AFFERENT REGULATION OF CHOLINERGIC FOREBRAIN NEURONS

胆碱能前脑神经元的传入调节

• 批准号: 8606251
• 负责人: LASZLO ZABORSZKY
• 金额: $ 42.65万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606251
• 关键词: Acetylcholine; Address; Affect; Alzheimer' s Disease; Animal Model; Animals; Area; Arousal; Atlases; Attention; Behavior; Behavioral; Brain; Brain region; Cell Density; Cells; Cerebral cortex; Cerebral hemisphere; Characteristics; Collection; Complex; Computing Methodologies; Data; Data Analyses; Dementia; Deposition; Development; Disease; Drug abuse; Electron Microscopy; Fluoro-Gold; Goals; In Vitro; Inbreeding; Individual; Injection of therapeutic agent; Interneurons; Investigation; Knowledge; Label; Laboratories; Lateral; Lead; Light; Location; Maps; Medial; Memory; Motivation; Neurobehavioral Manifestations; Neurons; Output; Parietal; Patients; Pattern; Play; Population; Process; Property; Prosencephalon; Rattus; Rattus norvegicus; Regulation; Role; Schizophrenia; Sensory; Sensory Process; Site; Structure; Surface; Synapses; System; Techniques; Testing; Tracer; Variant; basal forebrain; basal forebrain cholinergic neurons; base; cell type; cholinergic; cholinergic neuron; data acquisition; density; gamma-Aminobutyric Acid; improved; in vivo; innovation; neuronal cell body; neuropsychiatry; novel; public health relevance; reconstruction; relating to nervous system; research study; segregation; sensory integration; spatial relationship; treatment strategy

DESCRIPTION (provided by applicant): The basal forebrain (BF) is a complex brain region that plays an important role in modulating cortical activity. The BF contains cholinergic and various non-cholinergic corticopetal neurons and interneurons. The corticopetal BF projections, especially the cholinergic component, have been implicated in memory, sensory processing and attention. In spite of intensive efforts by many laboratories over the last two decades, it remains enigmatic how the BF is organized to support both general arousal as well as specific functions like attention. Novel 3D reconstructions and numerical analyses suggest that the distribution of the various cell types is not random but displays a general pattern of association. Within the cholinergic space (i.e. the volume occupied by the cell bodies of cortically projecting BF cholinergic neurons) different cell types occupy high- density cell clusters that are regionally specific. It is hypothesized that these cell groups (clusters) in various locations in the BF together with specific prefrontal and posterior cortical areas may provide the neural basis of a distributed functional network that orchestrates localized cortical modulation. Specific projects in this application are variants on the theme of anatomical segregation of functional domains in basalo-cortical networks. Specific Aim 1 will define and validate BF cell clusters across individuals of rats and will assess the intersubejct variability of clusters. Specific Aim 2 will define the cortical projection target of BF cell clusters. Specific Aim 3 will test the hypothesis that the BF is topographically organized such that specific prefrontal cortical areas target specific BF cell groups, which in turn innervate specific limbic, posterior sensory or associational cortical areas. Specific Aim 4 we will characterize the biophysical and anatomical properties of local processing with special reference to NPY-cholinergic interaction, using in vitro paired recordings with intrinsic (GFP-NPY) labeling for NPY neurons and in vivo (Cy3-192IgG) pre-labeling for cholinergic neurons. We hypothesize that NPY neurons suppress cholinergic firing. The data acquisition in these projects represents a complete transition from cell populations to electron microscopy reconstructions of single synapses and investigations of their functions. The project will employ highly innovative approaches to data analysis, that bridge several important methodological gaps relating to cross-scale integration of neuroanatomical data collected at the cellular and systems levels. The proposed study will lead to more realistic description of basalo-cortical networks at the brain-wide scale that can guide and constrain behavioral studies on cholinergic function, in particular mechanisms of sensory integration and attention. Concomitantly, it will facilitate the understanding of the aberrant processing in basalo-cortical networks that characterizes several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and drug abuse.

描述（由申请人提供）：基底前脑（BF）是一个复杂的大脑区域，在调节皮质活动中发挥着重要作用。 BF 包含胆碱能和各种非胆碱能皮质神经元和中间神经元。皮质脑血流预测，尤其是胆碱能成分，与记忆、感觉处理和注意力有关。尽管许多实验室在过去二十年中付出了巨大的努力，但 BF 是如何组织来支持一般唤醒以及注意力等特定功能的仍然是个谜。新颖的 3D 重建和数值分析表明，各种细胞类型的分布不是随机的，而是显示出一般的关联模式。在胆碱能空间（即皮质突出的 BF 胆碱能神经元的细胞体所占据的体积）内，不同的细胞类型占据区域特异性的高密度细胞簇。据推测，BF 中不同位置的这些细胞群（簇）与特定的前额叶和后皮质区域可能提供协调局部皮质调制的分布式功能网络的神经基础。该应用程序中的具体项目是基底皮质网络中功能域的解剖分离主题的变体。具体目标 1 将定义和验证大鼠个体之间的 BF 细胞簇，并评估簇的主体间变异性。具体目标 2 将定义 BF 细胞簇的皮质投射目标。具体目标 3 将检验以下假设：BF 按地形组织，特定的前额皮质区域针对特定的 BF 细胞群，而这些细胞群反过来又支配特定的边缘、后感觉或关联皮质区域。具体目标 4 我们将特别参考 NPY-胆碱能相互作用，使用体外配对记录来表征局部处理的生物物理和解剖学特性，并使用 NPY 神经元的内在 (GFP-NPY) 标记和体内 (Cy3-192IgG) 预标记的胆碱能神经元。我们假设 NPY 神经元抑制胆碱能放电。这些项目中的数据采集代表了从细胞群到单个突触的电子显微镜重建及其功能研究的完全转变。该项目将采用高度创新的数据分析方法，弥合与在细胞和系统级别收集的神经解剖数据的跨尺度整合相关的几个重要的方法论差距。拟议的研究将在全脑范围内对基底皮质网络进行更真实的描述，从而指导和限制胆碱能功能的行为研究，特别是感觉统合和注意力的机制。与此同时，它将有助于理解基底皮质网络中的异常处理，这是多种神经精神疾病的特征，包括阿尔茨海默病、精神分裂症和药物滥用。