Cortical Circuit Formation and Plasticity Following Neonatal Brain Injury

 描述（由申请人提供）：早产儿有脑损伤和长期神经和认知缺陷的风险。目前，没有预防或治疗过早脑损伤的治疗方法，并且对一系列长期神经系统后遗症的神经机制知之甚少。缺氧是弥漫性白色物质损伤（DWMI）和神经元/轴突异常的危险因素。先前的研究表明，新生小鼠中由慢性亚致死性缺氧（CSH）引起的DWMI和髓鞘减少可通过缺失A1腺苷受体（A1 AR）来预防，A1腺苷受体在大脑中普遍表达。因此，腺苷能系统是一个有吸引力的目标，旨在预防和/或改善围产期脑损伤的长期影响的治疗。然而，腺苷信号转导在介导缺氧对长期神经回路功能的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CSH引起轴突连接模式和初级视觉皮层（V1）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，以确定特定的皮层电路的发展和可塑性的脆弱性窗口围产期的侮辱，并建立是否A1 ARs介导的影响新生儿缺氧的长期突触连接和可塑性。 我们假设，皮层电路连接和功能在V1是敏感的缺氧暴露的时间和A1 ARs介导的新生儿缺氧对突触连接，可塑性和视觉学习V1的影响。我们将通过以下特定目的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中的突触连接和可塑性;（2）确定A1 AR介导缺氧对V1中轴突连接和突触可塑性的影响的程度。 我们预计，我们的研究结果将填补一个关键的知识空白， 围产期损伤的时间影响皮质回路的形成和长期可塑性。此外，它们将为腺苷能系统在过早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.