Identifying contributions of prefrontal cortical circuit plasticity to stress-induced deficits in cognitive function

项目摘要/摘要 长期的社会和环境压力使个人的适应能力(灵活性)加重。 被广泛认为是神经精神疾病风险和严重程度的主要决定因素。精神障碍 如重度抑郁症(MDD)、强迫症(OCD)和精神分裂症 一些重叠的行为症状，包括认知障碍，也可以观察到 慢性心理社会压力1-3。认知问题的范围是多种多样的，但最一致的是 记录在案的缺陷包括认知灵活性、抑制性控制和工作记忆受损2，3 在灵活性方面增加对负面生活事件的敏感性，减少情绪控制，促进发展 扰乱有效参与的能力的不适应行为2，3。尽管 完整的灵活性，负责参与这一行为的重合处理的神经底物仍然存在 不清楚。 内侧PFC的前皮质区域(PrLC)编码高阶功能，包括认知功能 灵活性使用下游谷氨酸投射到伏核(NAC)和 丘脑结构，如丘脑内侧背侧核(MDT)，用于指导行为、检测和解决冲突 当规则改变的时候。许多研究表明，与压力相关的精神病理学，包括减少 认知控制与PrLC回路中突触和结构的改变有关。然而，具体的 表现这些适应的皮质输出通路以及它们如何影响这些网络的功能 促进慢性压力的行为后果并没有明确的定义。我们最近发表的研究结果表明 在PrLC中，CUS促进内在兴奋性、神经元放电和 兴奋性：表达多巴胺D_1和D_2的锥体神经元(PN)的抑制性突触调节 感受器。先导数据显示，这些相反的效应发生在向NAC和D2-Pn投射的d1-pn内 投射到MDT。此探索性建议将以这些发现为基础，通过深入了解 在抑制的来源和解剖选择性方面作为这些适应的基础的神经病理学 突触改变(Aim1)和识别这些亚回路对与 认知灵活性(目标2)。我们将使用基于操纵者的注意定势转移模型(类似于威斯康星州 卡片分类任务)结合体外光遗传全细胞记录来评估 细胞类型/途径特异性可塑性和体内电路特异性化学遗传学，以确定如何增加或 这些电路活跃度的减少独特地改变了灵活的决策。

Project Summary/Abstract Prolonged social and environmental stress exposure tax the adaptive capacity (flexibility) of an individual and is widely recognized as a major determinant of risk and severity of neuropsychiatric disease. Disorders such as major depression disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia exhibit a number of overlapping behavioral symptomologies, including impaired cognition, that are also observed with chronic psychosocial stress1-3 . The range of cognitive problems is diverse, however the most consistently documented deficits include impaired cognitive flexibility, inhibitory control, and working memory2,3. Impairments in flexibility increase susceptibility to negative life events, reduce emotional control, and promote development of maladaptive behaviors that disrupt abilities to engage effectively2,3. Despite the widespread repercussions of intact flexibility, the neural substrates responsible for coincident processing involved in this behavior remain unclear. The prelimbic cortical region (PrLC) of the medial PFC encodes high order functions, including cognitive flexibility using a complex framework of downstream glutamate projections to the nucleus accumbens (NAc) and thalamic structures such as the mediodorsal thalamus (MDT) to guide behavior and detect and resolve conflicts when rules change. Numerous studies have shown that stress-related psychopathology, including reduced cognitive control is associated with synaptic and structural modifications in PrLC circuits. However, the specific cortical output pathways that exhibit these adaptations and how they impact the function of these networks to promote behavioral consequences of chronic stress are not well-defined. Our recently published findings indicate that in the PrLC, CUS promotes opposing changes in intrinsic excitability, neuronal firing, and balance of excitatatory:inhibitory synaptic regulation in pyramidal neurons (PN) expressing dopamine D1 vs. D2-type receptors. Pilot data show that these opposing effects occur within D1-PN projecting to the NAc and D2-PN projecting to the MDT. This exploratory proposal will build upon these findings by gaining insight into the neuropathology that underlies these adaptations in terms of the source and anatomical selectivity of inhibitory synaptic changes (Aim1) and identifying contributions of these sub-circuits to information processing related to cognitive flexibility (Aim 2). We will use an operant-based model of attentional set-shifting (akin to the Wisconsin Card Sorting Task) in transgenic Cre-mice combined with ex vivo optogenetic whole-cell recordings to assess cell-type/pathway-specific plasticity and in vivo circuit-specific chemogenetics to identify how increasing or decreasing activity of these circuits uniquely alters flexible decision-making.