Critical Period Plasticity Following Neonatal Brain Injury

描述（由申请人提供）：本项目的总体目标是了解早期脑损伤对随后脑可塑性的影响。一个普遍的看法是，新生儿脑损伤的恢复是由未成熟大脑的可塑性增强。然而，损伤往往会导致永久性的神经功能缺损，这突出了对损伤后可塑性更详细理解的必要性。这项建议的重点是最好的研究模型的皮质可塑性-眼优势的视觉系统的双眼哺乳动物。眼优势可塑性（ODP）是指单眼剥夺后眼特异性输入强度的变化。人类的一种密切相关的情况被称为弱视。该模型的一个优点是最近的进展，确定控制关键期的时间，包括成熟的皮层抑制电路和髓鞘形成的因素。该项目使用了一种非常早期的缺氧缺血性脑损伤的平移小动物（大鼠和小鼠）模型。使用这个模型，我们发现ODP受损。除了受伤最严重的动物外，所有动物的视觉皮层发育都很正常。然而，受损的ODP不是一个孤立的发现，因为躯体感觉皮层的可塑性也减少了。在这个模型中，我们已经报道了选择性的脆弱性subplate神经元，一个短暂的新皮层神经元的视觉丘脑皮层发育的重要人口。目前还不清楚为什么早期的亚板神经元死亡会限制随后的可塑性。然而，早期活动通过涉及底板神经元的瞬态回路传递到新皮层。我们的假设是，减少皮层兴奋，从基板神经元的损失，破坏活动依赖的成熟和完善的皮层电路。与这一想法一致，我们发现减少和改变皮质抑制性神经元标记物的表达损伤后。随着该模型的发展，我们现在定位于研究特定的可塑性机制在新生儿脑损伤恢复中的作用。为了实现这一点，我们的具体目标是：（1）确定早期HI后抑制作用改变的机制及其与受损ODP的关系;（2）测量早期HI后髓鞘形成中断对ODP的影响。ODP用固有信号光学成像定量。用组织学、免疫荧光和蛋白质生物化学研究抑制回路和髓鞘形成。我们将尝试通过药理学或生长因子治疗、移植前体细胞、功能阻断抗体或使用现有的转基因小鼠模型来特异性克服皮质抑制和髓鞘形成中的缺陷，从而恢复可塑性。这些实验将为亚板神经元在皮层回路和ODP成熟中的正常作用提供基本的见解。了解受损的可塑性将提供一种新的功能结果的措施和模型，以指导脑损伤后功能皮层连接再生的策略。 公共卫生相关性：新生儿脑损伤是难产或早产以及患有先天性心脏病的婴儿的常见问题。该项目的总体目标是了解新生儿脑损伤对随后的大脑可塑性的影响，大脑通过形成和修改神经元之间的连接来改变的能力。了解损伤后的可塑性将提供一个新的结果测量和模型，以指导治疗恢复脑功能。

DESCRIPTION (provided by applicant): The overall goal of this project is to understand the impact of early brain injury on subsequent brain plasticity. A common perception is that recovery from neonatal brain injury is augmented by plasticity of the immature brain. Yet often injury results in permanent neurologic deficits, highlighting the need for more detailed understanding of plasticity following injury. This proposal focuses on the most well studied model of cortical plasticity -- ocular dominance in the visual system of binocular mammals. Ocular dominance plasticity (ODP) refers to the change in strength of eye-specific inputs following monocular deprivation. A closely related condition in humans is known as amblyopia. An advantage of the model is recent progress identifying the factors controlling critical period timing, including maturation of cortical inhibitory circuits and myelination. The project uses a translational small animal (rat and mouse) model of very early hypoxic-ischemic brain injury. Using this model, we find that ODP is impaired. Visual cortical development is grossly normal in all but the most severely injured animals. Yet, impaired ODP is not an isolated finding, as plasticity in somatosensory cortex is also diminished. In this model, we have reported the selective vulnerability of subplate neurons, a transient population of neocortical neurons important for visual thalamocortical development. It is unclear why early subplate neuron death would restrict subsequent plasticity. However, early activity is transmitted into neocortex through transient circuits involving subplate neurons. Our hypothesis is that diminished cortical excitation, resulting from loss of subplate neurons, disrupts activity-dependent maturation and refinement of cortical circuits. Consistent with this idea, we find diminished and altered expression of cortical inhibitory neuronal markers following injury. With the development of this model, we are now positioned to investigate the role of specific plasticity mechanisms in recovery from neonatal brain injury. To accomplish this, our specific aims are: (1) determine the mechanism of altered inhibition following early HI and its relationship to impaired ODP and (2) measure the effect of disrupted myelination on ODP following early HI. ODP is quantified with intrinsic signal optical imaging. Inhibitory circuits and myelination are studied with histology, immunofluorescence and protein biochemistry. We will attempt to restore plasticity by specifically overcoming identified defects in cortical inhibition and myelination by pharmacologic or growth factor treatment, grafting of precursor cells, function blocking antibodies or the use of existing genetically modified mouse models. These experiments will offer fundamental insight into the normal role of subplate neurons in the maturation of cortical circuits and ODP. Understanding impaired plasticity will provide both a novel functional outcome measure and a model to guide strategies for regenerating functional cortical connections following brain injury. PUBLIC HEALTH RELEVANCE: Brain injury in the newborn is a common problem following difficult or premature birth and in babies with congenital heart disease. The overall goal of this project is to understand the impact of newborn brain injury on subsequent brain plasticity, the ability of the brain to change by forming and modifying connections between neurons. Understanding plasticity following injury will provide both a new outcome measure and a model to guide therapy for recovering brain function.