Mechanisms of remodeling circuit connectivity after traumatic brain injury

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，到2020年将成为世界人口死亡和残疾的第三大原因。虽然我们知道神经元退化和认知缺陷是人类创伤性脑损伤的共同特征，但我们才刚刚开始认识到这种疾病的一个全新层面：脑网络在损伤后如何立即发生变化，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、长期目标是确定脑外伤后神经活动和细胞内信号通路如何共同促进神经回路重建的基本机制。据我们所知，我们的初步数据是第一个证明脑外伤后神经回路结构如何变化的证据，也是第一个观察到如何将回路激活与药物结合起来重建网络的证据。基于我们的初步数据，我们提出了以下目标：具体目标1：在体外和体内研究机械损伤后神经元与网络断开的机制。特定目标2：确定活动诱导神经元随时间重新整合到受损微电路中的机制。我们的一般假设是：(a)连通性直接影响损伤后神经元与网络的分离，以及网络的恢复；(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)神经元的分离是由线粒体信号传导介导的；(d)延长回路激活，结合药物，可以最佳地控制网络的重建。影响：了解脑外伤后神经回路中神经元连接的重塑机制将使我们深入了解保护网络结构的治疗方法。一旦对创伤性脑损伤后重塑电路的机制有了更好的了解，我们设想在未来5-10年内在临床前创伤性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的重点从减少神经元死亡转向重建脑外伤后的功能电路。

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. 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 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.