Noninvasive Optogenetic Interventions for Epilepsy

在癫痫患者中，中枢神经系统的过度兴奋性和同步性导致癫痫发作和认知并存。使用抗癫痫药物的全身治疗不能充分控制癫痫发作，而且往往伴随着严重的副作用，在全球约6500万癫痫患者中，约有30%-40%是药物耐药的。因此，需要新的治疗方法。光遗传学的最新进展表明，通过精确的细胞类型特定方向控制神经活动来抑制癫痫发作。虽然闭合环光遗传干预提供了识别网络以减少癫痫发作的策略，但植入的光纤波导和转基因小鼠的使用排除了将其用作治疗工具的可能性。为了克服与光遗传学作为临床手段相关的挑战，这一提议将检验最近发现的超敏和红移通道视紫红质(CHRS)可以使自发性、复发性癫痫的经颅和细胞类型特异性终止的假设。这一假设将通过开发非侵入性病毒靶向策略来验证，该策略将这些新的CHR的表达限制在与治疗相关的中间神经元亚型，然后在大脑皮层和海马局灶性癫痫小鼠模型中进行经颅闭环光遗传控制。将在野生型动物身上进行慢性癫痫抑制，以测试这种方法的长期稳定性。进一步将刺激细化到特定的预测，将把偏离目标的影响降至最低。通过克服长期存在的光遗传学障碍，包括侵袭性、神经亚群的病毒靶向和可扩展性，这个经颅光遗传平台将发现治疗癫痫的新机会，并可能扩展到管理其他神经疾病。在拟议的研究和职业培训计划期间，我将得到一个经验丰富的专家团队的指导，这些专家包括系统神经科学、光遗传学、癫痫动物模型和行为、电生理学和计算分析。这个团队将通过在斯坦福大学巨大的科学环境中进行新技术培训、手稿和拨款写作、公开演讲、为被辅导者提供建议以及合作来为我的研究项目和专业发展提供建议，斯坦福大学提供了几个核心设施、职业发展中心和正规课程来支持我的工作。在完成这个有指导的研究项目后，我将获得坚实的技术和概念基础，将我的工程学背景与系统神经科学联系起来，我将利用这一背景建立独立的研究生涯，开发和应用方法来研究神经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.