Investigation of Structural Plasticity Mechanisms in the Mammalian Visual System

在出生后的早期，视觉驱动的经历调节了视觉系统中神经元结构的发展和神经连接的安排。在这个形成期，视觉体验的中断，就像先天性白内障或眼睛错位可能发生的那样，会导致视觉脑区内神经元的结构发育异常，并可能导致严重的视觉障碍。这项研究的目的是在导致功能损伤的情况下，提供对使神经元结构(可塑性)改变的细胞事件的基本理解。通过这项工作，我们的目的是促进新策略的发展，以增强神经可塑性，追求更有效的方法，促进神经恢复。这一目标的内在目的是试图了解神经过程，这种神经过程自然地和逐渐地降低了可塑性的能力随着年龄的增长，从而解释了在青少年和成人视觉系统中报道的有限的神经恢复。我们将以之前的研究为基础，表明随着年龄的增长，神经可塑性会随着年龄的增长而降低，这是因为一系列称为中间丝的细胞内蛋白质逐渐积累。这些蛋白质一旦由神经元产生，就被认为非常容易被磷酸化修饰，我们认为这会通过增强蛋白质的稳定性来降低可塑性。我们将测量蛋白质在发育过程中和结构可塑性阶段的磷酸化水平，以确定磷酸化是否有助于可塑性的“刹车”，以及它的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关的脑酶(蛋白水解酶)的活性，以确定神经元的修饰是否是通过主动蛋白分解移除限制可塑性的蛋白质“刹车”来介导的。在最后一组实验中，我们将调查一个新的假设，即在出生后早期观察到的可塑性机制也存在于成年人的大脑中，但保持着更高的参与门槛。我们将通过测量幼年和成年发育阶段诱导的可塑性之间的机械相似性来检验这个问题。这些研究将为细胞事件提供新的和重要的见解，这些细胞事件自然地调节神经的可塑性随着年龄的增长，并使神经元在异常视觉输入期间的结构改变，这是已知的加速功能障碍的发展。最后，我们期望这些研究将为青春期和成年期产生不良神经可塑性结果的因素提供更清晰的机制理解。

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.