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包含胆碱能和各种非胆碱能皮质脑神经元和中间神经元。皮质脑束投射，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，许多实验室进行了大量的努力，但BF如何组织以支持一般唤醒以及特定功能（如注意力）仍然是个谜。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，这些细胞群（集群）在不同的位置在BF与特定的前额叶和后皮质区一起可能提供一个分布式的功能网络，编排本地化的皮质调制的神经基础。在这个应用程序中的具体项目是在基底皮层网络的功能域的解剖隔离的主题上的变体。具体目标1将定义和验证大鼠个体间的BF细胞簇，并将评估簇的亚群间变异性。具体目标2将定义BF细胞簇的皮质投射靶点。具体目标3将检验以下假设：BF在地形学上是有组织的，使得特定的前额叶皮层区域靶向特定的BF细胞群，而这些细胞群又支配特定的边缘系统、后部感觉或关联皮层区域。具体目标4，我们将表征生物物理和解剖学特性的本地处理，特别是参考神经肽Y-胆碱能相互作用，使用在体外配对记录与内在的（GFP-NPY）标记神经肽Y神经元和在体内（Cy 3 - 192 IgG）预标记胆碱能神经元。我们推测，神经肽Y神经元抑制胆碱能放电。这些项目的数据采集代表了从细胞群到电子显微镜重建单个突触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，弥合与在细胞和系统水平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学差距。这项研究将在全脑范围内对基底皮层网络进行更真实的描述，从而指导和限制对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，它将有助于理解基底皮层网络的异常处理，其特征是几种神经精神疾病，包括阿尔茨海默病，精神分裂症和药物滥用。 公共卫生相关性：广泛分布于基底前脑的胆碱能细胞提供大脑皮层中发现的大部分乙酰胆碱。这个高度复杂的大脑区域与一系列行为有关，包括皮层激活，注意力，动机和记忆，但功能细节还不清楚。阿尔茨海默病和相关痴呆患者皮质中乙酰胆碱显著减少，并且在胆碱能基底前脑神经元中显示病理变化。理解BF的作用以及这些疾病的处理特征的部分困难在于该区域的解剖复杂性。本申请的总体目标是提高我们对BF的功能结构和连接的认识。这些结果将为行为研究中的功能研究提供更现实的动物模型。同时，它将促进对基底皮层网络异常处理的理解，并可能有助于开发新的治疗策略，以改善这些疾病的认知症状。

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. PUBLIC HEALTH RELEVANCE: Cholinergic cells, which are widely distributed in the basal forebrain BF), provide the majority of acetylcholine found in the cerebral cortex. This highly complex brain region has been implicated in a range of behaviors, including cortical activation, attention, motivation and memory, but the functional details are not well understood. Patients with Alzheimer's disease and in related dementias have a significant decrease of acetylcholine in the cortex and show pathological changes in cholinergic basal forebrain neurons. Part of the difficulty in understanding the role of the BF, as well as the processing characteristics of these disorders lies in the anatomical complexity of the region. The overall goal of this application is to improve our knowledge of the functional structure and connections of the BF. The results will lead to more realistic animal models for addressing function in behavioral studies. Concomitantly, it will facilitate the understanding of the aberrant processing in basalo-cortical networks and may help the development of new treatment strategies to ameliorate the cognitive symptoms in these disorders.