizing quantitative behavioral analysis, we will determine which aspects of decision-making are affected by RMS. We will use chemogenetic circuit manipulation (DREADDs) to link our behavioral findings to sensory and top-down inputs of the PPC. Next, we will use in vivo two-photon calcium imaging and signal detection theory to directly test the effect of RMS on information transfer between cortical regions. Finally, we will use dual-color optogenetics and whole-cell patch clamp recordings in acute brain slices to determine the effect of RMS on the integration of sensory and top-down synaptic inputs in PPC neurons. Successful completion of the proposed studies will establish an important mechanistic link between the PPC circuit and stress-induced deficits in decision-making. The generated insights will pave the way towards identifying novel targets for prevention and intervention strategies to address stress-related neuropsychiatric disorders.

项目摘要 /摘要压力通过认知功能受损并增加神经精神病的风险深刻影响心理健康疾病，导致生命损失，巨大的医疗保健成本和降低经济生产力。中心压力引起的认知障碍的机制是兴奋性突触的丧失，因此，关键大脑领域的连通性破坏了，包括参与决策的连通性。决定依赖于此连通性将感觉线索与内部因素相结合，例如注意力，记忆和结果预测。在新皮层，感官信息由自下而上的输入提供，而内部因素是通过顶部传达的下降系统。后顶叶皮层（PPC）的能力集成这些各种信息流是决策至关重要的。人类研究中有新兴的证据表明顶叶电路受慢性应激的影响。但是，关于机械的知识存在一个危险的差距 PPC电路的角色可能在调解压力与决策受损之间的联系中发挥作用。我们的初步发现表明，反复暴露于多个并发压力源（结合物理，视觉和听觉应力，简短的RMS会破坏PPC中的兴奋性突触。具体而言，突触对应于感官方式（视觉和听觉）传达应力的输入，而顶部则丢失保留了额脑区域的下输入。这些发现激发了我们的中心假设压力通过破坏感觉和自上而下信息的整合来阻碍决策 PPC电路中的流。我们将在行为，电路和突触水平上检验该假设。第一的，利用定量行为分析，我们将确定决策的哪些方面受到影响 RMS。我们将使用化学发电电路操纵（Dreadds）将我们的行为发现与感觉和 PPC的自上而下输入。接下来，我们将使用体内两光子钙成像和信号检测理论直接测试RMS对皮质区域之间信息传递的影响。最后，我们将使用双色急性脑切片中的光遗传学和全细胞贴片夹记录，以确定RMS对 PPC神经元中感觉和自上而下的突触输入的整合。成功完成拟议的研究将在PPC电路和应力引起的缺陷之间建立重要的机械联系决策。生成的见解将为识别预防新颖目标的铺平道路解决与压力相关的神经精神疾病的干预策略。