Functions of distinct interneuron subtypes in cortical dynamics and behavior

描述（由申请人提供）：我们研究项目的长期目标是了解动机行为背后的神经回路机制。前额叶皮层（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态性的基础。本研究旨在了解不同类型的中间神经元在前额皮质功能中的作用。我们的一般方法是基于这样一种观点，即获取细胞类型身份对于解锁新皮层回路的功能至关重要。由于中间神经元构成了高度多样化的神经群，其中一些具有很好的解剖专门化，它们既代表了揭示微电路功能的重要机会，也代表了展示使用基于细胞类型识别的功能研究的绝佳展示。因此，我们的第一个目标是为此目的开发一个光遗传学工具包。我们将设计并验证一种微型微驱动器，用于结合电生理记录和光纤刺激，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，记录和操作基因标记的细胞类型。我们建议使用敲入cre驱动系研究三种不重叠的中间神经元：小白蛋白（PV）、生长色素（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。利用这些工具，我们将研究不同的大脑皮层节律，协调神经活动的特征，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可以建立中间神经元亚型与振荡的相关性，还可以对不同中间神经元亚型的活动进行选择性控制，以追求产生不同脑节律的机制。我们将采用一种功能失得的方法来消除和诱导行为动物的不同脑节律。如果成功，该研究有望详细了解不同中间神经元亚型在前额皮质功能和行为中的作用。由于抑制中间神经元的不适应变化与从癫痫到精神分裂症和自闭症等多种疾病有关，我们的研究结果将对解释这些疾病状态的缺陷具有直接意义，并可能为补救提供途径。

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. PUBLIC HEALTH RELEVANCE: This proposal will lead to a better understanding about how different inhibitory neuron populations contribute to the generation of brain oscillations and behavior. Disruptions in inhibitory circuitry are implicated in epilepsy, as a well as in schizophrenia and autism. Because our studies will be conducted in rodents, we expect to gain mechanistic insights in terms of the neural subtypes and circuits involved, which will have the potential to generate improved strategies for treating these disorders.