AFFERENT REGULATION OF CHOLINERGIC FOREBRAIN NEURONS

描述(申请人提供)：基底前脑(BF)是一个复杂的大脑区域，在调节皮质活动方面发挥着重要作用。BF含有胆碱能神经元和各种非胆碱能皮质顶神经元和中间神经元。皮质顶叶BF投射，特别是胆碱能成分，与记忆、感觉处理和注意力有关。尽管许多实验室在过去20年里进行了密集的努力，但BF是如何组织起来的，以支持一般的唤醒以及注意力等特定功能，仍然是一个谜。新颖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，而是呈现出一种普遍的关联模式。在胆碱能空间内(即皮质投射的BF胆碱能神经元的细胞体占据的体积)，不同类型的细胞占据区域特有的高密度细胞团。假设BF中不同位置的这些细胞群(簇)以及特定的前额叶和后叶皮质区域可能为协调局部皮质调制的分布式功能网络提供神经基础。本申请中的具体项目是关于基底皮质网络中功能域的解剖分离这一主题的变体。具体目标1将定义和验证大鼠个体间的BF细胞群，并将评估群的亚群之间的可变性。特定目标2将定义BF细胞团的皮质投射靶点。具体目标3将检验这样一种假设，即BF是按地形图组织的，因此特定的前额叶皮质区域以特定的BF细胞群为靶点，而特定的BF细胞群反过来神经支配特定的边缘、后感觉或联合皮质区域。具体目的4我们将使用NPY神经元的体外成对固有(GFP-NPY)标记和在体(Cy3-192IgG)胆碱能神经元的预标记，特别参考NPY-胆碱能神经元的相互作用来表征局部处理的生物物理和解剖学特性。我们假设NPY神经元抑制胆碱能放电。这些项目中的数据获取代表了从细胞群体到电子显微镜的完全过渡，单个突触的重建和对其功能的研究。该项目将采用高度创新的数据分析方法，弥补在细胞和系统层面收集的神经解剖学数据的跨尺度整合方面的几个重要方法差距。这项拟议的研究将在全脑范围内更真实地描述基底皮质网络，从而指导和约束关于胆碱能功能的行为研究，特别是感觉整合和注意的机制。同时，它将有助于理解基底皮质网络中的异常处理，这种异常处理是几种神经精神障碍的特征，包括阿尔茨海默病、精神分裂症和药物滥用。 与公共健康相关：胆碱能细胞广泛分布于基底前脑(BF)，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，包括皮质激活、注意力、动机和记忆，但其功能细节尚不清楚。阿尔茨海默病及相关痴呆症患者大脑皮层乙酰胆碱显着减少，并表现出胆碱能前脑神经元的病理改变。了解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。这个应用程序的总体目标是提高我们对高炉功能结构和连接的了解。这一结果将导致在行为研究中建立更现实的动物模型来解决功能问题。同时，这将有助于理解基底皮质网络中的异常加工，并可能有助于开发新的治疗策略来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.