Subcellular Mapping and Post-Synaptic Impacts of Striatal Dopamine Release During Behavior

行为过程中纹状体多巴胺释放的亚细胞映射和突触后影响

• 批准号: 10615333
• 负责人: Mai-Anh Vu
• 金额: $ 3.43万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10615333
• 关键词: Animals; Area; BRAIN initiative; Basal Ganglia; Behavior; Behavioral; Biological; Brain; Calcium Signaling; Cell Nucleus; Cells; Complex; Corpus striatum structure; Cues; Data; Data Analyses; Dendrites; Dendritic Spines; Development; Disease; Dopamine; Electrophysiology (science); Exhibits; Foundations; Functional disorder; Glutamates; Head; Heterogeneity; Image; Individual; Label; Learning; Locomotion; Maps; Memory; Mental Depression; Mental Processes; Mental disorders; Methodology; Midbrain structure; Monitor; Motivation; Movement; Mus; Neurologic; Neurons; Neuropsychology; Obsessive-Compulsive Disorder; Output; Parkinson Disease; Pathway interactions; Pattern; Play; Positioning Attribute; Probability; Protocols documentation; Psychological reinforcement; Recommendation; Regulation; Reporting; Research; Resolution; Rewards; Rodent; Role; Running; Schizophrenia; Sensory; Signal Transduction; Spatial Distribution; Specificity; Statistical Data Interpretation; Stimulus; Subcellular structure; Symptoms; Synapses; System; Testing; Thalamic structure; Time; Training; Variant; addiction; awake; calcium indicator; classical conditioning; cognitive function; dopamine system; dopaminergic neuron; experience; experimental study; histological stains; in vivo; insight; interest; microscopic imaging; motor control; nerve supply; nervous system disorder; neuroimaging; neuropsychiatric disorder; novel; postsynaptic; regional difference; relating to nervous system; response; reward processing; segregation; spatiotemporal; temporal measurement; tool; treadmill; two photon microscopy; two-photon; visual stimulus

PROJECT SUMMARY/ABSTRACT The basal ganglia are a group of deep brain nuclei that play a central role in motivating, selecting, and learning actions. The largest of these nuclei, the striatum, serves as the principal input, receiving widespread convergent excitatory innervation from cortex and thalamus, as well as dopamine (DA) inputs from the midbrain. DA has been shown to be integral for numerous cognitive functions, including reward response, motivation, motor control, learning, and memory, and DA system abnormalities have been associated with a number of neurological and psychiatric illnesses, such as addiction, depression, schizophrenia, obsessive- compulsive disorder, and Parkinson's disease. Previous research has shown that dopamine neurons serving different functions project to broadly different targets within the striatum. However, little is known about the subcellular spatial organization of DA inputs onto single neurons, and whether there is also evidence for functional segregation at this level. Furthermore, it remains unknown as to how these inputs directly impact post-synaptic cell firing as a function of the spatial distribution of inputs along dendrites. This proposal seeks to 1) develop methodological advances by which dopamine release onto the dendrites of single striatal neurons can be investigated in real-time with subcellular resolution using 2-photon microscopy, 2) map functionally-relevant dopamine release onto striatal dendrites during spontaneous locomotion, unexpected reward, and expected reward, and 3) examine the relationship between dopamine input and the probability of postsynaptic neuronal firing output via simultaneous 2-photon microscopic imaging of dopamine and calcium signaling. The Brain Initiative, in its Brain 2025 Report, has stated among its priority areas “Maps at multiple scales: Generate circuit diagrams that vary in resolution from synapses to the whole brain”, “Identifying fundamental principles: Produce conceptual foundations for understanding the biological basis of mental processes through development of new theoretical and data analysis tools”, and “The brain in action… dynamic picture of the functioning brain”. We believe this proposal is very much in line with these stated priorities, by providing a deeper understanding of the in vivo spatial and functional mapping of dopaminergic striatal circuitry at the subcellular synaptic resolution, and further yielding novel insight into possible mechanisms by which behaviorally-relevant computations may be carried out in the brain at the cellular and subcellular level.

项目总结/摘要 基底神经节是一组脑深部核团，在激励、选择和学习中起着核心作用 行动这些核团中最大的，纹状体，作为主要的输入，接收广泛的 来自皮层和丘脑的会聚兴奋性神经支配，以及来自 中脑DA已被证明是许多认知功能不可或缺的一部分，包括奖励反应， 动机、运动控制、学习和记忆以及DA系统异常与 一些神经和精神疾病，如成瘾，抑郁症，精神分裂症，强迫症， 强迫症和帕金森病先前的研究表明，多巴胺神经元 不同的功能投射到纹状体内广泛不同的靶点。然而，人们对此知之甚少。 DA输入到单个神经元的亚细胞空间组织，以及是否也有证据表明 在这个层面上的功能分离。此外，尚不清楚这些投入如何直接影响 突触后细胞放电作为输入沿沿着树突的空间分布的函数。 这项建议旨在1）发展方法学的进步，通过这种方法，多巴胺释放到树突上， 可以使用双光子显微镜以亚细胞分辨率实时研究单个纹状体神经元， 2)在自发运动期间将功能相关的多巴胺释放映射到纹状体树突上， 意外奖励和预期奖励，以及3）检查多巴胺输入和 多巴胺双光子显微成像对突触后神经元放电输出的影响 和钙信号。 大脑倡议在其《大脑2025报告》中指出了其优先领域“多尺度地图： 生成从突触到整个大脑分辨率不同的电路图”，“识别基本原理 原则：通过以下方式为理解心理过程的生物学基础提供概念基础： 新的理论和数据分析工具的发展”，以及“大脑在行动中...... 大脑功能”。我们认为，这项建议非常符合这些既定的优先事项， 更深入地了解多巴胺能纹状体回路在体内的空间和功能映射， 亚细胞突触分辨率，并进一步产生新的见解可能的机制， 行为相关的计算可以在大脑中在细胞和亚细胞水平上进行。