Cortical Circuit Formation and Plasticity Following Neonatal Brain Injury

新生儿脑损伤后的皮质回路形成和可塑性

• 批准号: 8873442
• 负责人: Jason E Coleman
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8873442
• 关键词: Adenosine; Adenosine A1 Receptor; Adolescent; Affect; Area; Axon; Behavioral; Behavioral Assay; Biological Assay; Brain; Brain Injuries; Chronic; Cognitive deficits; Coupled; Data; Development; Diffuse; Evoked Potentials; Human; Hypoxia; Image; Impairment; Infant; Inhibitory Synapse; Injury; Knowledge; Learning; Long-Term Effects; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Motor Skills; Movement; Mus; Myelin; Neocortex; Neonatal; Neonatal Brain Injury; Neurodevelopmental Problem; Neurologic; Neurons; Oligodendroglia; Pattern; Perinatal; Perinatal Brain Injury; Phenotype; Physiological; Prevention; Process; Risk; Risk Factors; Role; Sensory; Signal Transduction; Staging; Stimulus; Stress; Study models; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Time; Visual; Work; area striata; axon injury; behavioral outcome; behavioral study; cognitive skill; gray matter; hypoxia neonatorum; improved; in vivo; insight; memory recognition; neural circuit; neuroimaging; neuromechanism; postnatal; premature; prevent; public health relevance; relating to nervous system; research study; targeted treatment; therapeutic target; two-photon; visual information; visual learning; visual motor; white matter injury; young adult

 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.

 描述（由申请人提供）：早产儿面临脑损伤以及长期神经和认知缺陷的风险。目前，尚无预防或治疗早产脑损伤以及一系列长期神经系统潜在神经机制的治疗方法。缺氧是弥漫性白质损伤 (DWMI) 和神经元/轴突异常的危险因素，此前的研究表明，慢性亚致死性缺氧 (CSH) 会导致 DWMI 和髓磷脂减少。新生小鼠中的 A1 腺苷受体 (A1AR) 的缺失可以预防这种情况，而 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的长期影响的治疗的一个有吸引力的靶点。然而，腺苷信号传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表明，CSH 对新生小鼠造成持久的影响。初级视觉皮层 (V1) 轴突连接模式和突触可塑性的扰动共同提供了一个独特的机会来确定特定皮层回路的发育和可塑性对围产期损伤的脆弱性窗口，并确定 A1AR 是否介导。新生儿缺氧对长期突触连接和可塑性的影响我们发现，V1 中的皮质回路连接和功能对缺氧暴露的时间敏感，而且 A1AR 也很敏感。介导新生儿缺氧对 V1 突触连接性、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检验我们的假设：（1）确定新生儿缺氧的时间和持续时间如何影响 V1 突触连接性和可塑性。 (2) 确定 A1AR 在多大程度上介导缺氧对 V1 轴突连接性和突触可塑性的影响，我们预计这一发现将填补一个关键问题。关于如何进行的知识差距 围产期损伤的时间会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/或治疗这种损伤的潜在治疗靶点。及其长期后果。