Cortical Circuit Formation and Plasticity Following Neonatal Brain Injury

 描述(由申请人提供)：早产婴儿有脑损伤和长期神经和认知缺陷的风险。目前，还没有预防或治疗早产儿脑损伤的治疗方法，而且对一系列长期神经后遗症背后的神经机制也知之甚少。缺氧是弥漫性白质损伤(DWMI)和神经元/轴突异常的危险因素。先前的工作表明，慢性亚致死性缺氧(CSH)引起的新生小鼠的DWMI和髓鞘减少可以通过缺失A1腺苷受体(A1AR)来预防，A1腺苷受体在大脑中普遍表达。因此，腺苷能系统是旨在预防和/或改善围产期脑损伤长期影响的治疗的一个有吸引力的靶点。然而，腺苷信号在介导低氧对长期神经回路功能影响中的作用尚不清楚。我们最近获得的初步数据显示，新生小鼠的CSH导致初级视皮层(V1)轴突连接模式和突触可塑性的持久扰动。总之，这些表型提供了一个独特的机会来确定特定皮质回路对围产期损伤的发育和可塑性的易损性窗口，并确定A1ARs是否介导了新生儿缺氧对长期突触连接和可塑性的影响。我们假设V1的皮质回路连通性和功能对低氧暴露的时间很敏感，A1AR介导了新生儿低氧对V1的突触连通性、可塑性和视觉学习的影响。我们将通过以下具体目标的实验来验证我们的假设：(1)确定新生儿缺氧的时间和持续时间如何影响V1区的突触连通性和可塑性；(2)确定A1ARs在多大程度上介导缺氧对V1区轴突连通性和突触可塑性的影响。我们预计，我们的发现将填补关于如何 围产期侮辱的时机影响皮质环路的形成和长期可塑性。此外，它们将为腺苷能系统在早产儿脑损伤中的作用提供新的见解，并揭示预防和/或治疗这种损伤及其长期后果的潜在治疗靶点。

 DESCRIPTION (provided by applicant): Infants born premature are at risk for brain injury and long-term neurological and cognitive deficits. Currently, there is no treatment for preventing or treating premature brain injury and the neural mechanisms underlying the array of long-term neurological sequelae are poorly understood. Hypoxia is a risk factor for diffuse white matter injury (DWMI) and neuronal/axonal abnormalities. Previous work has shown that DWMI and decreased myelin caused by chronic sublethal hypoxia (CSH) in neonatal mice are prevented by deletion of A1 adenosine receptors (A1ARs), which are ubiquitously expressed in the brain. Thus, the adenosinergic system is an attractive target for therapies aimed at preventing and/or ameliorating the long-term effects of perinatal brain injury. However, the role of adenosine signaling in mediating the effects of hypoxia on long-term neural circuit function is unknown. We recently obtained preliminary data showing that CSH in neonatal mice causes lasting perturbations in axonal connectivity patterns and synaptic plasticity in the primary visual cortex (V1). Together, these phenotypes provide a unique opportunity to determine the window of vulnerability of the development and plasticity of specific cortical circuits to perinatal insults,and to establish whether A1ARs mediate the effects of neonatal hypoxia on long-term synaptic connectivity and plasticity. We hypothesize that cortical circuit connectivity and function in V1 are sensitive to the timing of hypoxic exposure and that A1ARs mediate the effects of neonatal hypoxia on synaptic connectivity, plasticity, and visual learning in V1. We will test our hypothesi through experiments in the following Specific Aims: (1) Determine how the timing and duration of neonatal hypoxia affect synaptic connectivity and plasticity in V1; and (2) Determine the extent to which A1ARs mediate the effects of hypoxia on axon connectivity and synaptic plasticity in V1. We anticipate that our findings will fill a critical knowledge gap regarding how the timing of perinatal insults affects the formation and long-term plasticity of cortical circuitr. Furthermore, they will provide new insights into the role of the adenosinergic system in premature brain injury and reveal potential therapeutic targets for the prevention and/or treatment of this injury and its long-term consequences.