Inhibiting Inhibition: Circuit-level and Behavioral Functions of Interneuron-Specific Interneurons in Cortico-Hippocampal Networks

抑制抑制：皮质海马网络中中间神经元特异性中间神经元的电路水平和行为功能

• 批准号: 384230557
• 负责人: Professor Dr. Imre Vida
• 金额: --
• 依托单位: National Yang-Ming University
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/384230557?language=en
• 关键词: Inhibiting; Inhibition; Circuit; level; Behavioral

The dentate gyrus (DG) acts as a gateway to the hippocampus filtering and processing multimodal sensory information arriving from neocortex via the entorhinal cortex. Its principal neurons, the granule cells (GCs), fire sparsely both in vivo and ex vivo. Sparse firing not only serves as a protective mechanism for preventing overexcitation of hippocampal circuits, but also enables the transformation of the rich cortical code into discrete representations (orthogonalized code). In addition to the intrinsic properties of GCs, gamma-Aminobutyric acid-mediated, GABAergic inhibition provides an essential contribution to the sparse coding in the DG. Inhibition is mediated by multiple types of morphologically-, physiologically- and neurochemically-distinct interneuron (IN) types. The various types of INs are thought to serve a division of labor and differentially influence information flow in DG networks. Relative to excitatory activation of INs by long-range and local inputs, our knowledge about the inhibition of INs by local circuit INs is much more scarce. Among the various types, vasoactive intestinal peptide(VIP)-expressing INs are known to selectively target INs and thereby directly modulate the GABAergic system. However, several fundamental questions with respect to IN-specific inhibition remain to be answered: (1) What are the functional and anatomical properties of VIP INs in the DG? (2) What is the molecular specification of VIP INs? (3) What are the precise cellular and subcellular targets of VIP INs? (4) How are VIP INs activated by excitatory inputs and contribute to feedforward and feed-back inhibition onto DG INs? (5) What is the functional consequence of VIP IN-mediated disinhibition on hippocampal circuits? (6) Lastly, what is the behavioral relevance of VIP IN-mediated disinhibition? To answer these questions, in a collaborative effort with a Taiwanese partner, we will apply a combined neuroanatomical, electrophysiological, optogenetic and behavioral approach. We will examine genetically-defined VIP INs using VIP::Cre;Ai14 transgenic mice. To investigate physiological and morphological characteristics and synaptic inputs and outputs of the INs, ex vivo whole-cell recordings will be performed from single cells and synaptically coupled pairs. To gain more insights into the molecular specification of VIP INs, we will take advantage of the RiboTag method to analyze genetic components in genetically identified VIP INs. Finally, to investigate their roles on the synaptic, circuit and behavioral levels, we will use optogenetic and chemogenetic tools to activate or inactivate VIP INs in both ex vivo brain slices and in vivo freely moving animals. Information gained as a result of this multi-level multidisciplinary approach will provide essential insights into the self-organization of the GABAregic inhibitory system in cortical networks.

齿状回（DG）作为海马体的门户，过滤和处理从新皮层经内嗅皮层到达的多模态感觉信息。它的主要神经元，颗粒细胞（GCs），在体内和离体都是稀疏的。稀疏放电不仅可以作为防止海马体回路过度兴奋的保护机制，还可以将丰富的皮层编码转化为离散表征（正交化编码）。除了GCs的固有特性外，γ -氨基丁酸介导的gaba能抑制对DG的稀疏编码有重要贡献。抑制是由多种形态、生理和神经化学上不同的中间神经元（IN）类型介导的。各种类型的网络被认为是服务于劳动分工和不同的影响信息流动在DG网络。相对于远程输入和局部输入对INs的兴奋性激活，我们对局部回路INs的抑制作用的了解要少得多。在各种类型中，已知表达血管活性肠肽（VIP）的INs选择性靶向INs，从而直接调节gaba能系统。然而，关于in特异性抑制的几个基本问题仍有待回答：(1)DG中VIP INs的功能和解剖特性是什么？(2) VIP INs的分子规格是什么？(3) VIP INs的精确细胞靶点和亚细胞靶点是什么？(4) VIP INs如何被兴奋性输入激活，并对DG INs的前馈和反馈抑制起作用？(5) VIP in介导的去抑制对海马回路的功能影响是什么？(6)最后，VIP in介导的去抑制行为相关性是什么？为了回答这些问题，我们将与台湾合作伙伴共同努力，应用神经解剖学，电生理学，光遗传学和行为学相结合的方法。我们将使用VIP::Cre检查基因定义的VIP INs；Ai14转基因小鼠。为了研究INs的生理和形态特征以及突触输入和输出，将对单细胞和突触偶联对进行离体全细胞记录。为了更深入地了解VIP蛋白的分子特征，我们将利用RiboTag方法分析遗传鉴定VIP蛋白的遗传成分。最后，为了研究它们在突触、电路和行为水平上的作用，我们将使用光遗传学和化学遗传学工具在离体脑切片和体内自由运动动物中激活或灭活VIP INs。这种多层次多学科方法所获得的信息将为皮层网络中gaba猝睡抑制系统的自组织提供必要的见解。