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Dissecting the role of aggrecan and perineuronal nets in visual plasticity

剖析聚集蛋白聚糖和神经周围网络在视觉可塑性中的作用

基本信息

批准号：
10753758
负责人：
Aaron W McGee
金额：
$ 48.26万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753758
关键词：
Adult Affect Alleles Amblyopia Animal Model Behavioral Assay Brain Calcium Childhood Chondroitin ABC Lyase Chondroitin Sulfate Proteoglycan Depth Perception Development Disease Disinhibition Dissection Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Enzymes Equilibrium Extracellular Structure Eye Functional disorder Gene Expression Genes Genetic Image Impairment In Vitro Injections Injury Interneurons Knowledge Lazy Eyes Measures Mission Modeling Mus Nerve Degeneration Neuronal Plasticity Neurons Ocular Dominance Parvalbumins Population Property Public Health Rattus Recovery Research Role Signal Pathway Slice Source Stains Study models Synapses Testing Therapeutic Therapeutic Intervention Time United States National Institutes of Health Vision Vision Disorders Visual Visual Acuity Visual Cortex Visual System Visual impairment aggrecan area striata autism spectrum disorder brain circuitry chondroitin sulfate glycosaminoglycan clinically relevant conditional mutant critical developmental period critical period dark rearing effective therapy excitatory neuron experience experimental study flexibility genetic manipulation improved in vivo in vivo calcium imaging monocular deprivation neural circuit neuronal excitability neurotransmission progenitor response selective expression spatial vision targeted treatment visual plasticity

项目摘要

Summary Critical periods are time windows during development when experience-dependent plasticity is most robust. The developing visual system in the premier model for studying how circuits modified by experience-dependent plasticity are consolidated when a critical period closes. This model is clinically relevant because the closure of the visual critical period is implicated in the pathophysiology of amblyopia, a childhood visual disorder characterized by deficits in spatial vision including poor visual acuity and impaired depth perception. Effective therapy is more difficult after the critical period closes because the brain is less plastic. In animal models of amblyopia, monocular deprivation (MD) causes lasting deficits in ocular dominance (OD), binocular depth perception, and visual acuity. The closure of the critical period is coincident with the maturation of perineuronal nets in visual cortex, but how these extracellular structures may limit plasticity is not understood. In the proposed research, we will determine the role and cellular source of aggrecan, a principal component of perineuronal nets, in closing the developmental critical period for plasticity in visual circuits. Our hypothesis is that aggrecan operates outside of perineuronal nets to close the critical period. We will use a combination of behavioral assays of vision, multi-unit electrophysiology, calcium imaging in vivo, and slice electrophysiology in vitro, and genetic manipulations to determine how aggrecan regulates the plasticity of visual circuits. This project will improve understanding of the mechanisms by which experience-dependent plasticity is restricted in the maturing brain and may reveal new avenues for developing therapeutic approaches to treat developmental visual disorders such as amblyopia and central visual impairment.

摘要关键期是发育过程中的时间窗口，此时依赖经验的可塑性最强。研究经验依赖改变电路的首要模型中发展的视觉系统当一个关键期结束时，塑性就会得到巩固。这一模型具有临床意义，因为视觉关键期与弱视的病理生理学有关，弱视是一种儿童视觉障碍。以空间视觉缺陷为特征，包括视觉敏锐度差和深度知觉受损。有效在关键期关闭后，治疗变得更加困难，因为大脑的可塑性较小。在动物模型中弱视，单眼剥夺(MD)会导致眼优势(OD)、双眼深度的持续性缺陷知觉和视觉敏锐度。临界期的关闭与周围神经细胞的成熟是一致的。但这些细胞外结构如何限制可塑性还不清楚。在拟议的研究中，我们将确定aggrecan的作用和细胞来源，aggrecan是一种主要的神经周围神经网络的组成部分，在关闭视觉回路可塑性的发育关键期。我们的假说认为，aggrecan在周围神经网之外活动，以关闭临界期。我们将使用视觉、多单位电生理学、体内钙成像和切片的行为分析相结合体外电生理学和基因操作以确定聚集素如何调节视觉的可塑性电路。这个项目将提高对依赖经验的可塑性的机制的理解限制在成熟的大脑中，并可能揭示开发治疗方法的新途径发育性视力障碍，如弱视和中枢性视力障碍。