CHOLINERGIC MODULATION OF HIPPOCAMPAL INTERNEURON SUBTYPES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 从Broca内侧隔-斜角带(MS-DBB)释放乙酰胆碱(ACh)至丘脑 海马体深刻地改变了细胞的兴奋性、网络同步和行为 州政府。胆碱能功能缺陷会导致记忆损伤，例如阿尔茨海默氏症 疾病，而由神经毒剂或有机磷引起的胆碱能活动过多 农药中毒可导致癫痫发作并导致神经元死亡。ACH有不同的前置和 突触后靶向谷氨酸能和GABA能细胞群。最新数据 已经出现，表明ACh的作用可以是特定的，改变了 不同的GABA能以一种细胞类型特定的方式进行循环。然而，对 胆碱能神经对这些靶点的传递仍处于初级阶段，原因是 系统研究确定的中间神经元群体的技术困难，缺乏 接收到有关胆碱能传入的密度和空间定位的信息 中间神经元亚型，以及无法激活弥漫分布的隔区群体 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，以促进对已定义的 中间神经元亚型及其胆碱能神经调节能力。首先，我们 将开发出在神经化学受限的情况下表达GFP、CFP或RFP的AAV病毒 中间神经元群体。第二，结合小鼠转基因和病毒技术，我们将 然后检查胆碱能传入如何支配和激活这些已定义的中间神经元。 子类型。通过使用Cre/loxP转基因技术与AAV病毒相结合， 我们将把视紫红质2通道引入胆碱能神经元，以光激发乙酰胆碱。 释放到神经化学和形态定义的靶细胞上。第三，有了这个新的 ，我们将构建胆碱能神经传递的计算机模型 结合胆碱能神经密度的精确测量，空间 胆碱能受体在靶神经元上的分布、胆碱能的时间动力学 受体激活及其效应器，以及胆碱能 神经传递被终止。最后，我们将开发试验性和 检验胆碱能受体功能后果的计算范例 胆碱诱导的振荡活动中各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的流动 正常和患病的海马体中的信息。

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.