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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要基底神经节是一组深部大脑核团，在激励、选择和学习中发挥着核心作用这些核中最大的，纹状体，作为主要的输入，广泛接受。来自皮质和丘脑的聚合兴奋性神经支配，以及来自大脑皮层和丘脑的多巴胺（DA）输入 DA 已被证明是许多认知功能的组成部分，包括奖励反应、动机、运动控制、学习和记忆以及 DA 系统异常与许多神经和精神疾病，例如成瘾、抑郁症、精神分裂症、强迫症先前的研究表明，多巴胺神经元在强迫症和帕金森病中起作用。不同的功能投射到纹状体内广泛不同的目标，然而，人们对纹状体的作用知之甚少。 DA 输入到单个神经元的亚细胞空间组织，以及是否也有证据此外，目前尚不清楚这些投入如何直接影响。突触后细胞放电是沿树突输入的空间分布的函数。该提案旨在 1）发展方法学进步，通过该方法将多巴胺释放到树突上可以使用 2 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）将功能相关的多巴胺释放映射到自发运动过程中的纹状体树突上，意外奖励和预期奖励，3）检查多巴胺输入与通过多巴胺同步双光子显微成像获得突触后神经放电输出的概率和钙信号传导。 Brain Initiative 在其《Brain 2025 报告》中指出，其优先领域包括“多尺度地图：生成从突触到整个大脑的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：新理论和数据分析工具的开发”，以及“大脑在行动……动态图景” 我们认为该提案非常符合这些规定的优先事项，因为它提供了一个更深入地了解多巴胺能纹状体回路的体内空间和功能映射亚细胞突触分辨率，并进一步对可能的机制产生新的见解行为相关的计算可以在大脑中的细胞和亚细胞水平上进行。