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

阐明背外侧膝状核爆发模式放电在视网膜失活诱导的单眼剥夺恢复中的作用

• 批准号: 10609435
• 负责人: Madison Leet
• 金额: $ 4.77万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609435
• 关键词: Address; Adult; Age; Amaze; Amblyopia; Animal Model; Animals; Bilateral; Brain; Caregivers; Cells; Child; Chronic; Clinical; Cognitive Science; Collaborations; Development; Disease; Dorsal; Equipment; Excision; Excitatory Synapse; Exhibits; Eye; Felis catus; Fire - disasters; Functional disorder; Human; Individual; Infusion procedures; Injections; Injury; Laboratories; Lateral Geniculate Body; Massachusetts; Mediating; Medical; Methods; Mus; Nature; Neurons; Pathway interactions; Photic Stimulation; Recovery; Reporting; Research; Resistance; Resource Development; Retina; Role; Saline; Sensory Deprivation; Silicon; Slice; Sodium Channel Blockers; T-Type Calcium Channels; Techniques; Technology; Testing; Tetrodotoxin; Thalamic structure; Therapeutic; Time; Training; Vision Disorders; Visual; Visual Acuity; Visual impairment; Work; area striata; career; conventional therapy; disability; early childhood; experience; experimental study; in vivo; intravitreal injection; member; monocular deprivation; mouse model; novel; novel therapeutic intervention; optogenetics; pharmacologic; postsynaptic neurons; stem; vision development

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.

弱视是一种视觉系统发展的常见障碍，导致一只眼睛的视力差。 尽管已经进行了很多研究来了解该疾病的病理生理学，但治疗年龄较大 弱视的儿童和成人仍然是一个挑战。有趣的是，有临床报告 在移除后，可能会在成年人中表现出弱视眼的视力增长 由于受伤或疾病而导致的正常眼睛。在这些临床报告的激励下，我们的实验室最近发现 通过玻璃体内注射钠通道阻滞剂暂时使正常眼的视网膜沉默 四毒素（TTX）有效地促进CAT和小鼠模型的视力恢复 弱视。令人惊讶的是，这种治疗方法在较老的，更耐药的动物中有效，不会导致 注射眼睛的任何惩罚。通过阐明残留失活的机制促进 从动物模型中的弱视饲养时期恢复，我们有潜力确定如何最佳 利用这种机制来治疗人类弱视。最初假设使沉默 视网膜通过TTX注射会导致背侧遗传核（DLGN），，降低活性。 因为DLGN从视网膜到皮质的活性。令人惊讶的是，事实证明这是不正确的。实际上， 视网膜失活后，DLGN中的神经元表现出更多的赞助爆发活性。提议 项目将重点介绍以下假设：DLGN爆发模式的增加是机制 视网膜灭活使弱视饲养恢复。为了调查这一假设，我们将首先 通过使用慢性单位记录在视网膜灭活后描述DLGN活性。 DLGN 然后，将在药理上爆裂，以确定DLGN是否需要TTX的DLGN爆发 介导从弱视饲养中恢复。最后，DLGN爆发的活性将通过光遗传学施加 操纵以确定爆发是否足以从弱视时期驱动恢复 饲养。通过增强我们对DLGN活性在视网膜灭活中的作用的理解，引起了恢复 从弱视饲养中，该项目有可能告知我们未来的研究并建议新的临床 治疗弱视的方法。该项目将在大脑马克·贝尔博士的实验室中进行， 马萨诸塞州理工学院（MIT）的认知科学系（BCS）。熊实验室 包含拟议项目的所有必需设备。有关必需实验室的所有必要培训 技术将由高级实验室成员或通过与BCS中的其他实验室合作提供。熊 实验室，BCS和MIT将提供优质的科学和专业发展资源，以促进成功 过渡到申请人研究生涯的下一阶段。