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: 9896890
• 负责人: Nathan A Smith
• 金额: $ 21.86万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896890
• 关键词: Acute; Adrenergic Agents; Adrenergic Receptor; Adult; Alzheimer' s Disease; Astrocytes; Attention; Attention deficit hyperactivity disorder; Biology; Biomedical Research; Brain; Buffers; Carbenoxolone; Central Nervous System Diseases; Child; Connexin 43; Data; Development; Disease; Environment; Epilepsy; Faculty; Feedback; Functional disorder; Gap Junctions; Glutamates; Goals; Health; Health Sciences; Health system; Hippocampus (Brain); In Vitro; Inositol; Institution; Investigation; K-Series Research Career Programs; Knockout Mice; Learning; Learning Disorders; Long-Term Depression; Mediating; Memory; Memory Disorders; Mental Depression; Mentored Research Scientist Development Award; Mentors; Mentorship; Modeling; Mus; Neuroglia; Neuromodulator; Neurons; Neurotransmitters; Norepinephrine; Patch-Clamp Techniques; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacology; Physiology; Play; Potassium; Preparation; Process; Protocols documentation; Regulation; Research; Research Personnel; Role; SNAP receptor; Sensory; Serine; Short-Term Memory; Signal Transduction; Slice; Somatosensory Cortex; Stimulus; Synapses; Synaptic plasticity; Techniques; Testing; Training; Treatment Efficacy; Universities; Visual Cortex; Washington; alpha-adrenergic receptor; authority; base; career development; executive function; extracellular; in vivo; in vivo imaging; information processing; inhibitor/antagonist; insight; locus ceruleus structure; medical schools; metabotropic glutamate receptor 3; nervous system disorder; neuronal circuitry; neuropsychiatric disorder; neuroregulation; neurotransmission; novel; pediatric pharmacology; professor; programs; receptor; skills; somatosensory; terazosine; tripolyphosphate; vesicular release

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 Assistant Professor of Pediatrics, and Pharmacology and Physiology at Children’s National Health System (CNHS) and George Washington University School of Medicine and Health Sciences (GWSMHS). 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 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 a 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. Vittorio Gallo, Chief Research Officer at CNHS and a leading authority on glial signaling in health and disease, and two co-mentors: Dr. Stefano Vicini, who has expertise in slice physiology and synaptic plasticity; and Dr. Jason Triplett, 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 both 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 the release of ATP. 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 该建议是为K01指导的职业发展奖，以促进生物医学的教师多样性 新的儿科助理教授，药理学与生理学的研究 在儿童国家卫生系统（CNHS）和乔治华盛顿大学医学与卫生学院 科学（GWSMHS）。史密斯博士正在建立自己的突触机制的年轻研究者 可塑性特别关注去甲肾上腺素（NE）在突触可塑性的星形细胞调节中的作用。 该K01奖将为史密斯博士提供完成以下目标所需的支持：（1）获取补丁程序 用于切片制备的夹紧技术； （2）获取和应用Ltd协议将准备工作切成薄片 确定星形胶质细胞在学习和记忆中的作用； （3）获取和学习进步药理学 技术以特异性阻断星形胶质细胞中的肾上腺素受体； （4）发展所需的技能 通过各种职业发展活动和心态成为独立的研究者。实现 这些目标史密斯博士召集了一支精神团队，完成了主要的精神，酋长Vittorio Gallo博士 CNHS的研究官以及健康和疾病中神经胶质信号的领先权威，以及两名联合主管： Stefano Vicini博士，在切片生理学和突触可塑性方面具有专业知识；还有Jason Triplett博士 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，可调节包括突触可塑性在内的许多大脑功能。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 星形胶质细胞能够应对视觉皮层中局部突触活动的能力。但是，需要进一步调查 阐明NE介导的星形细胞对皮质网络和突触可塑性的机制。到 那一端，我将首先探索星形胶质细胞是否对于使用Sosatosensensory Cortex中的NE介导的LTD至关重要 在我们的新型GCAMP5G-TDTM/ALDH1L1小鼠AIM 1中，急性皮质切片。在AIM 2中，我将检查NE诱导的 星形胶质细胞的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 使用两者都使用两者 GCAMP5G-TDTM/ALDH1L1小鼠中的急性皮质切片和体内制剂。最后，在AIM 3中，我将测试 假设星形胶质细胞通过ATP的释放来调节NE介导的皮质有限公司。合并，提议 研究将为星形胶质细胞在突触调节中的作用提供新的见解，从而在较高 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。