Regulation of Plasticity in the Developing Visual System

感觉系统的发展是通过一个先天的过程开始的，这个过程创造了基本的神经回路，随后在出生后通过经验加以完善。经验和大脑发育之间的重要协同作用在视觉系统中得到了体现，支持正常感知的神经回路的完善需要在出生后的早期——即所谓的关键时期——有通畅的视觉。正是在这一阶段，神经回路表现出最高的可塑性，也正是在这一阶段，高可塑性水平使感觉神经脉冲的级联模式能够指导大脑回路发育到成熟形式。随着年龄的增长，超过临界时期，稳定神经连接的可塑性能力自然下降，使其终生保持。我的实验室最近的研究表明，关键时期的时间是由可塑性促进和抑制分子的发育调节平衡决定的。可塑性促进因子在发育早期占主导地位，而在年龄较大时，抑制因子积累以稳定神经回路并降低可塑性潜力。我们目前对调节神经可塑性的分子和过程只有表面的了解，对高等哺乳动物几乎一无所知。最近在动物模型和人类中操纵可塑性水平的失败尝试表明，我们对整个发育过程中控制可塑性的因素的理解存在重大差距。我的研究计划的重点是调查这些知识差距，以了解控制神经可塑性的特征，最终目标是阐明能够操纵大脑可塑性的原则。我和我的学员们提出了三个项目，作为这个建议的基础。（项目1）：我们将研究一系列假定的可塑性抑制剂，我们认为它们的特征适合在发育过程中巩固神经回路。（项目2）：我们将研究一个新的有趣的假设，即蛋白质的翻译后修饰是一个自然的发育过程，它赋予神经稳定性，从而抑制可塑性。（项目3）：我们的最终项目将采用一种实验操作，旨在降低塑性抑制因子的水平，并在正常情况下较低的年龄提高塑性能力。我们的建议旨在为大脑可塑性和发育的机制提供基本的见解。如何操纵这些机制，以及操纵这些机制会带来什么好处，是指导我们长期愿景的主要问题。这些项目的结果将在系统神经科学领域具有变革性，因为它揭示了改变整个生命的可塑性能力的现实途径，这是神经科学的前沿目标，也是我的实验室发挥主导作用的研究领域。

The development of sensory systems is initiated through an innate process that creates rudimentary neural circuits subsequently refined postnatally by experience. The important synergy that exists between experience and brain development is exemplified in the visual system where the refinement of neural circuits that support normal perception requires unobstructed vision early in postnatal life - during the so-called critical period. It is during this stage that neural circuits exhibit their highest capacity for plasticity, and is when high plasticity levels enable cascading patterns of sensory neural impulses to direct development of brain circuits to their mature form. With increasing age beyond the critical period there is a natural decline in plasticity capacity that acts to stabilize neural connections preserving them for a lifetime. Recent studies from my lab suggest that the timing of the critical period is governed by a developmentally-regulated balance of plasticity facilitating and inhibiting molecules. Plasticity facilitators dominate early in development, whereas at older ages inhibitors accumulate to stabilize neural circuits and reduce plasticity potential. We currently have only a surface understanding of the molecules and processes that regulate neural plasticity, and almost nothing is known in higher mammals. Recent failed attempts to manipulate plasticity levels in animal models and in humans have revealed a significant gap in our understanding of the factors that govern plasticity throughout development. The focus of my research program is to investigate these knowledge gaps to understand characteristics that govern neural plasticity with the ultimate goal of elucidating principles that will enable manipulation of brain malleability. My trainees and I propose three projects that form the basis of this proposal. (Project 1): We will examine a collection of putative plasticity inhibitors whose characteristics we believe are suited to consolidate neural circuitry during development. (Project 2): We will investigate a new and intriguing hypothesis that post-translational modification of proteins is a natural developmental process that confers neural stability and therefore acts to inhibit plasticity. (Project 3): Our final project will employ an experimental manipulation aimed to reduce levels of plasticity inhibitors and elevate plasticity capacity at ages when it would normally be low. Our proposal aims to contribute fundamental insight into the mechanisms that govern brain plasticity and development. How these mechanisms can be manipulated and what benefits arise from their manipulation are principal questions that guide our long-term vision. Results from these projects will be transformative in the field of systems neuroscience by revealing a realistic path to alter plasticity capacity throughout life, an objective that is at the forefront of neuroscience, and is a research area in which my lab has played a leading role.