Noninvasive Optogenetic Interventions for Epilepsy

在癫痫患者中，中枢神经系统过度兴奋和同步性有助于癫痫发作和认知共病。抗惊厥药物的全身治疗不能充分控制癫痫发作，并且通常伴有严重的副作用，其中全球估计的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了通过精确的细胞类型特异性定向控制神经活动来抑制癫痫发作。虽然闭环光遗传学干预提供了识别减少癫痫发作的网络的策略，但植入的光纤波导和转基因小鼠的使用排除了作为治疗工具的用途。为了克服与光遗传学作为临床模式相关的挑战，该提案将测试最近发现的超敏感和红移的视紫红质（ChR）可以使自发性复发性癫痫发作的经颅和细胞类型特异性终止的假设。将通过开发非侵入性病毒靶向策略来测试该假设，以将这些新ChR的表达限制于治疗相关的中间神经元亚型，然后在皮质和海马中的局灶性癫痫小鼠模型中进行经颅闭环光遗传学控制。将进行慢性癫痫发作抑制以测试该方法在野生型动物中的长期稳定性。进一步细化刺激到特定的投影将最大限度地减少脱靶效应。通过克服光遗传学的长期障碍，包括侵入性、神经亚群的病毒靶向和可扩展性，这种经颅光遗传学平台将确定治疗癫痫的新机会，并可能扩展到管理其他神经系统疾病。 在拟议的研究和职业培训计划期间，我将由系统神经科学，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指导。该团队将通过新技术培训，手稿和赠款写作，公开演讲，指导学员以及在斯坦福大学巨大的科学环境中的合作，为我的研究项目和专业发展提供建议，该大学提供了几个核心设施，职业发展中心和正式的课程来支持我的工作。在完成这个指导研究项目后，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，我将用它来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的神经机制，并为它们开发治疗概念。

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.