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: 10464250
• 负责人: Madison Leet
• 金额: $ 4.68万
• 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/10464250
• 关键词: Address; Adult; Age; 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; Institutes; Laboratories; Lateral Geniculate Body; Massachusetts; Mediating; Medical; Methods; Mus; Nature; Neurons; Pathway interactions; Pharmacology; 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; Ursidae Family; 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; optogenetics; postsynaptic neurons; stem; treatment strategy; 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.

弱视是一种常见的视觉系统发育障碍，导致一只眼睛的视力下降。 尽管已经有很多研究来了解这种疾病的病理生理学，但治疗老年患者 患有弱视的儿童和成人仍然是一个挑战。 这表明成人弱视眼摘除后视力可能会提高 受这些临床报告的启发，我们的实验室最近发现，由于受伤或疾病而导致的正常眼睛。 通过玻璃体内注射钠通道阻滞剂暂时抑制正常眼的视网膜 河豚毒素 (TTX) 可有效促进猫和小鼠模型视力的恢复 令人惊讶的是，这种治疗方法对年龄较大、治疗抵抗力更强的动物有效，并且不会引起弱视。 通过阐明促进视网膜失活的机制，可以减少对注射眼的任何惩罚。 从动物模型中弱视饲养一段时间的恢复中，我们有潜力确定如何最好地 利用这种机制来治疗人类弱视最初是通过沉默来实现的。 通过 TTX 注射视网膜会导致背外侧膝状核 (dLGN) 的活性降低， 因为 dLGN 将活动从视网膜传递到皮层，但令人惊讶的是，这实际上是不正确的； dLGN 中的神经元在视网膜失活后表现出更多的自发爆发活动。 项目将重点研究以下假设：dLGN 突发模式发射的增加是其机制 视网膜失活通过何种机制促进弱视养育的恢复。为了研究这一假设，我们首先要研究这一假设。 使用慢性单位记录描述通过 TTX 视网膜失活后的 dLGN 活性。 然后通过药理学阻断 dLGN 爆发，以确定 TTX 是否需要 dLGN 爆发 最后，dLGN 爆发样活动将通过光遗传学施加。 以确定突发是否足以推动弱视期的恢复 通过增强我们对 dLGN 活性在视网膜失活诱导恢复中的作用的理解。 从弱视饲养来看，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 该项目将在 Mark Bear 博士的大脑实验室中进行。 麻省理工学院 (MIT) 认知科学系 (BCS)。 包含拟议项目所需的所有设备。有关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。 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 过渡到申请人研究生涯的下一阶段。