Intrinsic Properties of Cortical Layer 3 Pyramidal Cells in Monkeys

猴子皮质第 3 层锥体细胞的内在特性

• 批准号: 9355828
• 负责人: David A Lewis
• 金额: --
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9355828
• 关键词: Accounting; Animal Model; Animals; Architecture; Area; Attention; Autopsy; Axon; Behavioral; Biological Models; Brain; Brain region; Cells; Cognition; Cognitive; Disease; Electrophysiology (science); Elements; Exhibits; Frequencies; Functional disorder; Gene Expression; Gene Expression Profile; Goals; Human; Human Genome; Impaired cognition; Impairment; In Vitro; Instruction; Label; Lasers; Length; Link; Macaca; Mediating; Membrane; Memory impairment; Microdissection; Molecular; Monkeys; Morphology; Neocortex; Neurons; Parietal Lobe; Parvalbumins; Pathology; Population; Prefrontal Cortex; Primates; Process; Production; Property; Pyramidal Cells; Rodent; Role; Sampling; Schizophrenia; Severities; Short-Term Memory; Slice; Specificity; Testing; Tracer; Trees; Vertebral column; Visual; base; cell type; cognitive testing; density; gamma-Aminobutyric Acid; human subject; in vivo; interest; molecular marker; molecular pathology; morphometry; neocortical; neural circuit; neurophysiology; nonhuman primate; regional difference; relating to nervous system; research study; retrograde transport; synaptic inhibition; translational approach; translational study

Visual working memory and attention depend on coordinated neural activity between the posterior parietal cortex (PPC) and dorsolateral prefrontal cortex (DLPFC). These two regions are directly linked by projections from layer 3 pyramidal cells (PCs) that are predicted to mediate their functional connectivity (Project 4). Consequently, cell-autonomous abnormalities in the neurons furnishing these projections are posited to impair functional connectivity between PPC and DLPFC in schizophrenia (Project 5), leading to deficits in WM and attention. A key element ofthis Central Hypothesis is that region-specific properties of layer 3 PCs moderate the severity of the molecular (Projecti) and morphological (Project 2) pathology of these neurons in schizophrenia; specifically, the pathology of layer 3 PCs is predicted to be more severe in DLPFC than in PPC, and thus the projections from DLPFC-to-PPC are predicted to be more impaired than those from PPC- to-DLPFC (Project 5). This project serves as a critical bridge between Project 1&2 studies of all layer 3 PCs in human PPC and DLPFC and the Project 4 studies that focus on the layer 3 connections between PPC and DLPFC in monkeys as follows: Aim 1 provides key assessments of our translational strategy for testing the Central Hypothesis. First, it tests the idea that regional differences in layer 3 PC gene expression between human PPC and DLPFC are conserved in monkeys. Second, by focusing on the layer 3 PCs that interconnect PPC and DLPFC, it provides a robust test of the idea that region of origin accounts for differences in gene expression by controlling for other factors known to be associated with differences in certain molecular features or dendritic morphology of PCs. Thus, Aim 1 provides a key transition from Project 1&2 studies in humans of all layer 3 PCs (which cannot currently be divided into subsets based on their principal axon projection) to studies of the subset that interconnect PPC and DLPFC in monkeys. These region-defined differences in gene expression are predicted to be associated with differences in morphological (Aim 2), and neurophysiological (Aim 3) properties of layer 3 PCs that provide the cellular basis for the functional connectivity between monkey PPC and DLPFC studied in Project 4. RELEVANCE (See instructions): This project will inform our understanding ofthe neural circuitry basis for attention and working memory impairments in schizophrenia through the use of a non-human primate model system to determine, with specificity at the levels of cell types, local circuits and inter-regional connections, the critical properties of the same neural circuitry studied at the functional and behavioral levels in human subjects.

视觉工作记忆和注意力依赖于顶叶后叶之间的协调神经活动 背外侧前额叶皮层（DLPFC）。这两个区域通过投影直接相连 从第3层锥体细胞（PC），预计介导其功能连接（项目4）。 因此，提供这些投射的神经元中的细胞自主异常被假定为 精神分裂症患者PPC和DLPFC之间功能连接受损（项目5），导致 WM和注意力。这个中心假设的一个关键要素是，第三层PC的区域特定属性 减轻这些神经元的分子（项目1）和形态（项目2）病理学的严重程度 在精神分裂症中，具体而言，DLPFC中第3层PC的病理学预测比DLPFC中更严重。 PPC，因此预测从DLPFC到PPC的预测比从PPC到PPC的预测受损更大。 至DLPFC（项目5）。该项目作为所有第3层PC的项目1和2研究之间的关键桥梁 在人类PPC和DLPFC和项目4研究，重点是PPC和DLPFC之间的第3层连接， 目的1提供了我们的翻译策略的关键评估，用于测试 中心假设首先，它测试了第三层PC基因表达的区域差异， 人PPC和DLPFC在猴中是保守的。其次，通过关注第3层PC， 它将PPC和DLPFC互连起来，为原产地占 通过控制已知与基因表达差异相关的其他因素， PC的某些分子特征或树突状形态。因此，目标1提供了从项目 所有第3层PC（目前无法根据其 主要轴突投射），以研究猴中PPC和DLPFC相互连接的子集。这些 基因表达的区域定义差异被预测与以下差异相关： 形态学（目标2）和神经生理学（目标3）的第3层PC的性质，提供细胞的 项目4中研究的猴PPC和DLPFC之间功能连接的基础。 相关性（参见说明）： 这个项目将告知我们对注意力和工作记忆的神经回路基础的理解 通过使用非人灵长类动物模型系统来确定精神分裂症中的损伤， 在细胞类型、局部电路和区域间连接水平上的特异性， 在人类受试者的功能和行为水平上研究相同的神经回路。