Glucocorticoids and Psychiatric Disorders: Mechanisms of Stress Induced Cognitive Deficits

慢性压力是抑郁症和焦虑症等精神疾病的主要风险因素。认知缺陷是这些疾病的一个重要后果，因为它们严重损害日常生活功能。慢性压力会导致糖皮质激素（GCs）的释放，这种激素会与整个大脑的糖皮质激素受体（GR）结合。许多研究表明，应激诱导的GC释放对认知有不利影响，这些影响是通过前额叶皮层（PFC）的GR激活介导的，该结构在认知过程中起着关键作用。然而，在PFC微电路中的不同细胞群中，GCs的作用是否以及如何由GRs介导尚不清楚。在这里，我们建议通过结合遗传和病毒策略，操纵锥体神经元和PFC中表达小蛋白的抑制性中间神经元中的GR表达来解决这个问题。然后，我们将研究这些细胞特异性操作如何影响对慢性应激的反应。通过利用申请者的综合技术专长，我们将采取全面的多层次方法来研究细胞特异性GR操作如何调节应激对基因转录、细胞形态和生理、区域间网络相互作用和认知行为的影响。我们将首先研究细胞特异性GR操作对压力诱导的认知缺陷的行为后果，使用一系列pfc依赖的认知任务。然后，我们将使用多地点、多单元记录来询问压力如何影响包括海马体和PFC在内的神经回路，这是啮齿动物认知功能的核心。我们还将讨论GR在调节该电路中的应力效应中的作用。最后，通过结合组织学、体外记录和转录组分析，我们将评估GR基因操作对PFC微电路的形态学、生理和分子影响。综上所述，这些研究将有助于揭示慢性压力改变PFC回路功能并导致在压力诱发的精神疾病中观察到的认知缺陷的机制。

Chronic stress is a major risk factor for psychiatric illnesses such as depression and anxiety disorders. Cognitive deficits are an important consequence of these disorders, because they severely compromise functioning in daily life. Chronic stress causes the release of glucocorticoids (GCs), which bind to glucocorticoid receptors (GR) throughout the brain. A number of studies suggest that stress-induced GC release has detrimental effects on cognition and that these effects are mediated via GR activation in the prefrontal cortex (PFC), a structure that plays a key role in cognitive processes. Yet it is not well understood whether and how the effects of GCs are mediated by GRs in distinct cell populations within PFC microcircuits. Here, we propose to address this by manipulating GR expression in pyramidal neurons and parvalbumin-expressing inhibitory nterneurons within the PFC using a combination of genetic and viral strategies. We will then examine how these cell-specific manipulations affect responses to chronic stress. By using the combined technical expertise of the applicants, we will take a comprehensive multi-level approach to examine how cell-specific GR manipulations modulate the effects of stress on gene transcription, cellular morphology and physiology, as well as inter-areal network interactions and cognitive behavior. We will first study the behavioral consequences of cell-specific GR manipulations on stress-induced cognitive deficits using a battery of PFC-dependent cognitive tasks. We will then use multi-site, multi-unit recordings to ask how stress affects a neural circuit involving the hippocampus and PFC, which is central for cognitive function in rodents. We will also address the role of GR in modulating the effects of stress in this circuit. Finally, by combining histology, in vitro recordings and transcriptome analysis, we will assess the morphological, physiological and molecular impact of GR gene manipulation on PFC microcircuits. Taken together, these studies will help reveal the mechanisms by which chronic stress alters PFC circuit function and causes the cognitive deficits that are observed in stress-induced psychiatric illnesses.