Functional and anatomical characterization of the striosomal system

纹状体对健康和幸福至关重要，对我们适应人类行为的能力也至关重要 环境。作为基底神经节的巨大输入输出中心，纹状体接受来自 新皮质的一部分，包括与被称为纹状体的专门纹状体相连的情绪相关区域， 以及投射到动作控制电路的感觉运动区，主要涉及另一个隔室，即矩阵。 最重要的是，纹状体是从黑质传入多巴胺的主要靶点。 Compacta(SNC)，它在帕金森氏症中退化。纹状体投射回SNC，从而形成 黑质纹状体黑质环常见于临床。DA-SNC细胞不仅调节运动的启动，而且 情绪、活力、学习和决策。纹状体黑质回束主要出现在纹状体中。因此， 纹状体被战略性地连接起来，直接影响这些DA神经元。由于巨大的技术障碍， 黑质-纹状体-黑质环的这一关键部分的功能尚不清楚。然而，有线索表明， 功能。先前的研究表明，纹状体可以处理情绪相关的皮质信息，并将 由此产生的神经信号传递给SNC中的DA神经元。模型表明，在其他方面，纹状体可以为 作为演员-评论家强化学习模型中的批评者。然而，严重缺乏的是对 纹状体-基质-轴线-纹状体(S)与周围基质(M)的关系 接受感觉运动/联合皮质输入--和纹状体的d1-d2轴--由直接(D1)组成 促进运动的纹状体投射神经元(DSPN)和间接(D2)运动抑制的iSPN 因为缺乏实验工具来分离这两个轴。我们已经克服了一些技术障碍。 并建议在我们的总体假设的指导下解决这些问题，即皮质-纹状体回路 盖茨是情绪、动机或行动活力背后的大脑网络的状态转换；这一回路 通过其与含DA的黑质神经元的强大联系来调节学习过程； 纹状体-多巴胺回路可以调节不同SPN亚型之间的功能平衡 在S-M间隔室和D1-D2通路上进行多路传输。我们将使用交叉点的方法在小鼠身上解剖 根据个体SPN亚型的D1-D2和S-M身份，DA传感器在 纹状体通路的控制和控制黑质纹状体各成分的化学遗传学 从而评估其在行为中的因果作用。因此，我们装备齐全，站在我们的基础上， 发现成本-收益、接近-避免冲突招募了皮质-纹状体回路，这是由 单个SPN亚型的SnRNA-seq差异基因表达模式，并已制定策略 用于同时记录和单独操作SPN子类型。这项工作直接符合 NIMH的目标是通过直接解决极其重要的问题来促进人类健康和福祉 在一系列精神健康障碍中受影响的关键功能回路的知识空白。

The striatum is critically important to health and well-being, and to our ability to adapt behaviorally to our environment. As the great input-output center of the basal ganglia, the striatum receives projections from all parts of the neocortex including mood-related areas connecting to specialized striatal zones called striosomes, and sensorimotor areas projecting to action control circuits, involving mainly the other compartment, the matrix. Crucially, the striatum is the main target of the tract input carrying dopamine (DA) from the substantia nigra pars compacta (SNc), which degenerates in Parkinson’s disease. Striosomes project back to the SNc, so as to form the nigro-striato-nigral loop famed in the clinic. The DA SNc cells not only modulate movement initiation, but also mood, vigor, learning and decision-making. The ‘return’ striatonigral tract mainly arises in striosomes. Thus striosomes are strategically wired to directly influence these DA neurons. Due to formidable technical hurdles, the functions of this critical part of the nigro-striato-nigral loop remain unclear. Yet, there are clues about the functions. Previous studies suggest that striosomes could process mood-related cortical information and send the resultant neural signals to DA neurons in SNc. Models suggest, among others, that striosomes could serve as critics in actor-critic reinforcement learning models. However, critically lacking is the understanding of the relationship between the striosome-matrix axis—striosomes (S) receiving limbic, and the surrounding matrix (M) receiving sensorimotor/associative cortical inputs—and the D1-D2 axis of the striatum—composed of direct (D1) movement-promoting striatal projection neurons (dSPNs) and indirect (D2) movement-suppressing iSPNs, due to the lack of experimental tools to dissociate the two axes. We have overcome some of the technical hurdles and propose to address these issues guided by our overarching hypotheses, that the cortico-striosomal circuit gates the state transitions of brain networks underlying mood, motivation, or vigor of action; that this circuit modulates learning processes through its powerful connections with DA-containing SNc neurons; and that striosome-dopamine circuits can adjust functional balance across distinct SPN subtypes with identities multiplexed across S-M compartments and D1-D2 pathways. We will use intersect methods in mice to dissect individual SPN subtypes according to their D1-D2 and S-M identities, DA sensors to measure DA release under the control of the striatonigral path, and chemogenetics to manipulate each component of the nigro-striato-nigral circuit so as to assess its causal role in behavior. Thus, we are fully equipped, standing on our groundworks that found that cost-benefit, approach-avoidance conflict recruit the cortico-striosomal circuit, that identified by snRNA-seq differential gene-expression patterns of individual SPN subtypes, and that have developed strategies for simultaneously recording and individually manipulating the SPN subtypes. This work is directly in line with the goals of the NIMH to advance human health and well-beings by directly addressing profoundly important gaps in knowledge about key functional circuits affected in a range of mental health disorders.