Bioenergetics and Neuronal Network Remodeling in a Rodent Model of Temporal Lobe Epilepsy

在美国，癫痫影响着300万成年人和45万儿童。三分之一的慢性癫痫是 对目前的抗癫痫药物难以治愈。最常见的获得性癫痫形式--颞叶癫痫 癫痫，通常由脑损伤引发，如癫痫持续状态(SE)，随后是潜伏期， 分子和细胞重塑导致慢性癫痫。改建的过程很糟糕 明白了。并不是每个经历发作性SE的患者都会进展到TLE，而且 癫痫的发生可能从几周到几年不等。迫切需要新的机械性的理解和 早期识别SE后TLE，以便进行风险分层和更好的管理。 线粒体功能障碍被越来越多地认为是TLE的诱发因素，不仅是在 Se，但也有助于难治性TLE的癫痫发生。然而，在以下方面存在着重大的知识差距 疾病阈值和缺乏敏感的体内工具来检测和监测亚临床癫痫发生 癫痫确诊前的早期干预程序。我们的长期目标是了解 从SE到TLE的过程。作为迈向这一目标的重要一步，我们现在处于有利地位，可以测试 一种新的4D氧子波MRI可以作为检测脑内线粒体功能异常的病灶的假说 SE后损伤可促进TLE的发展。当前提案的重点是验证和 建立4D氧子波MRI作为识别伴有线粒体功能障碍的脑内病灶的生物标志物。我们会 首次验证4D氧子波MRI是监测线粒体功能的一种无创、特定于区域的手段 在大脑里。我们将使用著名的线粒体药物鱼藤酮和2，4-二硝基苯酚， 药物上分别损害或增强线粒体的呼吸作用。然后我们将监测时空 SE后TLE大鼠线粒体功能区域特异性变化的4D氧子波MRI研究 模特。4Doxy小波MRI信号将与体外线粒体功能分析相关联，包括 Oroboros呼吸测量和活体磁共振波谱脑代谢图谱。 我们的研究将验证4D氧子波MRI作为一种非侵入性监测线粒体活动的方法 在大脑里。使用SE后TLE的大鼠模型，我们将使用新的MRI工具来观察颞叶和区域- 线粒体功能的特异性改变。这些数据可以促进4Doxy小波MRI作为一种非 预测SE后TLE的侵袭性生物标志物。由于该方法是非侵入性的，因此可以转化为临床 设定在未来。

Epilepsy affects 3 million adults and 450,000 children in the US. One-third of chronic epilepsy is intractable to current antiseizure medications. Temporal lobe epilepsy (TLE), the most frequent form of acquired epilepsy, is typically initiated by brain injury, such as status epilepticus (SE), followed by a latent period wherein molecular and cellular remodeling occurs leading to chronic epilepsy. The process of remodeling is poorly understood. Not every patient who experiences episodic SE will progress to TLE, and the latent period of epileptogenesis can vary from weeks to years. There is a critical need for new mechanistic understanding and early recognition of post-SE TLE for risk stratification and better management. Mitochondrial dysfunction is increasingly recognized as an inciting factor for TLE, not only acutely after SE, but also contributing to epileptogenesis for refractory TLE. However, there are major knowledge gaps in disease thresholds and a lack of sensitive in vivo tools to detect and monitor the subclinical epileptogenesis process for early intervention before epilepsy is established. Our long-term goal is to understand the remodeling process that leads from SE to TLE. As an important step towards this, we are now in a strong position to test the HYPOTHESIS that a novel 4D oxy-wavelet MRI can be a proxy to detect foci with mitochondrial dysfunctions in post-SE injury that can contribute to TLE development. The focus of the current proposal is to validate and establish 4D oxy-wavelet MRI as a biomarker for identifying brain foci with mitochondrial dysfunctions. We will first validate 4D oxy-wavelet MRI as a non-invasive, region-specific means of monitoring mitochondrial function in the brain. We will use the well-known mitochondrial drugs, rotenone and 2,4-dinitrophenol, to pharmacologically impair or enhance mitochondrial respiration, respectively. Then we will monitor spatiotemporal evolution of region-specific changes in mitochondrial functions with 4D oxy-wavelet MRI in a post-SE TLE rat model. The 4D oxy-wavelet MRI signal will be correlated with ex vivo mitochondrial functional assays, including Oroboros respirometry, and brain metabolic profiling with in vivo MR spectroscopy. Our study will validate 4D oxy-wavelet MRI as a non-invasive method for monitoring mitochondrial activity in the brain. Using a rat model of post-SE TLE, we will use the new MRI tool to observe temporal and region- specific changes of mitochondrial function. These data can advance use of the 4D oxy-wavelet MRI as a non- invasive biomarker for predicting post-SE TLE. As this method is non-invasive, it can be translated to clinical setting in the future.