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：
10615723
负责人：
Gyorgy Lur
金额：
$ 47.72万
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/10615723
关键词：
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 Disease Economics Elements Environment Excitatory Synapse Exposure to Functional disorder Future Genetic 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 Predisposition Prevention strategy Productivity Publishing Pyramidal Cells Research Risk Role Sensory Signal Detection Analysis Slice Stimulus Stream Stress Synapses System Testing Visual War area striata 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 neocortical neuropsychiatric disorder novel novel strategies operation optogenetics outcome prediction patch clamp preservation response sensory discrimination sensory input sensory integration 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.

项目概要/摘要压力会损害认知功能并增加神经精神疾病的风险，从而深刻影响心理健康疾病，导致生命损失、巨大的医疗费用和经济生产力下降。中央至压力引起的认知障碍的机制是兴奋性突触的丧失，因此，关键大脑区域的连接中断，包括那些参与决策的区域。决策取决于此将感官线索与注意力、记忆和结果预测等内部因素结合起来的连接性。在在新皮质中，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关闭系统。后顶叶皮层 (PPC) 整合这些不同信息的能力流是决策的基础。来自人类研究的新证据表明，顶叶电路受到慢性压力的影响。然而，我们对机械原理的认识存在严重差距。 PPC 回路在调节压力和决策受损之间的联系中可能发挥的作用。我们的初步研究结果表明，反复暴露于多种并发压力源（结合身体、视觉和听觉压力（简称 RMS）会破坏 PPC 中的兴奋性突触。具体来说，突触与传达压力的感觉方式（视觉和听觉）相对应的输入会丢失，而顶部- 来自额叶大脑区域的向下输入被保留。这些发现激发了我们的中心假设：压力会破坏感觉和自上而下信息的整合，从而阻碍决策 PPC 电路中的流。我们将在行为、回路和突触层面检验这一假设。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均方根。我们将使用化学遗传学电路操纵（DREADD）将我们的行为发现与感觉和 PPC 自上而下的输入。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。顺利完成拟议的研究将在 PPC 回路与应激引起的缺陷之间建立重要的机制联系决策。所产生的见解将为确定预防和预防的新目标铺平道路。解决与压力相关的神经精神疾病的干预策略。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sex-dependent long-term effects of prepubescent stress on the posterior parietal cortex.

青春期前压力对后顶叶皮层的性别依赖性长期影响。

DOI：
发表时间：
2021-05
期刊：
影响因子：
0
作者：
Fariborzi, Mona;Park, Soo Bin;Ozgur, Ali;Lur, Gyorgy
通讯作者：
Lur, Gyorgy

The Importance of Accounting for Movement When Relating Neuronal Activity to Sensory and Cognitive Processes.

将神经元活动与感觉和认知过程联系起来时考虑运动的重要性。

DOI：
发表时间：
2022-02-23
期刊：
影响因子：
0
作者：
Zagha, Edward;Erlich, Jeffrey C;Lee, Soohyun;Lur, Gyorgy;O'Connor, Daniel H;Steinmetz, Nicholas A;Stringer, Carsen;Yang, Hongdian
通讯作者：
Yang, Hongdian

To deconvolve, or not to deconvolve: Inferences of neuronal activities using calcium imaging data.

去卷积或不去卷积：使用钙成像数据推断神经元活动。