Functions of distinct interneuron subtypes in cortical dynamics and behavior

描述(由申请者提供)：我们研究计划的长期目标是了解动机行为背后的神经回路机制。前额叶皮质(PFC)微电路的精致神经结构被认为是负责认知的灵活性和动力学的基础。这一建议旨在了解不同类型的中间神经元在前额叶皮质功能中的作用。我们的一般方法是基于这样一个想法，即获得细胞类型的身份对于解锁新皮质回路的功能是必不可少的。由于中间神经元构成了一个高度多样化的神经群体，其中一些具有众所周知的解剖学特化，它们既是揭示微电路功能的重要机会，也是展示基于细胞类型身份的功能研究的良好展示。因此，我们的第一个目标是开发一个用于此目的的光遗传工具包。我们将设计并验证一种用于电生理记录和光纤刺激相结合的微型微驱动器，该驱动器重量轻，适合自由行为小鼠的慢性记录-使我们能够识别、记录和操纵基因标记的细胞类型。我们建议使用敲入CRE驱动器系来研究三类不重叠的中间神经元：小白蛋白(PV)、生长抑素(SOM)和血管活性肠肽(VIP)阳性细胞，每种细胞都具有不同的功能。使用这些工具，我们将研究不同的大脑皮层节律，即协调神经活动的标志，是如何与不同的中间神经元亚型的放电相关的。我们的光遗传学方法不仅将建立中间神经元亚型与振荡的相关性，而且还能够选择性地控制不同中间神经元亚型的活动，以探索产生不同大脑节律的机制。我们将使用一种功能丧失和功能获得的方法来废除和诱导行为动物的不同大脑节律。如果成功，这项拟议的研究有望导致详细了解不同的中间神经元亚型在前额叶皮质功能和行为中的作用。由于适应不良变化抑制中间神经元与从癫痫到精神分裂症和自闭症等多种疾病有关，我们的结果将对解释这些疾病状态的缺陷有直接影响，并可能提出补救的途径。

DESCRIPTION (provided by applicant): The long-term goal of our research program is to understand the neural circuit mechanisms underlying motivated behavior. The exquisite neural architecture of microcircuits in prefrontal cortex (PFC) is thought to underlie the flexibility and dynamics responsible for cognition. This proposal aims to understand the role of distinct interneuron types in prefrontal cortical function. Our general approach is predicated on the idea that access to cell-type identity is essential to unlocking the function of neocortical circuits. Because interneurons constitute a highly diverse neural population, some with well-understood anatomical specializations, they represent both an important opportunity to reveal microcircuit function as well as an excellent showcase for demonstrating the use of cell-type identity based functional studies. Our first objective therefore is to develop an optogenetic toolkit for this purpose. We will design and validate a miniature microdrive for combined electrophysiological recordings and fiberoptic stimulation that is light-weight and suitable for chronic recordings from freely behaving mice - enabling us to identify, record and manipulate genetically labeled cell-types. We propose to study three non-overlapping classes of interneurons: the parvalbumin (PV), somatostain (SOM), and vasoactive intestinal peptide (VIP) positive cells using knock-in Cre-driver lines, each with distinct functions. Using these tools we will examine how distinct cortical brain rhythms, signatures of coordinated neural activity, are correlated with the firing of distinct interneuron subtypes. Our optogenetic approach will not only establish the correlation of interneuron subtypes with oscillations but also enable selective control over the activity of distinct interneuron subtypes to pursue the mechanisms for generating different brain rhythms. We will employ a loss-and-gain-of-function approach to abolish and induce different brain rhythms in behaving animals. If successful, the proposed research is expected to result in a detailed understanding of the role of distinct interneuron subtypes in prefrontal cortical function and behavior. Because maladaptive changes inhibitory interneurons have been linked with a diverse set of diseases from epilepsy to schizophrenia and autism, our results will have direct implications for interpreting deficits in these disease states and potentially suggest avenues for remediation.