The impact of dopamine signaling on cell type-specific striatal neuron activity in vivo

纹状体中的多巴胺信号对行为有深远的影响，因为它影响运动、动机、认知和情感。这种神经递质的重要性得到了很好的认识，因为影响多巴胺信号的药物被广泛用于临床治疗一系列精神疾病。问题是，我们仍然不了解这个电路中的一些最基本的相互作用。主要的是，目前还不清楚体内的多巴胺信号如何改变两条主要的纹状体输出通路的活性。这项研究的目的是确定多巴胺信号对纹状体网络活动的影响，以深入了解构成和区分健康和病理性脑功能的电路动力学。长期以来，研究人员一直在努力确定多巴胺信号对特定纹状体回路成分的影响。挑战在于，受影响的细胞混合在表达不同类型多巴胺受体的细胞群中，这些受体反过来对神经元生理产生不同的影响。幸运的是，有了我用加拿大创新基金会的资金建造的实验室基础设施，我的团队处于有利地位，可以利用最近的方法进步，使光遗传控制行为动物的中脑多巴胺神经元活动成为可能，同时监测不同的神经活动荧光指示物(GCaMP和RCaMP)，这些指标在纹状体直接通路和间接通路神经元中差异表达。拟议的实验将揭示多巴胺信号在多大程度上不同地影响两条纹状体输出通路，反之亦然，跨越不同的行为状态。这项研究将提供对纹状体生理学的关键见解，这对于正在进行的了解和模拟基底节回路功能的努力至关重要。此外，由于我们对基底节生理学的了解不足，合理的药物开发努力受到了阻碍。拟议的研究将通过提高我们对健康大脑功能的理解来促进这些治疗开发工作。我已经聘请了两名优秀的新实习生(一名研究生和博士后)来帮助带头进行这项研究。我的出版记录证明了我在体内使用这些光遗传学和钙成像技术的广泛专业知识。我的实验室用我的第一笔发现基金(2014-2019年)资助的研究发表在《神经元》、《生物精神病学》和《细胞报告》上，我还在《细胞报告》和《神经电路前沿》上发表了其他文章。我的NSERC资助也让我写了一篇评论文章，并成功地合作了已发表在《自然神经科学》、《神经科学杂志》和《细胞报告》上的项目。麦吉尔大学也强烈支持我的研究项目，因为他们任命我为威廉·道森学者，最近还提名我担任加拿大研究教授。

Dopamine signaling in the striatum has profound effects on behaviour, as it influences movement, motivation, cognition, and affect. The importance of this neurotransmitter is well appreciated, as drugs that affect dopamine signaling are widely used to clinically treat a host of psychiatry disorders. The problem is that we still do not understand some of the most basic interactions in this circuitry. Principally, it is unclear how dopamine signaling in vivo modifies the activity of the two principal striatal output pathways. The aim of the research proposed here is to identify the influence of dopamine signaling on striatal network activity in order to gain insight into the circuit dynamics that underlie and differentiate healthy and pathological brain function. Researchers have long struggled to identify the influence of dopamine signaling on specific striatal circuit components. The challenge is that the affected cells are intermingled within cell populations that express different types of dopamine receptors, which in turn have differential effects on neuronal physiology. Fortunately, with the lab infrastructure I built with funds from the Canada Foundation for Innovation, my group is well-positioned to capitalize on the recent methodological advances that make it possible to optogenetically control midbrain dopamine neuron activity in behaving animals while simultaneously monitoring distinct fluorescent indicators of neural activity (GCaMP & RCaMP) differentially expressed in striatal direct and indirect pathway neurons. The proposed experiments will reveal the extent to which dopamine signalling differentially affects the two striatal output pathways, and vice versa, across different behavioural states. This research will provide key insights into striatal physiology that are critical for ongoing efforts to understand and model basal ganglia circuit function. Moreover, rational drug development efforts have been hampered by our inadequate understanding of basal ganglia physiology. The proposed research will foster these treatment development efforts by improving our understanding of healthy brain function. I have hired two outstanding new trainees (a graduate student and postdoc) to help spearhead this research. My publication record demonstrates my extensive expertise using these optogenetic and calcium imaging techniques in vivo. Research from my lab funded with my first Discovery Grant (2014-2019) is published in Neuron, Biological Psychiatry, and Cell Reports, and I have additional articles under review at Cell Reports and Frontiers in Neural Circuits. My NSERC funding also permitted me to write a review article and successfully collaborate on projects that have been published in Nature Neuroscience, Journal of Neuroscience, and Cell Reports. McGill University is also strongly supportive of my research program, as they have named me a William Dawson Scholar and recently nominated me for a Canada Research Chair.