Connectivity and function of inhibitory neurons in the primate visual cortex

项目摘要 在哺乳动物的新皮层中，抑制性神经元（INs）深刻地影响皮层计算， 动力学，并且它们的各种功能被认为是由不同的IN类型介导的。虽然大量的多样性 的IN的存在，在小鼠皮层分子标记识别三个主要的非重叠类：小白蛋白- (PV)、生长抑素-（SOM）和血管活性肠肽-（VIP）INS。 这些IN类中的每一种中的Cre重组酶都迅速揭示了不同的连接模式， 属性和体内功能。然而，仍然不清楚是否从 小鼠皮质适用于灵长类和人类的皮质IN。人类的IN功能障碍与 几种疾病，如癫痫，精神分裂症，焦虑和自闭症，因此重要的是要了解 灵长类动物中正常的皮质IN连接和功能。缺乏病毒工具来选择性地访问IN 亚型，以及在灵长类动物中进行遗传操作的困难一直是主要障碍， 在这个动物模型中研究神经内分泌。我们的目标是利用病毒工具开发的最新进展， 在特定IN亚型中表达转基因，以研究连接性、响应特性和 在灵长类动物的表层中，两种主要类型的IN，PV和SOM的计算功能 初级视皮层（V1）。Cre重组酶IN型特异性表达与狂犬病毒联合应用的研究 单突触电路追踪，我们将映射本地和全脑输入到特定的V1 IN类（Aim 1）。使用 IN型特异性靶向钙指示剂的双光子成像，或 通道视紫红质标记的IN类型，我们将表征不同V1 IN类的视觉响应特性 （目标2）。最后，我们将使用表达抑制性视蛋白的不同IN类型的光遗传学失活， 理解IN类在V1计算中的相对作用（Aim 3）。我们将测试特定的假设， 根据小鼠的现有数据，灵长类动物皮质中PV和SOM细胞的特定几何形状，发表于2009年10月25日， 视觉皮层中的特征调谐和环绕抑制的计算模型，以及我们的初步研究结果。 结果冲击拟议的研究将提供第一个帐户的连通性，视觉特性和 灵长类皮层PV和SOM INs的计算功能，为IN功能的研究铺平了道路。 秩序它们还将揭示跨物种IN功能的保守原则，以及基本的跨物种IN功能。 物种的差异，强调研究物种的皮质功能的重要性， 更接近人类。

PROJECT SUMMARY In the mammalian neocortex, inhibitory neurons (INs) profoundly influence cortical computations and dynamics, and their various functions are thought to be mediated by different IN types. While a large diversity of INs exists, molecular markers in mouse cortex identify three major non-overlapping classes: parvalbumin- (PV), somatostatin- (SOM), and vasoactive intestinal peptide- (VIP) INs. Studies in mouse lines expressing Cre-recombinase in each of these IN classes are rapidly revealing distinct patterns of connectivity, response properties and in vivo function for each class. However, it remains unknown whether insights gained from mouse cortex apply to cortical INs in primates and humans. IN dysfunction in humans has been implicated in several disorders, such as epilepsy, schizophrenia, anxiety and autism, therefore it is important to understand normal cortical IN connectivity and function in primates. The lack of viral tools to selectively access IN subtypes, and the difficulty of performing genetic manipulations in primates have been major impediments to studying INs in this animal model. Our goal is to leverage recent advances in the development of viral tools to express transgenes in specific INs subtypes to investigate the connectivity, response properties, and computational function of two major classes of INs, PV and SOM, in the superficial layers of the primate primary visual cortex (V1). Using IN-type specific expression of Cre-recombinase combined with rabies-virus monosynaptic circuit tracing, we will map local and brain-wide inputs to specific V1 IN classes (Aim1). Using two-photon imaging of IN-type specific targeted calcium indicators, or optogenetic identification of channelrhodopsin-tagged IN types, we will characterize the visual response properties of distinct V1 IN classes (Aim2). Finally, we will use optogenetic inactivation of distinct IN-types expressing inhibitory opsins, to understand the relative roles of IN classes in V1 computations (Aim3). We will test specific hypotheses derived from available data in mouse, the specific geometry of PV and SOM cells in primate cortex, published computational models of feature tuning and surround suppression in visual cortex, and our preliminary results. Impact. The proposed studies will provide the first account of the connectivity, visual properties and computational function of PV and SOM INs in primate cortex, paving the way for studies of IN function in this order. They will also reveal conserved principles of IN function across species, as well as fundamental inter- species differences, stressing the importance of studying cortical function in species that are evolutionarily closer to humans.