CHOLINERGIC MODULATION OF HIPPOCAMPAL INTERNEURON SUBTYPES

海马中间神经元亚型的胆碱能调节

• 批准号: 7959453
• 负责人: John Joshua Lawrence
• 金额: $ 15.82万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959453
• 关键词: Acetylcholine; Alzheimer' s Disease; Behavioral; Cells; Cessation of life; Cholinergic Receptors; Classification; Computer Retrieval of Information on Scientific Projects Database; Computer Simulation; Data; Diagonal Band of Broca; Funding; Glutamates; Grant; Hippocampus (Brain); Institution; Interneurons; Lead; Measurement; Medial; Memory impairment; Molecular; Neurons; Neurosciences; Organophosphates; Population; Receptor Activation; Research; Research Personnel; Resources; Seizures; Sensory; Source; Spatial Distribution; Staging; Technology; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Viral; Virus; cell type; cholinergic; cholinergic neuron; density; innovation; nerve agent; nerve supply; neuroregulation; neurotransmission; pesticide poisoning; postsynaptic; presynaptic; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Acetylcholine (ACh) release from the medial septum-diagonal band of Broca (MS-DBB) to the hippocampus profoundly alters cellular excitability, network synchronization, and behavioral state. Deficits in cholinergic function induce memory impairments, such as in Alzheimer's disease, while excessive cholinergic activity resulting from nerve agent or organophosphate pesticide poisoning can induce seizures and lead to neuronal death. ACh has diverse pre- and postsynaptic targets onto both glutamatergic and GABAergic cell populations. Recent data has emerged indicating that the actions of ACh can be specific, altering the excitability of distinct GABAergic circuits a cell type-specific manner. However, an understanding of cholinergic neurotransmission onto these targets still remains at a nascent stage due to technical difficulties in systematically studying defined interneuron populations, the lack of information on the density and spatial localization of cholinergic afferents received by defined interneuron subtypes, and the inability to activate diffusely distributed populations of septal cholinergic neurons in a selective yet coordinated manner. To overcome these limitations, we will develop new molecular tools that will facilitate the systematic study of defined interneuron subtypes and their capacity to undergo cholinergic neuromodulation. First, we will develop AAV viruses that express GFP, CFP, or RFP in neurochemically restricted interneuron populations. Secondly, combining mouse transgenic and viral technology, we will then examine how cholinergic afferents innervate and activate these defined interneuron subtypes. With the use of CRE/loxP transgenic technology in combination with AAV viruses, we will introduce channelrhodopsin2 into cholinergic neurons to light-evoke acetylcholine release onto neurochemically and morphologically defined target cells. Third, with this newly available data, we will construct computer models of cholinergic neurotransmission that incorporate precise measurements of the density of cholinergic innervation, spatial distributions of cholinergic receptors on target neurons, temporal dynamics of cholinergic receptor activation and their effectors, and mechanisms by which cholinergic neurotransmission is terminated. Finally, we will develop both experimental and computational paradigms to examine the functional consequence of cholinergic receptor activation in each interneuron subtype during cholinergically induced oscillatory activity. Together, these innovative approaches will allow us to obtain a greater understanding of how ACh engages neurochemically distinct interneuron subtypes to alter the flow of sensory information in the normal and diseased hippocampus.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 乙酰胆碱 (ACh) 从 Broca 内侧隔对角带 (MS-DBB) 释放到 海马体深刻改变细胞兴奋性、网络同步和行为 状态。胆碱能功能缺陷会导致记忆障碍，例如阿尔茨海默氏症 疾病，而神经毒剂或有机磷导致胆碱能活动过度 农药中毒可诱发癫痫发作并导致神经元死亡。 ACh 具有多种预作用和 突触后靶标同时作用于谷氨酸能和 GABA 能细胞群。 近期数据 已经出现表明 ACh 的作用可以是特异性的，可以改变 不同的 GABA 能回路以细胞类型特异性的方式进行。 然而，了解 由于以下原因，胆碱能神经传递到这些目标仍处于初级阶段 系统研究确定的中间神经元群体的技术困难，缺乏 定义的胆碱能传入的密度和空间定位信息 中间神经元亚型，以及无法激活弥漫分布的间隔群体 胆碱能神经元以选择性但协调的方式。 为了克服这些限制，我们 将开发新的分子工具，以促进已定义的系统研究 中间神经元亚型及其进行胆碱能神经调节的能力。 首先，我们 将开发在神经化学限制中表达 GFP、CFP 或 RFP 的 AAV 病毒 中间神经元群体。其次，结合小鼠转基因技术和病毒技术，我们将 然后检查胆碱能传入神经如何支配和激活这些定义的中间神经元 亚型。 利用CRE/loxP转基因技术结合AAV病毒， 我们将通道视紫红质2引入胆碱能神经元以光诱发乙酰胆碱 释放到神经化学和形态学上定义的靶细胞上。 三、有了这个新 根据现有数据，我们将构建胆碱能神经传递的计算机模型 结合胆碱能神经支配密度、空间分布的精确测量 目标神经元上胆碱能受体的分布，胆碱能的时间动态 受体激活及其效应器，以及胆碱能的机制 神经传递终止。最后，我们将开发实验性和 检查胆碱能受体功能结果的计算范例 在胆碱能诱导的振荡活动期间每个中间神经元亚型的激活。 总之，这些创新方法将使我们能够更好地了解如何 ACh 参与神经化学上不同的中间神经元亚型来改变感觉流 正常和患病海马体中的信息。