Single cell resolution multiscope recording and manipulation of striatal circuitry during decision making

决策过程中纹状体电路的单细胞分辨率多范围记录和操作

• 批准号: RTI-2023-00406
• 负责人: Britt, Jonathan
• 金额: $ 10.93万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Research Tools and Instruments
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=763965
• 关键词: Single; cell; resolution; multiscope; recording

This proposal aims to implement simultaneous multi-region, single-cell resolution neural recording and manipulation in behaving mice at McGill University. This exciting new technology enables imaging two fluorescent indicators of neural activity in up to four brain regions, in combination with targeted optogenetic manipulations, all at single-cell resolution. It will be used in the labs of Drs. Jonathan Britt and Rosemary Bagot - two CRC professors in the Department of Psychology - to investigate how ensemble activity of genetically-defined striatal neurons is coordinated within cortico-meso-limbic circuits across varying behavioural states. Single-cell multiscope imaging will dramatically accelerate the NSERC-funded research of both applicants in two key ways. First, this technology is unique in providing simultaneous single-cell measurement of neural activity across multiple brain regions in freely moving mice, thus permitting high-resolution computational analysis of network activity within and across cell types in behaviourally-relevant circuits. Second, it allows for fully integrated optogenetic manipulations that can be targeted to subsets of cells. The technology ideally complements the expertise of both labs in population-level recording techniques such as fiber photometry. While powerful, population-level techniques cannot resolve certain phenomena. For example, an increase in signal could be driven by an increase in the number of active cells or by increased synchrony of a stable population of cells. The necessity to resolve single-cell activity in projection- and genetically-defined populations was recently underscored by demonstrations that dopamine does not alter the firing rate of active neurons but rather determines how many striatal neurons get recruited during behaviour (i.e., the size of the active ensemble; Maltese et al., eLife 2021). Thus, to identify how striatal circuits respond to precise perturbations of dopamine signaling (Britt lab) and ultimately integrate information about reward and loss (Bagot lab), single-cell resolution is critical for tracking the ensemble size, identity, coherence, and balance of activity across striatal afferent and efferent cell populations. Implementation of this technology will promote collaborations with computational neuroscientists within and beyond McGill, as the uniquely rich physiological and behavioural data offer interesting opportunities to test computational theories about neuronal networks as well as development of dimensionality reduction techniques and dynamic pattern analyses. This equipment will support HQP recruitment, as it provides cutting-edge training opportunities for HQP and increases the overall impact of the research.

该提案旨在对麦吉尔大学的行为小鼠实施同时多区域、单细胞分辨率的神经记录和操作。这项令人兴奋的新技术能够在多达四个大脑区域中对神经活动的两种荧光指标进行成像，并结合有针对性的光遗传学操作，所有这些都以单细胞分辨率进行。它将在博士的实验室中使用。乔纳森·布里特 (Jonathan Britt) 和罗斯玛丽·巴戈特 (Rosemary Bagot) 是心理学系的两位 CRC 教授，旨在研究基因定义的纹状体神经元的整体活动如何在不同行为状态下的皮质-中脑-边缘回路内协调。单细胞多镜成像将以两个关键方式极大地加速两位申请人的 NSERC 资助研究。首先，该技术的独特之处在于，可以对自由活动的小鼠的多个大脑区域的神经活动进行同步单细胞测量，从而可以对行为相关回路中的细胞类型内部和细胞类型之间的网络活动进行高分辨率计算分析。其次，它允许完全集成的光遗传学操作，可以针对细胞子集。该技术完美地补充了两个实验室在光纤光度测定等人口水平记录技术方面的专业知识。人口层面的技术虽然强大，但无法解决某些现象。例如，信号的增加可以由活性细胞数量的增加或稳定细胞群的同步性的增加来驱动。最近有证据表明，多巴胺不会改变活跃神经元的放电率，而是决定在行为过程中招募多少纹状体神经元（即活跃神经元的大小；Maltese et al., eLife 2021），这强调了解决投射和遗传定义群体中单细胞活动的必要性。因此，为了确定纹状体回路如何响应多巴胺信号传导的精确扰动（Britt 实验室）并最终整合有关奖励和损失的信息（Bagot 实验室），单细胞分辨率对于跟踪纹状体传入和传出细胞群的整体大小、身份、一致性和活动平衡至关重要。这项技术的实施将促进与麦吉尔内外计算神经科学家的合作，因为独特丰富的生理和行为数据为测试神经网络计算理论以及降维技术和动态模式分析的发展提供了有趣的机会。该设备将支持 HQP 的招募，因为它为 HQP 提供了前沿的培训机会，并提高了研究的整体影响力。