Astrocytes Modulate Synaptic Plasticity via Norepinephrine

星形胶质细胞通过去甲肾上腺素调节突触可塑性

• 批准号: 10826310
• 负责人: Nathan A Smith
• 金额: $ 24.19万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10826310
• 关键词: Astrocytes; Modulate; Synaptic; Plasticity; via

Project Summary/Abstract: This proposal is for a K01 Mentored Career Development Award to Promote Faculty Diversity in Biomedical Research for Dr. Nathan A. Smith, a new Associate Professor of Neuroscience and Associate Dean of Equity and Inclusion for research and research education. Dr. Smith is establishing himself as a young investigator in mechanisms of synaptic plasticity with a particular focus on the role of norepinephrine (NE) in astrocytic modulation of synaptic plasticity. This K01 award will provide Dr. Smith with the support necessary to complete the following goals: (1) to acquire patch clamping techniques for slice preparation; (2) to acquire and apply LTD protocols to slice preparation to determine the role of astrocytes in learning and memory; (3) to acquire and learn advance pharmacology techniques in order to specifically block adrenergic receptors in astrocytes; (4) to develop the skills needed to be an independent investigator through a variety of career development activities and mentorship. To achieve these goals, Dr. Smith has assembled a mentoring team comprised of a primary mentor, Dr. Kerry O’Banion, Professor and Vice-Chair of Neuroscience, is a leading authority on glial signaling in health and disease, and two co-mentors: Dr. Stefano Vicini (Georgetown), who has expertise in slice physiology and synaptic plasticity; and Dr. Jason Triplett (Children’s National/George Washington), who has expertise in sensory circuit development and function and one consultant/collaborator: Dr. Baljit Khakh (UCLA), who is an established investigator and a leader in the field of glial biology and physiology. NE is a major neurotransmitter that modulates a number of brain functions, including synaptic plasticity. Recent studies suggest that astrocytes could be involved in NE-induced network modulation. For example, NE has been demonstrated to evoke global Ca2+ transients in cortical astrocytes. Additionally, NE has been shown to enhance astrocytes’ ability to respond to local synaptic activity in the visual cortex. However, further investigation is needed to elucidate the mechanisms of NE-mediated astrocytic effects on cortical networks and synaptic plasticity. To that end, I will first explore if astrocytes are essential for NE-mediated LTD in the somatosensory cortex using acute cortical slices in our novel GCaMP5G-tdTm/Aldh1l1 mice in Aim 1. In Aim 2, I will examine NE-induced priming of astrocytes to respond to local synaptic activity. Specifically, I will explore NE-mediated enhancement of astrocytic mGluR3-induced Ca2+ signaling to local synaptic activity in the somatosensory cortex using acute cortical slices and in vivo preparations in GCaMP5G-tdTm/Aldh1l1 mice. Finally, in Aim 3, I will test the hypothesis that astrocytes modulate NE-mediated cortical LTD via ATP release. Combined, the proposed studies will provide novel insights into the role of astrocytes in synaptic regulation and thereby in higher information processing through NE-mediated neuromodulation. This research will also form the basis for an R01 application before the end of the K award cycle.

项目摘要/摘要：该提案是为K01指导的职业发展奖，以促进教师 Nathan A. Smith博士的生物医学研究多样性，神经科学的新副教授和 公平与包容性研究和研究教育的副院长。史密斯博士正在确立自己 年轻的研究人员突触可塑性机制，特别关注去甲肾上腺素的作用（NE） 在突触可塑性的星形细胞调节中。该K01奖将为史密斯博士提供必要的支持 要完成以下目标：（1）获取贴片夹紧技术以进行切片准备； （2）获取和 应用LTD方案进行切片准备，以确定星形胶质细胞在学习和记忆中的作用； （3）获取 并学习预先的药物技术，以特异性阻断星形胶质细胞中的肾上腺素受体； （4）通过各种职业发展发展成为独立调查员所需的技能 活动和心态。为了实现这些目标，史密斯博士召集了一个心理团队 主要导师，神经科学教授兼副主席Kerry O'Banion博士，是Glial的领先权威 健康和疾病的信号传导，以及两个副主管：Stefano Vicini博士（乔治敦），他在Slice方面具有专业知识 生理和突触可塑性；还有Jason Triplett博士（儿童国家/乔治·华盛顿） 感觉电路发展和功能方面的专业知识以及一名顾问/合作者：Baljit Khakh（UCLA）博士， 他是一位既定的研究者，也是神经胶质生物学和生理学领域的领导者。 NE是一种主要的神经递质，可调节许多大脑功能，包括突触可塑性。最近的 研究表明，星形胶质细胞可能参与NE诱导的网络调节。例如，NE一直是 证明是在皮质星形胶质细胞中唤起全局Ca2+瞬态。此外，已显示NE可以增强 星形胶质细胞对视觉皮层中局部突触活动做出反应的能力。但是，进一步的调查是 需要阐明NE介导的星形细胞对皮质网络和突触的机制 可塑性。为此，我将首先探讨星形胶质细胞对于体感中的NE介导的LTD是否必不可少 在我们的新型GCAMP5G-TDTM/ALDH1L1小鼠AIM 1中使用急性皮质切片的皮质。在AIM 2中，我将检查 NE诱导的星形胶质细胞启动以应对局部突触活动。具体来说，我将探索NE介导的 增强星形细胞MGLUR3诱导的Ca2+信号转导向体感皮质中的局部突触活性 使用急性皮质切片和GCAMP5G-TDTM/ALDH1L1小鼠中的体内制剂。最后，在AIM 3中，我将测试 星形胶质细胞通过ATP释放调节NE介导的皮质有限公司的假设。合并，提议 研究将提供有关星形胶质细胞在突触调节中的作用的新见解，从而在较高的情况下提供 通过NE介导的神经调节来处理信息。这项研究还将构成R01的基础 在K颁发周期结束之前的申请。