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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