Critical Period Plasticity Following Neonatal Brain Injury

描述（由申请人提供）：该项目的总体目标是了解早期脑损伤对后续脑可塑性的影响。一种普遍的看法是，新生儿脑损伤的恢复是由未成熟大脑的可塑性增强。然而，损伤通常会导致永久性的神经功能缺损，因此需要更详细地了解损伤后的可塑性。这一建议侧重于研究最充分的皮质可塑性模型——双目哺乳动物视觉系统中的眼优势。眼优势可塑性（ODP）是指单眼被剥夺后眼特异性输入强度的变化。与之密切相关的人类疾病是弱视。该模型的一个优点是最近在确定控制关键时期时间的因素方面取得了进展，包括皮层抑制回路的成熟和髓鞘形成。该项目使用了早期缺氧缺血性脑损伤的小动物（大鼠和小鼠）模型。利用该模型，我们发现ODP受到了损害。除了受伤最严重的动物外，所有动物的视觉皮层发育基本正常。然而，ODP受损并不是一个孤立的发现，因为体感觉皮层的可塑性也减弱了。在这个模型中，我们报道了亚板神经元的选择性易感性，亚板神经元是一种对视觉丘脑皮质发育很重要的暂时性新皮层神经元。目前尚不清楚为什么早期板下神经元死亡会限制随后的可塑性。然而，早期活动通过涉及亚板神经元的瞬态电路传递到新皮层。我们的假设是，由于底板神经元的丧失，皮层兴奋减弱，破坏了活动依赖的皮层回路的成熟和完善。与这一观点一致，我们发现损伤后皮层抑制性神经元标志物的表达减少和改变。随着这一模型的发展，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。为了实现这一目标，我们的具体目标是：(1)确定早期HI后抑制改变的机制及其与ODP受损的关系；(2)测量早期HI后髓鞘破坏对ODP的影响。用本征信号光学成像对ODP进行量化。用组织学、免疫荧光和蛋白质生化研究抑制回路和髓鞘形成。我们将尝试通过药物或生长因子治疗、前体细胞移植、功能阻断抗体或使用现有的转基因小鼠模型来克服皮质抑制和髓鞘形成中已确定的缺陷，从而恢复可塑性。这些实验将为底板神经元在皮层回路成熟和ODP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测量和模型，以指导脑损伤后功能性皮质连接的再生策略。公共卫生相关性：新生儿脑损伤是难产或早产以及先天性心脏病婴儿的常见问题。该项目的总体目标是了解新生儿脑损伤对随后大脑可塑性的影响，即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为脑功能恢复的治疗提供新的结果测量和模型。

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.