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: 8813628
• 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/8813628
• 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; Health; 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; differential expression; executive function; expectation; flexibility; laser capture microdissection; locus ceruleus structure; molecular phenotype; motor control; neural circuit; neuropsychiatry; noradrenergic; norepinephrine system; operation; patch clamp; relating to nervous system; response; signal processing; spatial relationship; sustained attention

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支配大鼠前额叶和运动皮层子区域的蓝斑（LC）神经元的解剖结构、分子表型和电生理特性。前额皮质 (PFC) 包括其子区域：眶额皮质 (OFC)、内侧前额皮质 皮层 (mPFC)、前扣带皮层 (ACC) 和初级运动皮层 (M1) 由 LC 支配，并受到其主要递质去甲肾上腺素 (NE) 的调节作用。 PFC 的每个子区域都介导执行功能的不同方面，这些方面在许多神经精神疾病（包括 ADHD、PTSD 和精神分裂症）中受到损害。同样，NE 系统也涉及许多 PFC 依赖性行为功能的控制，包括灵活和持续的注意力。拟议研究的第一个目标将包括逆行追踪研究和免疫组织化学程序，以识别和表征 LC 内投射到每个 PFC 亚区域的含有 NE 的神经元子集。在这个目标和所有后续目标中，M1 将作为非认知大脑区域进行比较。该项目的第二个目标是通过结合激光显微切割、RNA 微阵列分析和 qRT-PCR 检查其转录组和对去甲肾上腺素能功能至关重要的选定基因的表达水平，确定每类投射细胞的分子互补性。第三个目标是使用全细胞膜片钳技术，根据膜特性、突触反应性和对药物激活的敏感性来分析单个 LC-PFC 和 M1 投射细胞。这些研究将提供对 LC 皮质投射的解剖学、分子和生理学属性的更全面的了解，并挑战长期以来的观念，即 LC 是功能同质的含有 NE 的神经元簇，同时在所有 LC 去甲肾上腺素能末端区域发挥统一的调节作用。相反，一般的工作假设是 LC-NE 系统通过特定模态终端字段的异构和异步调制来运行。这种新的理论构建对于我们理解正常大脑功能以及涉及去甲肾上腺素能和前额皮质功能障碍的许多神经精神疾病的治疗具有深远的影响。