CHOLINERGIC MODULATION OF HIPPOCAMPAL INTERNEURON SUBTYPES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 Broca内侧隔-斜角带（MS-DBB）向 海马深刻地改变了细胞的兴奋性，网络同步性和行为 状态胆碱能功能的缺陷会导致记忆障碍，如阿尔茨海默氏症 疾病，而过量的胆碱能活动造成的神经毒剂或有机磷酸盐 农药中毒可诱发癫痫并导致神经元死亡。乙酰胆碱具有多种前和 突触后靶点作用于谷氨酸能和GABA能细胞群。 最近的数据 已经出现表明ACh的作用可以是特异性的， 不同的GABA能电路的细胞类型特异性的方式。 然而，理解 这些靶点上的胆碱能神经传递仍然处于新生阶段， 在系统研究定义的中间神经元群体的技术困难，缺乏 关于胆碱能传入的密度和空间定位的信息， 中间神经元亚型，以及无法激活弥漫性分布的隔 胆碱能神经元以选择性但协调的方式。 为了克服这些局限性，我们 将开发新的分子工具，这将有助于系统研究定义的 中间神经元亚型及其经历胆碱能神经调节的能力。 一是 将开发在神经化学限制性表达GFP、CFP或RFP的AAV病毒。 中间神经元群体。其次，将小鼠转基因技术与病毒技术相结合， 然后研究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 通过使用CRE/loxP转基因技术与AAV病毒的组合， 我们将把通道视紫红质2引入胆碱能神经元， 释放到神经化学和形态学定义的靶细胞上。 第三，新 根据现有的数据，我们将构建胆碱能神经传递的计算机模型， 结合精确测量胆碱能神经支配的密度、空间 胆碱能受体在靶神经元上的分布，胆碱能受体的时间动力学 受体激活及其效应物，以及胆碱能 神经传递被终止。最后，我们将开发实验性和 计算范例来检查胆碱能受体的功能后果 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 ACh参与神经化学上不同的中间神经元亚型， 正常和患病海马体中的信息。

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.