Elucidating the Role of Dorsal Lateral Geniculate Nucleus Burst-Mode Firing in Retinal Inactivation Induced Recovery from Monocular Deprivation

弱视是一种常见的视觉系统发育障碍，导致单眼视力低下。 虽然已经有很多研究来了解这种疾病的病理生理学，但治疗老年人 患有弱视的儿童和成年人仍然是一个挑战。有趣的是，有临床报道 提示弱视眼的视力在成人弱视摘除后可能有所提高。 由于受伤或疾病而导致的正常眼睛。在这些临床报告的推动下，我们的实验室最近发现 玻璃体内注射钠通道阻滞剂使正常眼视网膜暂时沉默 河豚毒素(TTX)能有效地促进猫和小鼠视力的恢复。 弱视。令人惊讶的是，这种治疗方法对年龄较大、抗药性较强的动物有效，而且不会导致 对注射眼睛的任何处罚。通过阐明视网膜失活促进 从弱视动物模型的饲养中恢复过来，我们有潜力确定如何最好 利用这一机制来治疗人类弱视。最初的假设是，让 经TTX注射视网膜会导致膝状体背外侧核(DLGN)活动减少， 因为dLGN将活动从视网膜传递到皮质。令人惊讶的是，事实证明这是不正确的；事实上， 在视网膜失活后，dLGN中的神经元表现出更多的自发爆发活动。建议数 该项目将专注于研究dLGN突发模式激发增加是其机制的假设 通过视网膜失活推动弱视养育的恢复。为了研究这一假设，我们将首先 使用慢性单位记录，通过TTX描述视网膜失活后的dLGN活动。DLGN 然后，药物将阻断猝发，以确定dLGN猝发是否对TTX是必要的 从弱视养育中调解恢复。最后，dLGN爆发式活动将通过光遗传施加 操作以确定突发是否足以推动从一段时间的弱视恢复 养育。通过加强对dLGN活性在视网膜失活诱导恢复中的作用的理解 通过弱视的养育，这个项目有可能为我们未来的研究提供信息，并提出新的临床建议。 弱视的治疗方法。该项目将在马克·贝尔博士的大脑和 麻省理工学院认知科学系(BCS)。熊实验室 包含提议项目所需的所有设备。关于所需实验室的所有必要培训 技术将由高级实验室成员提供，或通过与BCS的其他实验室合作提供。《熊》 实验室、BCS和麻省理工学院将提供优质的科学和专业发展资源，以促进成功的 过渡到申请者研究生涯的下一个阶段。

Amblyopia is a common disorder of visual system development, resulting in poor visual acuity in one eye. Though there has been much research to understand the pathophysiology of the disorder, treating older children and adults with amblyopia remains a challenge. Interestingly, there have been clinical reports suggesting gains in the visual acuity of the amblyopic eye may be possible in adults following removal of the normal eye due to injury or disease. Motivated by these clinical reports, our lab recently discovered that temporarily silencing the retina of the normal eye via intravitreal injection of the sodium channel blocker tetrodotoxin (TTX) is effective at promoting a recovery in visual acuity in both cat and mouse models of amblyopia. Amazingly, this treatment is effective in older, more treatment resistant animals and does not cause any penalty to the injected eye. By elucidating the mechanism by which retinal inactivation is promoting recovery from a period of amblyopic rearing in animal models, we have the potential to determine how to best exploit this mechanism for the treatment of human amblyopia. It was initially hypothesized that silencing the retina via TTX injection would result in reduced activity in the dorsal lateral geniculate nucleus (dLGN), because the dLGN relays activity from retina to cortex. Surprisingly, this turned out to be incorrect; in actuality, neurons in the dLGN exhibit more spontaneous bursting activity following retinal inactivation. The proposed project will focus on investigating the hypothesis that this increase in dLGN burst mode firing is the mechanism by which retinal inactivation drives recovery from amblyopic rearing. To investigate this hypothesis, we will first describe dLGN activity following retinal inactivation via TTX with the use of chronic unit recordings. dLGN bursting will then be pharmacologically blocked to determine whether dLGN bursting is necessary for TTX mediated recovery from amblyopic rearing. Finally, dLGN burst-like activity will be imposed via optogenetic manipulation in order to determine whether bursting is sufficient to drive recovery from a period of amblyopic rearing. By enhancing our understanding of the role of dLGN activity in retinal inactivation induced recovery from amblyopic rearing, this project has the potential to inform our future research and suggest novel clinical approaches for treating amblyopia. This project will be carried out in the lab of Dr. Mark Bear in the Brain and Cognitive Sciences Department (BCS) at the Massachusetts Institute of Technology (MIT). The Bear lab contains all required equipment for the proposed project. All necessary training regarding required laboratory techniques will be provided by senior lab members or through collaboration with other labs in BCS. The Bear lab, BCS, and MIT will offer quality scientific and professional development resources to facilitate a successful transition into the next stage of the applicant’s research career.