Cortical mechanisms of stress-induced cognitive impairment

项目总结/摘要 压力通过认知功能受损和神经精神疾病风险增加深刻影响心理健康 疾病，导致生命损失，巨大的医疗保健成本和经济生产力下降。的核心 应激诱导的认知损害的机制是兴奋性突触的丧失， 破坏了关键大脑区域的连接，包括那些参与决策的区域。决策依赖于此 联合收割机的连通性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。在 在新皮层中，感觉信息由自下而上的输入提供，而内部因素则通过自上而下的输入传递。 下系统。后顶叶皮层整合这些不同信息的能力 流是决策的基础。人类研究中有新的证据表明顶骨 电路受到慢性压力的影响。然而，在我们的知识中存在着一个关键的空白， PPC电路在调解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，重复暴露于多种并发的压力源（结合身体， 视觉和听觉应激，简称RMS）破坏PPC中的兴奋性突触。具体来说，Synaptic 与传达压力的感觉模态（视觉和听觉）相对应的输入丢失， 来自额叶脑区域的下行输入被保留。这些发现激发了我们的核心假设， 压力通过破坏感官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这一假设。第一、 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。我们将使用化学发生回路操纵（DREADDs）将我们的行为发现与感觉和 PPC的自顶向下输入。接下来，我们将利用在体双光子钙离子成像和信号检测理论 直接测试RMS对皮层区域之间信息传递的影响。最后，我们将使用双色 在急性脑切片中进行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突触输入的整合。圆满完成拟议的 研究将在PPC回路和应激诱导的缺陷之间建立重要的机制联系， 决策的所产生的见解将为确定新的预防目标铺平道路， 干预策略，以解决与压力有关的神经精神疾病。

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.