Functions of distinct interneuron subtypes in cortical dynamics and behavior

描述（由申请人提供）：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。前额叶皮层（PFC）中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。这个提议的目的是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的想法，即获得细胞类型的身份是必不可少的解锁新皮层电路的功能。由于中间神经元构成了一个高度多样化的神经群体，一些具有很好的理解解剖学专业化，他们既代表了一个重要的机会，揭示微电路功能，以及一个很好的展示展示使用细胞类型的身份为基础的功能研究。 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。我们将设计和验证一种微型微驱动器，用于组合电生理记录和光纤刺激，该微驱动器重量轻，适用于自由行为小鼠的慢性记录-使我们能够识别，记录和操纵遗传标记的细胞类型。我们建议研究三个非重叠类的中间神经元：小白蛋白（PV），生长抑素（SOM），血管活性肠肽（VIP）阳性细胞使用敲入Cre-driver线，每个具有不同的功能。使用这些工具，我们将研究不同的皮质脑节律，协调神经活动的签名，是如何与不同的中间神经元亚型的发射。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性，以追求产生不同脑节律的机制。我们将采用功能丧失和获得的方法来消除和诱导行为动物的不同脑节律。 如果成功的话，这项研究有望详细了解不同的中间神经元亚型在前额叶皮层功能和行为中的作用。由于适应不良的变化抑制性中间神经元与从癫痫到精神分裂症和自闭症的各种疾病有关，我们的研究结果将对解释这些疾病状态的缺陷产生直接影响，并可能提出补救途径。

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.