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

• 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
• 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disorder; neuropsychiatry; optogenetics; psychosocial; receptor; relating to nervous system; social; stress resilience; unpublished works

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.

项目总结/摘要 长期的社会和环境压力暴露税的适应能力（灵活性）的个人 并且被广泛认为是神经精神疾病的风险和严重性的主要决定因素。障碍 如重度抑郁症（MDD）、强迫症（OCD）和精神分裂症， 一些重叠的行为障碍，包括认知受损，也观察到与 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 记录的缺陷包括认知灵活性、抑制控制和工作记忆受损2，3。障碍 在灵活性方面，增加对消极生活事件的敏感性，减少情绪控制，促进发展 适应不良的行为会破坏有效参与的能力2，3。尽管有广泛的反响， 完整的灵活性，神经基板负责同步处理参与这一行为仍然存在 不清楚 内侧前额叶皮层的边缘前皮质区（PrLC）编码高级功能，包括认知功能， 灵活性使用复杂的框架下游谷氨酸预测的核延髓（NAc）和 丘脑结构，如中背丘脑（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，与压力有关的精神病理学，包括减少 认知控制与PrLC回路中的突触和结构修饰相关。但具体 显示这些适应的皮层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没有很好的定义。我们最近发表的研究结果表明 在PrLC中，CUS促进内在兴奋性，神经元放电和平衡的相反变化。 表达多巴胺D1与D2型的锥体神经元（PN）中的兴奋性：抑制性突触调节 受体。试验数据表明，这些相反的影响发生在D1-PN内，投射到NAc和D2-PN 投射到数据终端这一探索性建议将以这些发现为基础，深入了解 神经病理学的基础，这些适应的来源和解剖选择性的抑制 突触的变化（Aim 1），并确定这些子电路的信息处理相关的贡献， 认知灵活性（目标2）。我们将使用基于操作的注意定势转换模型（类似于威斯康星州 卡片分类任务）与离体光遗传学全细胞记录相结合，以评估 细胞类型/途径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 减少这些回路的活动独特地改变了灵活的决策。