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

描述(申请人提供)：哺乳动物新皮质的一个显著特征是它在一生中，特别是在早期发育期间具有显著的变化能力。因此， 每个人大脑的功能组织和连接都是根据特定环境的物理参数量身定做的，从而使行为能够针对给定的感觉环境进行独特的优化。这种可塑性在塑造正常人类的大脑方面发挥着不可或缺的作用，对于那些因视网膜异常或发生在发育不同阶段的皮质损伤而患有严重视觉障碍的人来说，也是如此。这项建议将调查在发育过程中对视觉系统进行实验诱导操作后皮质可塑性的程度。我们的第一个目标是研究感觉调节行为的变化，以及由于两种诱导神经损伤之一导致的新大脑皮层功能组织、连接性和细胞组成的变化：1)失去正常发育成视觉皮质的新皮质；2)失去通常由视网膜提供的视觉输入。第二个目标是确定早期、普遍的感觉增强是否可以用于指导新皮质的功能重组和优化感觉调节的行为。操作将在三个发育里程碑中的一个进行：1)在视网膜神经节细胞轴突进入间脑和丘脑皮质传入神经到达皮质之前。2)睁眼前、丘脑皮质传入神经支配新皮质后、轴突修剪和皮质发育完成前。3)就在眼睛睁开之后，视网膜脱离细胞和丘脑皮质发育完成，脑室下区和所有六层皮质都存在。这些动物将暴露在正常或触觉(对于双侧核)或视觉(对于皮质损伤)增强的环境中。我们的动物模型，短尾负鼠(Monodelphis Home Tica)是早产的，允许在发育时间点对神经系统进行宫外操作，而其他哺乳动物的神经系统可能是在宫内进行的。在动物成熟后，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、重组皮质的功能组织和神经反应特性、皮质和丘脑的连通性，以及重组皮质的细胞组成包括神经元数量和密度。这些研究在范围上是新颖的，提供了一个机会来转化在细胞和系统水平上获得的详细知识，以产生重要的治疗干预措施，旨在指导多感觉可塑性，并优化失明后感觉调节的行为。

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.