Stress and flexibility in serotonin signalling

血清素信号传导的压力和灵活性

• 批准号: RGPIN-2018-06791
• 负责人: Lambe, Evelyn
• 金额: $ 8.01万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 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=763298
• 关键词: Stress; flexibility; serotonin; signalling

This NSERC research program will investigate the cellular mechanisms and behavioural consequences of stress-elicited plasticity in brain serotonergic signalling. We will probe the mechanisms that control the excitability of serotonin neurons in the raphe nuclei and those by which they exert their influence in the cerebral cortex. We will also examine how cortical serotonin release affects the performance of complex cognitive tasks. Serotonin plays key roles in cognitive and emotional responses, so we aim to understand its cell and circuit mechanisms and their sensitivity to the effects of stress at different developmental time points.Key foci of this grant are the flexibility of serotonin signalling, how this flexibility is altered by developmental stress, and implications for cognitive behaviour. Broadly, my laboratory investigates the cellular mechanisms of neuromodulation using rodent models, electrophysiological tools, optogenetics, multiphoton imaging, and behavioural and molecular assays. For this grant, we will start with the serotonergic neurons themselves and interrogate the signalling pathways that provide flexibility to respond with different firing patterns on behaviourally-relevant time frames. This work segues naturally into ongoing NSERC research in our lab examining whether mice exposed to prolonged social isolation show changes in serotonin receptor electrophysiological signalling in cerebral cortex and identifying the underlying receptors and channel effectors involved. Finally, we will investigate using in vivo optogenetics the role of cortical serotonin in disrupting performance on a complex attention task under acutely stressful or emotional conditions.This program of NSERC research will train students and postdocs in cutting-edge neuroscience techniques and will advance our understanding of the cellular mechanisms that regulate the serotonin system. The integrated experiments bring together mechanistic studies in the raphe and cortex to understand more fully the flexibility inherent in the serotonergic signalling and the lasting consequences of developmental perturbations. Our behavioural work aims to elucidate the relationship between the cellular and circuit effects of serotonin and its consequences for cognition. Overall, this NSERC program will probe the extent to which our personal history shapes the ability of serotonin to modulate our neural circuitry and behaviour.

这个NSERC研究项目将研究应激引起的大脑血清素信号可塑性的细胞机制和行为后果。我们将探索控制中缝核中血清素神经元兴奋性的机制，以及它们在大脑皮层中发挥作用的机制。我们还将研究皮质血清素释放如何影响复杂认知任务的表现。血清素在认知和情绪反应中起着关键作用，因此我们旨在了解其细胞和电路机制以及它们在不同发育时间点对压力影响的敏感性。这项资助的重点是血清素信号的灵活性，这种灵活性是如何被发育压力改变的，以及对认知行为的影响。广泛地说，我的实验室使用啮齿动物模型、电生理工具、光遗传学、多光子成像以及行为和分子分析来研究神经调节的细胞机制。对于这项资助，我们将从血清素能神经元本身开始，并询问提供灵活性的信号通路，以在行为相关的时间框架内响应不同的放电模式。这项工作自然地进入了我们实验室正在进行的NSERC研究，研究暴露于长期社会隔离的小鼠是否表现出大脑皮层中血清素受体电生理信号的变化，并确定潜在的受体和相关的通道效应物。最后，我们将利用体内光遗传学研究皮质5 -羟色胺在急性应激或情绪条件下干扰复杂注意力任务中的作用。这个NSERC研究项目将培养学生和博士后尖端神经科学技术，并将推进我们对调节血清素系统的细胞机制的理解。综合实验将中脑和大脑皮层的机制研究结合起来，以更全面地了解血清素能信号的内在灵活性和发育扰动的持久后果。我们的行为研究旨在阐明5 -羟色胺的细胞和回路效应及其对认知的影响之间的关系。总的来说，这个NSERC项目将探索我们的个人历史在多大程度上影响了血清素调节我们神经回路和行为的能力。