Delineation of astrocyte microdomain calcium events during cortical activity

皮质活动期间星形胶质细胞微区钙事件的描绘

• 批准号: RGPIN-2020-05688
• 负责人: Stobart, Jillian
• 金额: $ 2.99万
• 依托单位: University of Manitoba
• 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=762137
• 关键词: Delineation; astrocyte; microdomain; calcium; events

Astrocytes, a type of brain glial cell, are important for normal neuronal function. They are known to support neurons in many ways: by supplying energy, removing wastes, and maintaining an environment for proper neuronal activity. There is also evidence that astrocytes sense neuronal activity and actively release molecules to change neuronal function. The long-term goal of my research program is to determine the nature of neuron-astrocyte communication and define how astrocytes can change neuronal activity within sensory circuits to influence cortical information processing. Neuronal activity causes local increases in astrocyte calcium, termed "microdomain calcium events" (MCEs). These MCEs have become an important biomarker of astrocyte activity, since they are necessary for astrocyte signaling back to neurons. Therefore, in order to understand the functional roles of astrocytes, it is important that we fully characterize astrocyte MCEs. My HQP will use novel genetic tools and cutting-edge in vivo two-photon microscopy in awake animals during somatosensory stimulation to study astrocyte MCEs and nearby neurons within intact circuits. First, we will correlate cortical astrocyte MCEs with nearby neuronal activity to determine the neuronal type (excitatory vs. inhibitory) and subcellular compartment (soma vs. dendrite) that induces astrocyte MCEs, particularly during physiological whisker stimulation. Next, we will examine astrocyte MCE recruitment during neuronal reorganization during a sensory deprivation paradigm, which will provide insight into how astrocytes respond to and possibly tune neuronal population changes. Finally, my preliminary data shows that astrocyte N-methyl-D-aspartate receptors, ionotropic receptors activated by excitatory glutamate, play an important role in astrocyte MCEs and affect nearby neuronal activity. My group will further investigate the functional role of these astrocyte receptors, including in how they influence excitatory or inhibitory neuronal populations and ultimately affect mouse sensory perception.  Overall, results will provide an important characterization of several unknown aspects of cortical astrocyte MCEs, including identification of specific mechanisms and neuronal contributions that evoke these astrocyte signals and conversely, the influence these localized signals have on nearby synaptic transmission. This will advance current concepts of astrocytes in directions that provide a more solid foundation for understanding neuron-astrocyte communication and how astrocytes are integrated into brain circuits. This is directly relevant for our understanding of synaptic level microcircuits but also has broader implications for large-scale brain system connectivity. The training environment created by this research program will provide cutting-edge technical and transferable skills for a minimum of two graduate students and ten undergraduate students in this 5-year cycle.

星形胶质细胞是一种脑胶质细胞，对正常的神经功能非常重要。已知它们以多种方式支持神经元：通过提供能量，清除废物，并维持适当的神经元活动环境。还有证据表明，星形胶质细胞感知神经元活动并主动释放分子以改变神经元功能。我的研究计划的长期目标是确定神经元-星形胶质细胞通信的性质，并确定星形胶质细胞如何改变感觉回路中的神经元活动，以影响皮层信息处理。神经元活动导致星形胶质细胞钙的局部增加，称为“微区钙事件”（MCE）。这些MCE已成为星形胶质细胞活性的重要生物标志物，因为它们是星形胶质细胞向神经元传递信号所必需的。因此，为了了解星形胶质细胞的功能作用，重要的是，我们充分表征星形胶质细胞MCE。 我的HQP将使用新的遗传工具和尖端的体内双光子显微镜在清醒的动物在体感刺激研究星形胶质细胞MCE和附近的神经元完整的电路。首先，我们将皮层星形胶质细胞MCE与附近的神经元活动，以确定神经元类型（兴奋与抑制）和亚细胞区室（索马与树突），诱导星形胶质细胞MCE，特别是在生理胡须刺激。接下来，我们将研究星形胶质细胞MCE招聘神经元重组过程中的感觉剥夺范例，这将提供深入了解星形胶质细胞如何响应，并可能调整神经元群体的变化。最后，我的初步数据表明，星形胶质细胞N-甲基-D-天冬氨酸受体，离子型受体兴奋性谷氨酸激活，在星形胶质细胞MCE中发挥重要作用，并影响附近的神经元活动。我的小组将进一步研究这些星形胶质细胞受体的功能作用，包括它们如何影响兴奋性或抑制性神经元群体，并最终影响小鼠的感觉知觉。总体而言，结果将提供皮质星形胶质细胞MCE的几个未知方面的重要表征，包括识别引起这些星形胶质细胞信号的特定机制和神经元贡献，反之亦然，这些局部信号对附近突触传递的影响。这将推进星形胶质细胞的方向，为理解神经元-星形胶质细胞通信以及星形胶质细胞如何整合到大脑电路中提供更坚实的基础。这与我们对突触水平微电路的理解直接相关，但对大规模大脑系统连接也有更广泛的影响。该研究计划创造的培训环境将在这个5年周期内为至少两名研究生和十名本科生提供尖端技术和可转移技能。