Investigation of Structural Plasticity Mechanisms in the Mammalian Visual System

出生后早期的视觉驱动经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。在这一形成时期，视觉体验的中断，如先天性白内障或眼睛错位，会导致大脑视觉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。本研究的目的是提供一个基本的细胞事件的理解，使神经元结构的修改（可塑性）在导致功能障碍的情况下。通过这项工作，我们的目标是促进新策略的发展，以提高神经可塑性，追求更有效的方法来促进神经恢复。这一目标的内在目的是试图理解随着年龄增长而自然地逐渐减少可塑性能力的神经过程，从而解释青少年和成人视觉系统中有限的神经恢复。我们将在我们之前的研究基础上，表明神经可塑性随着年龄的增长而降低，这是由于细胞内一种被称为中间细丝的蛋白质的逐渐积累。一旦由神经元产生，这些蛋白质就非常容易受到磷酸化修饰的影响，我们认为磷酸化可以通过增强蛋白质稳定性来降低可塑性。我们将测量蛋白质磷酸化水平在整个发育过程和结构可塑性期间，以确定磷酸化是否作为可塑性的“制动器”，以及它的减少是否与神经恢复有关。在一项相关研究中，我们将测量几种与可塑性相关的脑酶（蛋白酶）的活性，以确定神经元的修饰是否通过去除限制可塑性的蛋白质“制动器”的活性蛋白水解来介导。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。我们将通过测量年轻和成年发育阶段的可塑性之间的机制相似性来检验这个问题。这些研究将为随着年龄的增长自然调节神经可塑性的细胞事件提供新的和重要的见解，并使神经元在异常视觉输入期间的结构修改成为可能，而异常视觉输入会导致功能障碍的发展。最后，我们希望这些研究将提供一个更清晰的机制理解的因素，产生不良的神经可塑性结果开始在青春期和成年期。

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.