Heterogeneous properties of LC efferents to modality-specific terminal fields

LC 传出信号与特定模态终端场的异质特性

• 批准号: 8693195
• 负责人: BARRY Dale WATERHOUSE
• 金额: $ 38.4万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8693195
• 关键词: Affect; Anterior; Area; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Brain; Brain Stem; Brain region; Cause of Death; Cell Nucleus; Cells; Cognitive; Complement; Consensus; Disease; Dissection; Fiber; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Goals; Individual; Injection of therapeutic agent; Label; Lasers; Lesion; Medial; Mediating; Membrane; Methods; Microarray Analysis; Modality; Molecular; Molecular Profiling; Motor; Motor Cortex; Movement; Nature; Neocortex; Neurons; Norepinephrine; Output; Patch-Clamp Techniques; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Polymerase Chain Reaction; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Procedures; Property; Prosencephalon; Proteins; RNA; Rattus; Research; Schizophrenia; Slice; Source; Synapses; System; Thinking; Time; Tracer; Work; base; cingulate cortex; design; executive function; expectation; flexibility; laser capture microdissection; locus ceruleus structure; molecular phenotype; motor control; neural circuit; neuropsychiatry; noradrenergic; norepinephrine system; operation; patch clamp; public health relevance; relating to nervous system; response; signal processing; spatial relationship

DESCRIPTION (provided by applicant): The primary goal of this project is to determine the anatomical organization, molecular phenotype, and electrophysiological properties of locus coeruleus (LC) neurons that innervate sub-regions of the rat prefrontal and motor cortex. The prefrontal cortex (PFC) including its sub-regions the orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and anterior cingulate cortex (ACC), and the primary motor cortex (M1) are innervated by the LC and subject to the modulatory actions of its primary transmitter, norepinephrine (NE). Each of the PFC sub-regions mediates distinct aspects of executive function that are compromised in many neuropsychiatric disorders including ADHD, PTSD, and schizophrenia. Likewise, the NE system has been implicated in the control of many PFC-dependent behavioral functions including flexible and sustained attention. The first aim of the proposed research will include retrograde tracing studies and immunohistochemical procedures to identify and characterize the subsets of NE-containing neurons within the LC that project to each PFC sub-region. In this and all subsequent aims M1 will serve as a non-cognitive brain region for comparison. The second aim of the project will determine the molecular complement of each class of projection cells by examining their transcriptomes and their expression levels of selected genes that are critical for noradrenergic function using combinations of laser micro-dissection, RNA microarray analysis and qRT-PCR. The third aim will profile individual LC-PFC and M1 projection cells on the basis of membrane properties, synaptic responsiveness, and sensitivity to drug activation using whole cell patch clamp techniques. These studies will provide a more complete understanding of the anatomical, molecular, and physiological attributes of the LC-cortical projection and challenge the longstanding notion that the LC is a functionally homogeneous cluster of NE-containing neurons that exert uniform modulatory effects across all LC- noradrenergic terminal fields, simultaneously. Instead, the general working hypothesis is that the LC-NE system operates by heterogeneous and asynchronous modulation of modality-specific terminal fields. This new theoretical construct has far reaching implications for our understanding of normal brain function and treatment of many neuropsychiatric disorders that involve noradrenergic and prefrontal cortical dysfunction.

描述（由申请人提供）：该项目的主要目标是确定基因座（LC）神经元的解剖组织，分子表型和电生理特性，这些神经元神经支配了大鼠前额叶和运动皮质的子区域。前额叶皮层（PFC），包括其子区域的眶额皮质（OFC），内侧前额叶 皮层（MPFC）和前扣带回皮层（ACC）和一级运动皮层（M1）由LC支配并受其主要发射器Norepinephrine（NE）的调节作用。每个PFC子区域都介导了执行功能的不同方面，这些方面在包括ADHD，PTSD和精神分裂症在内的许多神经精神疾病中受到损害。同样，NE系统也涉及控制许多依赖PFC的行为函数，包括灵活和持续关注。拟议的研究的第一个目的包括逆行追踪研究和免疫组织化学程序，以识别和表征LC中每个PFC子区域内含NE的神经元子集的子集。在此以及随后的所有目标中，M1将作为一个非认知大脑区域进行比较。该项目的第二个目的将通过检查其转录组及其表达水平来确定每类投影细胞的分子补体，而其所选基因的表达水平使用激光微脱吸岩，RNA微阵列分析和QRT-PCR的组合对去甲肾上腺素能功能至关重要。第三个目标将基于膜特性，突触反应能力以及使用全细胞贴片夹技术对药物激活的敏感性来介绍单个LC-PFC和M1投影细胞。这些研究将为LC皮质投影的解剖学，分子和生理属性提供更全面的了解，并挑战长期以来的观念，即LC是一个功能均匀的NE含NE含NE含神经元的簇，它们同时在所有LC- NORADRADRENERAGIC终端领域都具有均匀的调节作用。取而代之的是，一般的工作假设是LC-NE系统是通过异态特异性终端场的异质和异步调节运行的。这种新的理论结构对我们对正常脑功能的理解以及涉及去甲肾上腺素能和前额叶皮质功能障碍的许多神经精神疾病的治疗具有很大的影响。