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

项目摘要/摘要 基底节是一组大脑深层核团，在激励、选择和学习方面起着中心作用。 行为。这些核团中最大的纹状体作为主要的输入，接受广泛的 来自皮质和丘脑的会聚兴奋性神经支配以及来自大脑皮质和丘脑的多巴胺传入 中脑。DA已被证明对许多认知功能是不可或缺的，包括奖赏反应， 动机、运动控制、学习和记忆以及DA系统异常与 神经和精神疾病的数量，如成瘾、抑郁症、精神分裂症、强迫症- 强迫症和帕金森氏症。先前的研究表明，多巴胺神经元服务于 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 这一级别的功能隔离。此外，目前还不清楚这些投入如何直接影响 突触后细胞放电是输入沿树突的空间分布的函数。 这项建议寻求1)发展方法的进展，通过这种方法，多巴胺释放到树突上。 单个纹状体神经元可以使用双光子显微镜以亚细胞分辨率实时研究， 2)在自发运动中将功能相关的多巴胺释放映射到纹状体树突上， 意想不到的奖励和预期的奖励，以及3)检查多巴胺输入和 多巴胺同时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《2025年大脑报告》中指出，其优先领域包括： 生成分辨率不同的电路图，从突触到整个大脑“，”识别基础 原则：为理解心理过程的生物学基础提供概念基础 开发新的理论和数据分析工具“，以及”大脑在行动…“动态的图片， 正常运作的大脑“。我们认为，这项提议非常符合这些既定的优先事项，因为它提供了一个 更深入地了解体内多巴胺能纹状体环路的空间和功能图谱。 亚细胞突触分辨，并进一步对可能的机制产生了新的见解 与行为相关的计算可以在大脑的细胞和亚细胞水平上进行。

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.