Mechanisms of remodeling circuit connectivity after traumatic brain injury

 描述(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，并有望在2020年前成为世界人口死亡和残疾的第三大原因。尽管我们知道神经元变性和认知缺陷都是人类脑外伤的共同特征，但我们才刚刚开始认识到这种疾病的一个全新维度：脑网络在损伤后立即发生变化，以及认知恢复如何关键地依赖于这些网络的重建。我们工作的广泛和长期目标确定了神经活动和细胞内信号通路如何共同促进脑损伤后电路重建的基本机制。据我们所知，我们的初步数据是第一个显示脑外伤后神经回路结构如何变化的证据，也是第一个观察到将回路激活与药物相结合如何共同重建网络的证据。我们在初步数据的基础上提出了以下目标：具体目标1：在体外和体内研究机械损伤后神经元脱离网络的机制。具体目标2：确定随着时间的推移，活动诱导的神经元重新整合到受损微电路中的机制，将其扩展到测量受脑创伤后清醒的行为动物的电路重构。我们的一般假设是：(A)连通性直接影响损伤后神经元从网络断开，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介导的，以及(D)延长电路激活结合药物可以最佳地控制网络的重建。影响：了解脑外伤后随着时间的推移重塑电路中神经元连接的机制将使我们深入了解保护网络结构的治疗方法。一旦更好地了解了脑外伤后活体大脑中重塑电路的机制，我们设想在未来5-10年内在临床前脑损伤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移到脑外伤后重建功能回路的方法上。

 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.