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。随着影响多巴胺信号的药物被广泛用于临床治疗许多精神疾病，这种神经递质的重要性得到了很好的认识。问题是，我们仍然不了解这个电路中一些最基本的相互作用。目前尚不清楚多巴胺信号如何在体内改变两种主要纹状体输出通路的活性。本文提出的研究目的是确定多巴胺信号对纹状体网络活动的影响，以便深入了解构成和区分健康和病理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，受影响的细胞混杂在表达不同类型多巴胺受体的细胞群中，这反过来又对神经生理学产生不同的影响。幸运的是，我用加拿大创新基金会的资金建立了实验室基础设施，我的团队有能力利用最近的方法进步，使光遗传学控制行为动物中脑多巴胺神经元活动成为可能，同时监测纹状体直接和间接通路神经元中不同表达的神经活动的不同荧光指标（GCaMP和RCaMP）。拟议的实验将揭示多巴胺信号在不同行为状态下对两种纹状体输出通路的不同影响程度，反之亦然。这项研究将为纹状体生理学提供关键的见解，这对于正在进行的理解和模拟基底神经节回路功能的努力至关重要。此外，由于我们对基底神经节生理学的理解不足，合理的药物开发工作受到了阻碍。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发展的努力。我已经聘请了两名优秀的新学员（一名研究生和一名博士后）来帮助领导这项研究。我的发表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。我的实验室的研究得到了我的第一笔发现基金（2014-2019）的资助，发表在《神经元》、《生物精神病学》和《细胞报告》上，我还有其他文章正在《细胞报告》和《神经回路前沿》上进行审查。我的NSERC资助也允许我写一篇评论文章，并成功地在Nature Neuroscience， Journal of Neuroscience和Cell Reports上发表了项目合作。麦吉尔大学也非常支持我的研究项目，他们提名我为威廉·道森学者，最近还提名我为加拿大研究主席。

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.