AFFERENT REGULATION OF CHOLINERGIC FOREBRAIN NEURONS

描述（由申请人提供）：基底前脑（BF）是一个复杂的大脑区域，在调节皮质活动中起重要作用。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BF投射，特别是胆碱能成分，与记忆、感觉加工和注意有关。尽管在过去的二十年里，许多实验室进行了密集的研究，但BF是如何组织起来支持一般唤醒以及诸如注意力之类的特定功能的，仍然是一个谜。新的三维重建和数值分析表明，各种细胞类型的分布不是随机的，而是显示出一种普遍的关联模式。在胆碱能空间（即由皮质投射BF胆碱能神经元的细胞体所占据的体积）内，不同类型的细胞占据高密度的区域特异性细胞团。据推测，这些位于BF不同位置的细胞群（簇）以及特定的前额叶和后皮层区域可能为协调局部皮层调节的分布式功能网络提供了神经基础。该应用的具体项目是玄武岩-皮质网络中功能域解剖分离主题的变体。特异性目标1将定义和验证大鼠个体的BF细胞簇，并评估簇的主体间变异性。特异性靶2将定义BF细胞簇的皮质投射靶。特异性目标3将测试脑前部的地形组织假设，使得特定的前额皮质区域靶向特定的脑前部细胞群，这些细胞群反过来支配特定的边缘、后感觉或关联皮层区域。我们将通过NPY神经元的内在（GFP-NPY）标记和体内（Cy3-192IgG）预标记来表征局部处理的生物物理和解剖特性，特别参考NPY-胆碱能相互作用，使用体外配对记录对NPY神经元进行标记。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体到单个突触的电子显微镜重建及其功能研究的完整过渡。该项目将采用高度创新的方法进行数据分析，以弥合与细胞和系统水平收集的神经解剖学数据的跨尺度集成相关的几个重要方法差距。该研究将在全脑范围内对基底皮层网络进行更现实的描述，从而指导和限制胆碱能功能的行为研究，特别是感觉整合和注意力的机制。同时，它将促进对基底皮层网络异常处理的理解，这种异常处理是几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。

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.