Investigation of Structural Plasticity Mechanisms in the Mammalian Visual System

哺乳动物视觉系统结构可塑性机制的研究

• 批准号: RGPIN-2015-05320
• 负责人: Duffy, Kevin
• 金额: $ 1.75万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=631156
• 关键词: Investigation; Structural; Plasticity; Mechanisms; Mammalian

Visually-driven experience early in postnatal life modulates the development of neuron structure and the arrangement of neural connections in the visual system. A disruption to visual experience during this formative period, as can occur with congenital cataracts or misaligned eyes, causes the structure of neurons within visual brain areas to develop abnormally and can result in severe visual impairments. The objective of this research is to provide a fundamental understanding of the cellular events that enable the modification of neuron structure (plasticity) in the context of circumstances that lead to functional impairments. Through this work we aim to facilitate the development of novel strategies to enhance neural plasticity in the pursuit of more effective ways to promote neural recovery. Inherent in this objective is an attempt to understand the neural processes that naturally and progressively diminish the capacity for plasticity with age, and that consequently explain the limited neural recovery reported in juvenile and adult visual system. We will build upon our previous research showing that neural plasticity is reduced with age by the progressive accumulation of a collection of intracellular proteins called intermediate filaments. Once produced by neurons, these proteins are known to be highly susceptible to modification by phosphorylation, which we propose reduces plasticity by enhancing protein stability. We will measure the level of protein phosphorylation across development and during episodes of structural plasticity to determine if phosphorylation contributes as a plasticity ‘brake’, and furthermore whether its reduction is linked to neural recovery. In a related study we will measure the activity of several brain enzymes (proteases) with conceivable links to plasticity in order to determine if the modification of neurons is mediated by an active proteolytic removal of protein ‘brakes’ that constrain plasticity. In the final set of experiments we will investigate a novel hypothesis that the mechanisms of plasticity observed early in postnatal life are also present in the adult brain, but maintain a higher threshold for their engagement. We will examine this question by measuring the mechanistic similarity between plasticity induced at young and adult stages of development. These studies will offer new and important insight into the cellular events that naturally regulate neural plasticity with age, and that enable the structural modification of neurons during periods of abnormal visual input that are known to precipitate the development of functional impairments. Finally, we expect these studies will provide a clearer mechanistic understanding of the factors that yield poor neural plasticity outcomes initiated in adolescence and adulthood.

出生后早期的视觉驱动体验调节了视觉系统中神经元结构的发育和神经连接的排列。在这个形成期，视觉体验的中断，如先天性白内障或眼睛错位，会导致视觉大脑区域内的神经元结构发育异常，并可能导致严重的视觉障碍。这项研究的目的是提供一个基本的理解，使修改神经元结构（可塑性）的情况下，导致功能障碍的细胞事件。通过这项工作，我们的目标是促进新的策略，以提高神经可塑性的发展，在追求更有效的方法来促进神经恢复。内在的这个目标是试图了解神经过程，自然和逐渐减少可塑性的能力，随着年龄的增长，从而解释有限的神经恢复报告在青少年和成人的视觉系统。我们将建立在我们以前的研究表明，随着年龄的增长，神经可塑性降低的细胞内蛋白质的集合称为中间丝的渐进积累。一旦由神经元产生，已知这些蛋白质非常容易受到磷酸化修饰，我们提出通过增强蛋白质稳定性来降低可塑性。我们将测量整个发育过程中和结构可塑性发作期间蛋白磷酸化的水平，以确定磷酸化是否有助于可塑性“刹车”，以及其减少是否与神经恢复有关。在一项相关的研究中，我们将测量几种与可塑性有可能联系的脑酶（蛋白酶）的活性，以确定神经元的修饰是否是通过蛋白质的主动蛋白水解去除来介导的。在最后一组实验中，我们将研究一个新的假设，即在出生后早期观察到的可塑性机制也存在于成人大脑中，但保持更高的参与阈值。我们将研究这个问题，通过测量可塑性之间的机制相似性诱导在年轻和成年阶段的发展。这些研究将提供新的和重要的见解，自然调节神经可塑性与年龄的细胞事件，并使神经元的结构修改期间异常的视觉输入，已知沉淀功能障碍的发展。最后，我们希望这些研究将提供一个更清晰的机制的理解，产生不良的神经可塑性结果开始在青春期和成年期的因素。