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

确定前额皮质回路可塑性对压力引起的认知功能缺陷的贡献

基本信息

批准号：
10057869
负责人：
Matthew Carl Hearing
金额：
$ 40.49万
依托单位：
MARQUETTE UNIVERSITY
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：
2020-06-15 至 2023-06-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057869
关键词：
Adaptive Behaviors Anatomy Attention Behavior Behavior Control Behavioral Cells Chronic Chronic stress Cognitive Communication Complex Conflict (Psychology)Corpus striatum structure Data Decision Making Development Disease Dopamine Emotional Enterobacteria phage P1 Cre recombinase Equilibrium Etiology Event Exhibits Exposure to Functional disorder Glutamates Habits Impaired cognition Impairment Individual Interneurons Life Maintenance Major Depressive Disorder Medial Modeling Modification Mus Neurobehavioral Manifestations Neurons Noise Nucleus Accumbens Obsessive-Compulsive Disorder Opsin Output Parvalbumins Pathway interactions Performance Physiological Physiology Predisposition Prefrontal Cortex Probability Property Proteins Psychopathology Publishing Regulation Reporting Risk Schizophrenia Severities Signal Transduction Slice Sorting - Cell Movement Source Stress Structure Synapses Synaptic Transmission Taxes Testing Thalamic structure Transgenic Mice Transgenic Organisms Viral Whole-Cell Recordings Wisconsin Work base cell type cognitive control cognitive function cognitive testing emotional behavior experience flexibility frontal lobe hippocampal pyramidal neuron impaired capacity in vivo information processing insight nerve supply neuropathology neuropsychiatric disorder neuropsychiatry optogenetics psychosocial receptor relating to nervous system social stress resilience unpublished works

项目摘要

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.

项目概要/摘要长期的社会和环境压力会降低个人的适应能力（灵活性）并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。疾病例如重度抑郁症（MDD）、强迫症（OCD）和精神分裂症一些重叠的行为症状，包括认知受损，也观察到慢性社会心理压力1-3。认知问题的范围多种多样，但最一致的记录的缺陷包括认知灵活性、抑制控制和工作记忆受损2,3。减值灵活性增加对负面生活事件的敏感性，减少情绪控制，促进发展破坏有效参与能力的适应不良行为2,3。尽管引起广泛反响完整的灵活性，负责参与这种行为的一致处理的神经基质仍然存在不清楚。内侧 PFC 的前边缘皮质区 (PrLC) 编码高阶功能，包括认知功能使用下游谷氨酸投射到伏隔核（NAc）的复杂框架的灵活性和丘脑结构，例如内侧丘脑 (MDT)，用于指导行为并检测和解决冲突当规则改变时。大量研究表明，与压力相关的精神病理学，包括减少认知控制与 PrLC 回路中的突触和结构修饰有关。不过，具体表现出这些适应性的皮质输出通路以及它们如何影响这些网络的功能慢性压力导致的行为后果尚不明确。我们最近发表的研究结果表明在 PrLC 中，CUS 促进内在兴奋性、神经元放电和平衡的相反变化表达多巴胺 D1 与 D2 型的锥体神经元 (PN) 的兴奋性：抑制性突触调节受体。试点数据表明，这些相反的效应发生在投射到 NAc 和 D2-PN 的 D1-PN 内投影到 MDT。这项探索性提案将以这些发现为基础，深入了解神经病理学是这些适应在抑制的来源和解剖选择性方面的基础突触变化（目标1）并确定这些子电路对与以下相关的信息处理的贡献认知灵活性（目标 2）。我们将使用基于操作的注意力转移模型（类似于威斯康星州卡片分类任务）在转基因 Cre-小鼠中结合离体光遗传学全细胞记录来评估细胞类型/通路特异性可塑性和体内回路特异性化学遗传学，以确定如何增加或这些回路活动的减少会独特地改变灵活的决策。