Cortical mechanisms of stress-induced cognitive impairment

压力引起的认知障碍的皮质机制

• 批准号: 10030148
• 负责人: Gyorgy Lur
• 金额: $ 50.94万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 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/10030148
• 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; Preventive Intervention; 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; response; sensory discrimination; sensory input; sensory integration; stress related disorder; stressor; therapy development; two-photon; visual stimulus

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和神经精神疾病风险增加而深刻影响心理健康 疾病，导致生命损失、巨大的医疗费用和降低的经济生产力。中心到 应激诱导的认知损害的机制是兴奋性突触的丧失，因此， 大脑关键区域的连接中断，包括参与决策的区域。决策有赖于此 将感觉线索与注意力、记忆和结果预测等内部因素相结合的连接性。在……里面 大脑皮层的感觉信息是由自下而上的输入提供的，而内部因素是通过自上而下的输入传递的。 系统出现故障。后顶叶皮质(PPC)整合这些信息的能力 STREAMS是决策的基础。有来自人类研究的新证据表明，顶叶 电路受到慢性应激的影响。然而，我们对机械论的认识存在着严重的差距。 PPC回路可能在调节压力和决策受损之间的联系方面发挥作用。 我们的初步发现表明，反复暴露于多种同时存在的应激源(结合身体上的、 视觉和听觉应激(简称RMS)破坏PPC中的兴奋性突触。具体地说，突触 与传达压力的感觉模式(视觉和听觉)相对应的输入丢失，而顶部- 来自额叶脑区的向下输入被保留下来。这些发现支持了我们的中心假设 压力通过破坏感觉和自上而下信息的整合来阻碍决策 PPC电路中的数据流。我们将在行为、回路和突触水平上检验这一假说。第一, 利用定量行为分析，我们将确定决策的哪些方面受到 均方根。我们将使用化学发生回路操作(DREADD)将我们的行为发现与感觉和 PPC的自上而下输入。接下来，我们将利用体内双光子钙成像和信号检测理论 直接测试RMS对大脑皮层区域间信息传递的影响。最后，我们将使用双色 急性脑片的光遗传学和全细胞膜片钳记录以确定RMS对 PPC神经元中感觉和自上而下的突触输入的整合。圆满完成拟议中的 研究将在PPC回路和应激诱导的缺陷之间建立一个重要的机制联系 决策。产生的见解将为确定新的预防和预防目标铺平道路。 应对应激相关神经精神障碍的干预策略。