The Role of Striatonigrostriatal Circuitry in Habit Formation

描述（由申请人提供）：习惯允许快速，流畅，几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，在某些情况下，它们会导致强迫性行为，如强迫症（OCD）或药物滥用和成瘾复发的行为模式。习惯的形成需要两个相互连接的脑区：纹状体、基底神经节输入核和向纹状体提供调节多巴胺能信号的黑质（SN）。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起着不同的作用。目标导向的初始任务习得由背内侧纹状体介导，而习惯形成则由背外侧纹状体介导。这两个纹状体区域，在生理和解剖学上都非常相似，是如何支持这两种截然不同的行为模式的呢？在这个提议中探索的一个假设是，纹状体和SN的连接基序-输入和输出之间的特定关系-因区域而异。本研究的长期目标将是建立一个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习惯形成过程中不同的投射特异性功能。为了实现这一总体目标，提出了三个具体的、立即可以实现的目标，每一个目标都可以通过最近开发的技术方法实现。这些方法是(1)TRIO，一种基于狂犬病的电路测绘技术，允许同时研究感兴趣的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，允许功能电路测绘和(3)体内光度法。允许检测由其输出定义的SN多巴胺神经元亚群的钙指示剂荧光，以测量自由行为动物中特定电路元件的活性。总之，这些方法将对习惯形成过程中纹状体间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.