The Role of Striatonigrostriatal Circuitry in Habit Formation

描述(申请人提供)：习惯允许快速、流畅、近乎毫不费力地执行复杂的任务，但它们也可能是有害的，例如，当它们导致强迫症(OCD)或药物滥用和成瘾复发的行为模式时。习惯的形成需要两个相互连接的大脑区域：纹状体，基本神经节的输入核，以及黑质(SN)，它向纹状体提供调制的多巴胺能信号。几十年来对人类、猴子和啮齿动物的研究表明，纹状体的不同区域在习惯形成中扮演着不同的角色。最初的任务习得是以目标为导向的，由背内侧纹状体调节，而习惯形成则由背外侧纹状体调节。纹状体的这两个区域在大体生理和解剖上非常相似，如何支持这两种截然不同的行为模式？本研究探讨的一个假设是，纹状体和SN的连接主题--输入和输出之间的特定关系--因区域而异。这项研究的长期目标将是建立SN多巴胺神经元的功能输入-输出连接图，以阐明这些神经元在动物经历习性养成时的不同投影特异性功能。为了服务于这一总体目标，提出了三个具体的、可立即实现的目标，每个目标都是通过最近开发的技术方法实现的。这些方法是(1)TRIO，这是一种基于狂犬病的电路映射技术，可以同时研究感兴趣大脑区域的输入和输出；(2)切片电生理学与光遗传学相结合，可以进行功能电路映射；(3)活体光度法，可以从由其输出定义的SN多巴胺神经元亚群中检测钙指示剂荧光，以便测量自由行为动物中特定电路元素的活性。总而言之，这些方法将对习惯形成过程中纹状体-纹状体回路元件的结构和功能产生新的见解。

DESCRIPTION (provided by applicant): Habits allow for the fast, fluid, nearly effortless execution of complex tasks, yet they can also be detrimental, for example in cases where they lead to compulsive behaviors such as in obsessive-compulsive disorder (OCD) or to behavioral patterns of drug abuse and relapse in addiction. Habit formation requires two reciprocally connected brain areas: the striatum, the input nucleus of the Basal Ganglia, and the substantia nigra (SN), which provides modulatory dopaminergic signals to the striatum. Decades of research on humans, monkeys and rodents have shown that different regions of striatum have different roles in habit formation. Initial task acquisition, which is goal-directed, is mediated b the dorsomedial striatum, while habit formation is mediated by the dorsolateral striatum. How can these two regions of striatum, which are very similar in their gross physiology and anatomy, support these two very different behavioral modes? One hypothesis, explored in this proposal, is that the connectivity motifs - the specific relationships between the inputs and the outputs - o the striatum and the SN differ by region. The long-term objective of this research will be to establish a functional input-output connectivity map of SN dopamine neurons that elucidates the diverse projection-specific functions of these neurons as an animal undergoes habit formation. In service of this overarching objective, three specific, immediately achievable aims are proposed, each of which is made possible by a recently developed technological approach. The approaches are (1) TRIO, a rabies-based circuit mapping technology that allows the simultaneous study of the inputs and outputs of a brain region of interest, (2) slice electrophysiology in combination with optogenetics, allowing for functional circuit mapping and (3) in vivo photometry, permitting the detection of calcium indicator fluorescence from subsets of SN dopamine neurons defined by their output in order to measure the activity of specific circuit elements in freely behaving animals. Together, these approaches will yield new insights into the structure and function of striatonigrostriatal circuit elements during the process of habit formation.