Noninvasive Optogenetic Interventions for Epilepsy

在癫痫患者中，中枢神经系统的高兴奋性和同步性会导致癫痫发作和认知合并症。使用抗惊厥药物进行全身治疗不能充分控制癫痫发作，而且常常伴有严重的副作用，在全世界估计的6500万癫痫患者中，约有30-40%是药物难治性的。因此，需要新的治疗方法。光遗传学的最新进展已经证明，通过精确的细胞类型特定的神经活动定向控制来抑制癫痫发作。虽然闭环光遗传干预提供了识别网络以减少癫痫发作的策略，但植入光纤波导和转基因小鼠的使用排除了作为治疗工具的使用。为了克服与光遗传学作为临床模式相关的挑战，本提案将验证最近发现的超敏感和红移通道视紫红质（ChRs）可以实现经颅和细胞类型特异性终止自发性复发性癫痫发作的假设。该假设将通过开发非侵入性病毒靶向策略来验证，以限制这些新ChRs在治疗相关的中间神经元亚型中的表达，然后在小鼠局灶性癫痫模型中进行经颅闭环光遗传控制。慢性癫痫抑制将在野生型动物中进行，以测试这种方法的长期稳定性。进一步细化刺激，以特定的预测将最大限度地减少脱靶效应。通过克服光遗传学长期存在的障碍，包括侵入性、神经亚群的病毒靶向性和可扩展性，这个经颅光遗传学平台将为治疗癫痫找到新的机会，并可能扩展到治疗其他神经系统疾病。在拟议的研究和职业培训计划期间，我将受到系统神经科学，光遗传学，癫痫动物模型和行为，电生理学和计算分析方面经验丰富的专家团队的指导。这个团队将为我的研究项目和专业发展提供建议，包括新技术培训、手稿和拨款写作、公开演讲、为学员提供建议，以及斯坦福大学巨大的科学环境中的合作。斯坦福大学提供了几个核心设施、职业发展中心和正式课程来支持我的工作。在完成这个受指导的研究项目后，我将获得一个强大的技术和概念基础，将我的工程背景与系统神经科学联系起来，我将利用它建立一个独立的研究生涯，开发和应用方法来研究神经系统疾病背后的神经机制，并为它们制定治疗概念。

In patients with epilepsy, central nervous system hyperexcitability and synchrony contribute to seizures and cognitive comorbidities. Systemic treatments with anticonvulsant drugs do not adequately control seizures and are often accompanied by severe side effects, where approximately 30-40% of the estimated 65 million epileptic patients worldwide are drug refractory. Consequently, new therapies are needed. Recent advances in optogenetics have demonstrated seizure suppression through precise cell type specific directional control of neural activity. While closed-loop optogenetic interventions provide strategies to identify networks to curtail seizures, the use of implanted fiber optic waveguides and transgenic mice precludes usage as a therapeutic tool. To overcome challenges associated with optogenetics as a clinical modality, this proposal will test the hypothesis that recently discovered supersensitive and red-shifted Channelrhodopsins (ChRs) can enable transcranial and cell type specific termination of spontaneous, recurrent seizures. The hypothesis will be tested by developing noninvasive viral-targeting strategies to restrict expression of these new ChRs to therapeutically- relevant interneuron subtypes followed by transcranial closed-loop optogenetic control in mouse models of focal epilepsy in the cortex and hippocampus. Chronic seizure suppression will be performed to test the long- term stability of this approach in wild-type animals. Further refining stimulation to specific projections will minimize off-target effects. By overcoming long standing hurdles of optogenetics, including invasiveness, viral- targeting of neural subpopulations, and scalability, this transcranial optogenetic platform will identify new opportunities for the treatment of epilepsy and may be extended to manage other neurological disorders. During the proposed research and career training plan, I will be mentored by an experienced team of experts in systems neuroscience, optogenetics, animal models of epilepsy and behavior, electrophysiology and computational analysis. This team will advise my research project and professional development through training in new techniques, manuscript and grant writing, public speaking, advising of mentees, and collaborations within the tremendous scientific environment at Stanford University, which offers several core facilities, career development centers, and formal coursework to support my work. Upon completion of this mentored research project, I will gain a strong technical and conceptual foundation to bridge my background in engineering with systems neuroscience, which I will use to establish an independent research career to develop and apply methods to study the neural mechanisms that underly neurological disorders and to develop treatment concepts for them.