Can Cortical Plasticity be Directed and Amplified Following Early Loss of Vision?

描述（由申请人提供）：哺乳动物新皮层的一个显著特征是其在一生中发生变化的显著能力，特别是在早期发育期间。因此 每个人的大脑的功能组织和连接是根据特定环境的物理参数定制的，允许行为针对给定的感官环境进行独特的优化。这种可塑性在塑造正常人的大脑中起着不可或缺的作用，以及那些由于视网膜异常或在不同发育阶段发生的皮质病变而患有严重视觉障碍的人。这项建议将调查皮层可塑性的程度以下实验诱导的操纵视觉系统在发展过程中。我们的第一个目标是检查感觉介导的行为的改变，以及由两种诱导的神经损伤之一引起的新皮层的功能组织、连接和细胞组成的变化：1）正常发育成视觉皮层的新皮层的丧失; 2）正常由视网膜提供的视觉输入的丧失。第二个目标是确定早期的、普遍的感觉增强是否可以用于指导新皮层的功能重组和优化感觉介导的行为。操作将在三个发育里程碑之一时进行：1）在视网膜神经节细胞轴突进入间脑之前和在丘脑皮质传入神经到达皮质之前。2)在睁眼之前，在丘脑皮层传入神经支配新皮层之后，但在轴突修剪和皮层发育完成之前。3)眼睛刚睁开后，离视网膜和丘脑皮质发育建立，脑室下区和所有六个皮质层都存在。这些动物将暴露于正常或视觉（双侧去核）或视觉（皮质病变）增强环境。我们的动物模型，短尾负鼠（Monodelphis arctica）早产，允许在发育时间点对神经系统进行子宫外操作，而其他哺乳动物则在子宫内。在动物达到成熟后，我们将使用行为测试结合电生理和神经解剖学技术来检查感觉辨别，重组皮层的功能组织和神经反应特性，皮层和丘脑连接，以及重组皮层的细胞组成，包括神经元数量和密度。这些研究在其范围内是新颖的，提供了一个机会来翻译在细胞和系统水平上获得的详细知识，以产生旨在指导多感觉可塑性的重要治疗干预措施，并优化视觉丧失后的感觉介导行为。

DESCRIPTION (provided by applicant): A distinguishing feature of the mammalian neocortex is its remarkable ability to change over a lifetime, especially during early development. Thus, the functional organization and connectivity of each individual's brain is tailored to the physical parameters of a specific environment, permitting behavior to be uniquely optimized for a given sensory milieu. Such plasticity plays an integral role in shaping the brains of normal humans as well those who suffer from severe visual impairments due to retinal abnormalities or cortical lesions that occur at various stages of development. This proposal will investigate the extent of cortical plasticity following experimentally induced manipulations to the visual system during development. Our first objective is to examine the alterations in sensory mediated behavior, as well as changes in the functional organization, connectivity and cellular composition of the neocortex that result from one of two induced neural insults: 1) loss of neocortex that would normally develop into visual cortex; 2) loss of visual input normally provided by the retina. The second objective is to determine if early, pervasive sensory enhancement can be used to direct the functional reorganization of the neocortex and optimize sensory mediated behavior. Manipulations will be made at one of three developmental milestones: 1) Before retinal ganglion cell axons enter the diencephalon and before thalamocortical afferents have reached the cortex. 2) Before eye opening, after thalamocortical afferents have innervated the neocortex, but before axonal pruning and the completion of cortical development. 3) Just after the eyes have opened, when retinofugal and thalamocortical development is established and the subventricular zone and all six cortical layers are present. These animals will be exposed to either a normal or to a tactilely (for bilateral enucleates) or visually (for cortical lesions) enhanced environment. Our animal model, the short-tailed opossum (Monodelphis domestica) is born prematurely, allowing ex-utero manipulations to the nervous system at developmental time points that would be in-utero in other mammals. After the animals have reached maturity we will use behavioral testing combined with electrophysiological and neuroanatomical techniques to examine sensory discrimination, the functional organization and neural response properties of re-organized cortex, cortical and thalamic connectivity, and the cellular composition including neuronal number and density of re-organized cortex. These studies, which are novel in their scope, provide an opportunity to translate detailed knowledge gained at the cellular and systems level to produce significant therapeutic interventions designed to direct multisensory plasticity, and optimize sensory mediated behavior following loss of vision.