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: 9035447
• 负责人: Jason E Coleman
• 金额: $ 18.75万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9035447
• 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; Health; Human; Hypoxia; Image; Impairment; 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; Premature Infant; 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; 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（由适用提供）：婴儿早产的婴儿有脑损伤以及长期神经系统损伤的风险。当前，尚无预防或治疗早产脑损伤的治疗方法，并且对长期神经系统后遗症阵列阵列的神经元机制知之甚少。缺氧是弥漫性白质损伤（DWMI）和神经/轴突异常的危险因素。先前的工作表明，由慢性余生缺氧（CSH）引起的DWMI和发育的新生小鼠引起的髓磷脂是通过删除A1腺苷受体（A1AR）（A1ARS）来预防的，而A1腺苷受体（A1AR）在大脑中无处不在。这，腺苷能系统是旨在防止和/或改善围产期脑损伤的长期影响的疗法的有吸引力的靶标。但是，腺苷信号传导在介导缺氧对长期中性电路功能的影响中的作用尚不清楚。我们最近获得了初步数据，表明新生儿小鼠中的CSH会导致轴突连通性模式的持久扰动和一级视觉皮层（V1）中的突触可塑性。这些表型一起提供了一个独特的机会，可以确定特定皮质回路对围产期感染的发育和可塑性的脆弱性窗口，并确定A1ARS是否介导了新生儿缺氧对长期突触连通性和可塑性的影响。我们假设V1中的皮质电路连接性和功能对低氧暴露时间敏感，并且A1ARS介导了新生儿缺氧对V1中合成连通性，可塑性和视觉学习的影响。我们将通过以下特定目的进行实验来测试我们的假设：（1）确定新生儿缺氧的时间和持续时间如何影响V1中的合成连通性和可塑性； （2）确定A1AR介导缺氧对V1中轴突连通性和突触可塑性的影响的程度。我们预计我们的发现将填补有关如何 围产期损伤的时机会影响皮质回路的形成和长期可塑性。此外，他们将提供有关腺苷能系统在过早脑损伤中的作用的新见解，并揭示了预防和/或治疗这种损伤及其长期后果的潜在治疗靶标。

项目成果

Neonatal seizures induced by pentylenetetrazol or kainic acid disrupt primary cilia growth on developing mouse cortical neurons.

戊四唑或红藻氨酸诱导的新生儿癫痫发作会破坏发育中的小鼠皮质神经元的初级纤毛生长。

• DOI: 10.1016/j.expneurol.2016.05.015
• 发表时间: 2016
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Parker,AlexanderK;Le,MeganM;Smith,TylerS;Hoang-Minh,LanB;Atkinson,EricW;Ugartemendia,George;Semple-Rowland,Susan;Coleman,JasonE;Sarkisian,MatthewR
• 通讯作者: Sarkisian,MatthewR