Functional and anatomical characterization of the striosomal system

纹状体系统的功能和解剖学特征

• 批准号: 10596653
• 负责人: Ann M Graybiel
• 金额: $ 38.78万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-03 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596653
• 关键词: Address; Affect; Anatomy; Animals; Area; Automobile Driving; Axon; Back; Basal Ganglia; Behavior; Behavior assessment; Behavioral; Binding; Brain; Cells; Clinic; Cognition; Corpus striatum structure; Costs and Benefits; Cues; Date of birth; Decision Making; Dedications; Dendrimers; Dendrites; Desire for food; Discrimination; Dissociation; Dopamine; Environment; Equilibrium; Evaluation; Exhibits; Face; Fiber; Funding; Gene Expression Profile; Genetic; Goals; Head; Health; Human; Image; Individual; Knowledge; Label; Learning; Link; Maintenance; Measures; Mental Health; Mental disorders; Methods; Mission; Modeling; Moods; Motivation; Movement; Mus; National Institute of Mental Health; Negative Valence; Neocortex; Neurodegenerative Disorders; Neurons; Output; Parkinson Disease; Pathway interactions; Pattern; Personal Satisfaction; Persons; Photometry; Positive Valence; Process; Psychological reinforcement; Research; Rewards; Role; Schedule; Signal Transduction; Substantia nigra structure; System; Testing; Tissue-Specific Gene Expression; Training; Viral; Work; approach avoidance behavior; conditioning; cost; designer receptors exclusively activated by designer drugs; dopaminergic neuron; neocortical; nervous system disorder; neuropsychiatric disorder; neurotransmission; pars compacta; prevent; recruit; sensor; single nucleus RNA-sequencing; striosome; tool; two-photon

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.

纹状体对健康和幸福以及我们在行为上适应我们的能力至关重要。 环境作为基底神经节的输入输出中心，纹状体接受来自所有神经元的投射。 包括情绪相关区域在内的新皮层部分连接到称为纹状体的专门纹状体区， 以及投射到动作控制回路的感觉运动区，主要涉及另一个隔室，即矩阵。 重要的是，纹状体是从黑质部携带多巴胺（DA）的束输入的主要目标 帕金森氏病患者的神经退行性变。纹状体投射回SNc，从而形成 临床上著名的黑质-纹状体-黑质环DA SNc细胞不仅调节运动起始， 情绪、活力、学习和决策。纹状体黑质束的“返回”主要发生在纹状体中。因此 纹状体被策略性地连接以直接影响这些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仍不清楚。然而，有线索表明， 功能协调发展的先前的研究表明，纹状体可以处理与情绪相关的皮层信息， 将所产生的神经信号传递到SNc中的DA神经元。模型表明，除其他外， 作为行动者-批评者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-纹状体（S）接受边缘系统和周围基质（M）之间的关系 接收感觉运动/关联皮层输入-和纹状体的D1-D2轴-由直接（D1） 运动促进纹状体投射神经元（dSPNs）和间接（D2）运动抑制iSPNs，由于 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指导下解决这些问题，即皮质-纹状体回路 门控着情绪、动机或行动活力背后的大脑网络的状态转换;这条回路 通过与含DA的SNc神经元的强大连接调节学习过程; 纹状体-多巴胺回路可以调节不同SPN亚型的功能平衡， 在S-M隔室和D1-D2途径中多重化。我们将在老鼠身上使用intersect方法来解剖 根据它们的D1-D2和S-M身份的单个SPN亚型，测量DA释放的DA传感器， 纹状体黑质路径的控制，以及操纵黑质-纹状体-黑质的每个组分的化学遗传学 电路，以评估其在行为中的因果作用。因此，我们完全装备，站在我们的基础上， 发现，成本效益，接近-回避冲突招募皮质-纹状体回路，确定由 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纵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 对一系列精神健康疾病影响的关键功能回路的知识存在差距。