Enhancing Dendritic Inhibition for the Control of Critical Period Plasticity

增强枝晶抑制以控制关键期塑性

• 批准号: 9356313
• 负责人: Courtney Yaeger
• 金额: $ 3.54万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9356313
• 关键词: Acetylcholine; Acute; Address; Adolescent; Adult; Age; Amblyopia; Arousal; Attention; Blindness; Cells; Cholinergic Receptors; Data; Dendritic Cells; Development; Disease; Disinhibition; Educational workshop; Elderly; Genetic; Goals; Injury; Interneurons; Investigation; Learning; Link; Maps; Measures; Mediating; Microscopy; Mus; Natural regeneration; Nerve Degeneration; Neurons; Pathway interactions; Physiological; Plasticizers; Proteins; Pyramidal Cells; Recovery; Sensory; Slice; Somatostatin; TNFRSF5 gene; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Treatment Efficacy; Up-Regulation; Vasoactive Intestinal Peptide; Vision; Vision Disorders; Visual; Visual Cortex; Visual Perception; Visual system structure; age group; cell type; cholinergic; critical period; excitatory neuron; experience; hippocampal pyramidal neuron; in vivo; in vivo calcium imaging; inhibitory neuron; neural circuit; novel; novel therapeutics; response; therapeutic target; tool; two-photon; vision development

Project Summary/Abstract Globally, millions of people suffer loss of vision as a result of injury, degeneration, or improperly formed neural circuitry within the visual system. While there are many efforts to regenerate inputs to the visual cortex, any successful therapy must include the integration of new inputs into existing cortical circuitry. During normal visual development, this occurs as a result of heightened sensory plasticity during a limited time window, referred to as a critical period. It is not understood how critical period plasticity can be re-opened in adulthood for effective therapeutic strategies. Furthermore, inhibition and cholinergic modulation are known components of critical period plasticity but have yet to be linked. My preliminary data demonstrates a common pathway for these mechanisms: out of the major inhibitory interneuron groups, only somatostatin-expressing (SST) interneurons undergo a reversal in their response during attentive vision at the closure of the critical period. While it is known that SST interneurons mediate pyramidal cell dendritic activity during attention in adults, it is not known how cholinergic inputs are directly acting on SST interneurons to alter dendritic activity during critical period plasticity. My working hypothesis is that the shift in modulation of SST cells alters dendritic learning rules to close the critical period. Here I am proposing two specific aims to address the challenge of re- establishing strong plasticity in the adult cortex. In Aim 1, in order to understand how cholinergic inputs may be changing in the transition to adulthood, I will test cholinergic inputs to SST interneurons across age groups using channelrhodopsin-assisted circuit mapping. In Aim 2, I will use in vivo two-photon microscopy to compare normal SST responses to those seen in mice lacking a cholinergic receptor antagonist, Lynx1, which is an essential component for critical period closure. These aims should advance a circuit-level understanding of how plasticity becomes limited in adulthood and will inform novel therapeutic strategies for visual disorders.

项目总结/摘要 在全球范围内，数百万人因受伤、退化或神经系统发育不良而丧失视力。 视觉系统中的电路。虽然有许多努力来再生视觉皮层的输入，但任何 成功的治疗必须包括将新的输入整合到现有的皮层回路中。在正常 视觉发育，这是由于在有限的时间窗口内提高了感官可塑性， 被称为关键时期。目前尚不了解关键期可塑性如何能在成年期重新开启 有效的治疗策略。此外，抑制和胆碱能调节是已知的组分， 关键期的可塑性，但尚未联系起来。我的初步数据显示， 这些机制：在主要的抑制性中间神经元群中，只有生长抑素表达（SST） 中间神经元在关键期结束时的专注视觉期间经历其反应的逆转。 虽然已知SST中间神经元在成人注意期间介导锥体细胞树突活性，但它是不可能的。 尚不清楚胆碱能输入如何直接作用于SST中间神经元以改变树突活动， 临界期塑性我的工作假设是，SST细胞调节的转变改变了树突状细胞， 学习规则关闭关键期。在此，我提出两个具体目标，以应对重新调整的挑战。 在成年人的大脑皮层中建立了强大的可塑性。在目标1中，为了理解胆碱能输入如何 在向成年过渡的过程中发生变化，我将测试不同年龄组的SST中间神经元的胆碱能输入 使用通道视紫红质辅助电路映射。在目标2中，我将使用体内双光子显微镜， 将正常SST反应与缺乏胆碱能受体拮抗剂Lynx 1的小鼠中观察到的SST反应进行比较， 是关键时期关闭的一个重要组成部分。这些目标应该能促进电路级的理解 关于可塑性在成年期是如何受到限制的，并将为视觉障碍的新治疗策略提供信息。