Mechanisms of remodeling circuit connectivity after traumatic brain injury

脑外伤后回路连接重塑机制

• 批准号: 8885321
• 负责人: DAVID F MEANEY
• 金额: $ 34.45万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885321
• 关键词: Algorithms; Animals; Brain; Brain Diseases; CREB1 gene; Calcineurin; Calcium; Cause of Death; Cessation of life; Cognitive deficits; Data; Dimensions; Disease; Equilibrium; Genetic Transcription; Goals; Human; Image; In Vitro; Individual; Injury; Lead; Life; Maintenance; Measures; Mechanics; Mediating; Mitochondria; Modeling; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurons; Outcome; Pathway interactions; Patients; Pattern; Pharmacy (field); Phosphorylation; Population; Pre-Clinical Model; Protocols documentation; Public Health; Receptor Activation; Recovery; Relative (related person); Role; Signal Pathway; Signal Transduction; Structure; Testing; Therapeutic; Time; Trauma; Traumatic Brain Injury; Traumatic Brain Injury recovery; Work; awake; brain circuitry; calmodulin-dependent protein kinase II; cognitive recovery; disability; improved; in vivo; injured; innovation; insight; mitochondrial permeability transition pore; nervous system disorder; neural circuit; neurobehavior; novel; pre-clinical; public health relevance; reconstruction; relating to nervous system; repaired; response

 DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) remains a major public health problem and is on pace to become the third leading cause of death and disability in the world population by 2020. Although we know that both neuronal degeneration and cognitive deficits are common features of human TBI, we are only beginning to appreciate an entirely new dimension of the disease: how brain networks change immediately after injury, and how cognitive recovery may depend critically on rebuilding these networks. The broad, long-term goal of our work identifies the fundamental mechanisms on how neural activity and intracellular signaling pathways together contribute to rebuilding a circuit after TBI. To our knowledge, our preliminary data is the first evidence showing how the structure of neural circuits changes after TBI, and the first observation on how combining circuit activation with pharmaceutics can together rebuild a network. We build on our preliminary data and propose the following aims: Specific Aim 1: To examine mechanisms of neuronal disconnection from a network after mechanical injury in vitro and in vivo. Specific Aim 2: To determine mechanisms for the activity-induced re-integration of neurons into an injured microcircuit over time, extending this into measuring circuit remodeling in awake, behaving animals subjected to TBI. Our general hypotheses are: (a) Connectivity directly influences neuronal disconnection from a network following injury, as well as network recovery (b) neuronal re-integration into the network is mediated by calcineurin activity and CREB-phosphorylation, (c) neuronal disconnection is mediated by mitochondrial signaling, and (d) prolonged circuit activation, in combination with pharmaceutics, can optimally control the reconstruction of networks. Impact: Knowing the mechanisms for remodeling neuronal connections in a circuit over time after TBI will give us insight into treatments protecting the network structure. Once the mechanisms for remodeling circuitry in the living brain after TBI are better understood, we envision testing therapies in preclinical TBI models within the next 5-10 years. Broadly, we believe this work will shift the therapeutic focus away from reducing neuronal death and towards approaches to rebuild functional circuits after TBI.

 描述（由申请人提供）：创伤性脑损伤 (TBI) 仍然是一个主要的公共卫生问题，并且到 2020 年将成为世界人口死亡和残疾的第三大原因。尽管我们知道神经退化和认知缺陷虽然这些都是人类 TBI 的共同特征，但我们才刚刚开始认识到这种疾病的一个全新维度：大脑网络在受伤后如何立即发生变化，以及认知恢复如何关键取决于重建这些网络。这是我们广泛、长期的目标。这项工作确定了神经活动和细胞内信号通路如何共同促进 TBI 后神经回路重建的基本机制，据我们所知，我们的初步数据是显示 TBI 后神经回路结构如何变化的第一个证据，也是关于如何变化的第一个观察。将电路激活与药物相结合可以重建网络。我们以初步数据为基础，提出以下目标： 具体目标 1：研究体外和体内机械损伤后神经网络断开的机制。确定机制随着时间的推移，活动诱导的神经元重新整合到受伤的微电路中，并将其扩展到测量清醒的、行为正常的遭受 TBI 的动物的电路重塑中。以及网络恢复（b）神经元重新整合到网络中是由钙调神经磷酸酶活性和CREB磷酸化介导的，（c）神经元断开是由线粒体信号传导介导的，以及（d）延长的电路激活，与药物相结合，可以最佳地控制网络的重建。随着时间的推移，了解 TBI 后神经回路的重塑机制将使我们深入了解活体大脑中回路重塑的机制。在更好地了解 TBI 后，我们预计在未来 5-10 年内在临床前 TBI 模型中测试治疗方法。总的来说，我们相信这项工作将把治疗重点从减少神经元死亡转向重建功能回路的方法。创伤性脑损伤。