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）：基础前脑（BF）是一个复杂的大脑区域，在调节皮质活性中起着重要作用。 BF含有胆碱能和各种非胆碱能皮质神经元和中间神经元。皮质的BF投影，尤其是胆碱能成分，已与记忆，感觉处理和注意力有关。尽管在过去的二十年中，许多实验室都进行了大量努力，但它仍然是如何组织BF来支持一般唤醒和特定功能（如注意力）的神秘事物。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，而是显示一般的关联模式。在胆碱能空间（即皮层投射BF胆碱能神经元的细胞体占据的体积）中，不同的细胞类型占据了区域特异性的高密度细胞簇。假设BF的各个位置的这些细胞组（簇）以及特定的前额叶和后皮质区域可能会提供分布式功能网络的神经基础，该功能网络策划了局部皮质调节。本应用程序中的特定项目是底层 - 皮层网络中功能域解剖隔离主题的变体。具体目标1将定义和验证大鼠个体中的BF细胞簇，并将评估簇的间变异性。特定的目标2将定义BF细胞簇的皮质投影靶标。特定的目标3将检验BF在地形上的假设，使得特定的前额叶皮质区域针对特定的BF细胞组，而BF细胞组构成了特定的BF细胞组，而BF细胞组又支配特定的边缘，后感觉或联想皮质区域。具体目的4我们将使用固有的（GFP-NPY）标记为NPY神经元和体内（CY3-192IGG）预循环蛋白的固有（GFP-NPY）标记的体外配对记录来表征局部加工的生物物理和解剖学特性，并特别提及NPY-胆碱能相互作用。我们假设NPY神经元抑制了胆碱能的触发。这些项目中的数据采集代表了从细胞种群到单个突触的电子显微镜重建以及其功能研究的完全过渡。该项目将采用高度创新的方法来进行数据分析，该方法弥合了与在细胞和系统级别收集的神经解剖学数据的跨尺度整合有关的几个重要方法论差距。拟议的研究将导致对脑层面上的底层网络的更现实描述，这可以指导和限制行为研究胆碱能功能，特别是感觉整合和注意力的机制。同时，它将有助于理解玄武岩网络中异常处理的理解，这些加工特征是几种神经精神疾病，包括阿尔茨海默氏病，精神分裂症和药物滥用。