Crosby_Gregory_Mechanisms of Post-Anesthetic CNS Dysfunction in Aging

Crosby_Gregory_衰老过程中麻醉后中枢神经系统功能障碍的机制

• 批准号: 8056059
• 负责人: GREGORY CROSBY
• 金额: $ 35.72万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056059
• 关键词: Actins; Adult; Affect; Age; Aging; Alteplase; Anesthesia procedures; Anesthetics; Animals; Attention; Birth; Brain; Brain-Derived Neurotrophic Factor; Cells; Cognition; Cognitive; Communication; DLG4 gene; Dendritic Spines; Development; Down-Regulation; Elderly; Enzymes; Event; Excitatory Synapse; Exposure to; F-actin-binding proteins; Functional disorder; General Anesthesia; General anesthetic drugs; Genes; Glutamates; Health; Hippocampus (Brain); Human; Impaired cognition; Impairment; In Vitro; Ischemia; Isoflurane; Life; Long-Term Effects; Mediating; Molecular; Morbidity - disease rate; Morphogenesis; Morphology; N-Methyl-D-Aspartate Receptors; NGFR Protein; NR1 gene; Neuraxis; Neurons; Nitrous Oxide; Operative Surgical Procedures; Outcome; Plasmin; Plastics; Postoperative Period; Process; Propofol; Proteins; Rattus; Recovery; Relative (related person); Research; Research Design; Rodent; Signal Transduction; Site; Slice; Synapses; Synaptic Vesicles; Synaptic plasticity; System; Testing; Vertebral column; Work; age related; aged; aging brain; base; cognitive change; cognitive recovery; critical period; drebrins; improved; in vitro Model; in vivo; in vivo Model; indexing; interest; nerve stem cell; neurogenesis; neurotrophic factor; newborn neuron; preconditioning; prevent; synaptogenesis

DESCRIPTION (provided by applicant): General anesthesia is typically considered to be a rapidly and completely reversible state. The demonstration of anesthetic preconditioning against ischemia makes it clear, however, that anesthetic agents can alter molecular and synaptic events in the central nervous system for days. Along similar lines, our research shows that in rodents general anesthesia produces enduring cognitive impairment, with the old recovering more slowly. The mechanisms of this post-anesthetic cognitive dysfunction are unclear but evidence points to lasting changes in processes involved in synaptic plasticity. We have evidence that the volatile anesthetic isoflurane produces profound and persistent down-regulation of drebrin, an F-actin binding protein involved in formation of dendritic spines and excitatory synapses, loss of dendritic spines, and reduced neuronal release of tPA, an enzyme that regulates synthesis of the neurotrophin BDNF, implying that isoflurane interferes with neurotrophic support and synaptogenesis. Moreover, isoflurane decreases proliferation of neural progenitors both in vitro and in vivo, possibly leading to reduced cellular plasticity in the mature brain. Accordingly, using in vitro models of cultured mature and immature neurons and hippocampal slices from young and old animals, as well as a behaviorally well-characterized in vivo model, we propose to systematically examine anesthetic effects on dendritic spine morphogenesis, synaptogenesis, and neurogenesis to test the hypotheses that isoflurane but not propofol 1. causes sustained disruption of mechanisms underlying spine and synapse formation; and 2. reduces the capacity for synaptic and cellular remodeling, particularly in the aged brain. There has been little attention to these aspects of anesthetic action previously and elucidating how general anesthetics interfere acutely and persistently with morphological and functional indices of synaptic communication may provide a morphological / molecular basis for their lingering short- and long-term effects on brain function. This proposal is a logical extension of our previous efforts and, by improving understanding of the impact of general anesthetics on the aged brain, may eventually help improve cognitive outcomes after surgery and general anesthesia in elders, the group most vulnerable to postoperative cognitive morbidity. PUBLIC HEALTH RELEVANCE: These studies are designed to investigate the cause of persistent neuroplastic and cognitive changes in the aged brain following general anesthesia. This work may help to prevent or treat postoperative cognitive dysfunction in the aged.

描述（申请人提供）：通常认为全身麻醉是一种快速且完全可逆的状态。然而，对缺血的麻醉预调节的证明很明显，麻醉剂可以在中枢神经系统中改变分子和突触事件几天。同样，我们的研究表明，在啮齿动物中，全身麻醉会产生持久的认知障碍，旧的恢复较慢。这种麻醉后认知功能障碍的机制尚不清楚，但证据表明，突触可塑性涉及的过程的持久变化。 We have evidence that the volatile anesthetic isoflurane produces profound and persistent down-regulation of drebrin, an F-actin binding protein involved in formation of dendritic spines and excitatory synapses, loss of dendritic spines, and reduced neuronal release of tPA, an enzyme that regulates synthesis of the neurotrophin BDNF, implying that isoflurane干扰神经营养的支持和突触发生。此外，异氟烷会在体外和体内降低神经祖细胞的增殖，可能导致成熟大脑的细胞可塑性降低。因此，我们使用来自年轻动物和老年动物的培养成熟和未成熟神经元以及海马切片的体外模型，以及在体内模型中的行为表现良好的模型，我们建议系统地检查对树突状脊柱形态发生的麻醉作用，对突触的形成，突触形成，并测试具有同假设的神经形成，而不是促进症状的假设。潜在的脊柱和突触形成；和2。降低了突触和细胞重塑的能力，尤其是在老化的大脑中。先前几乎没有关注麻醉作用的这些方面，并阐明了一般麻醉药如何急剧和持续地与突触通信的形态和功能指标持一定程度地干扰，这可能会为它们对短期和长期对脑功能的影响提供形态 /分子基础。该提议是我们以前的努力的逻辑扩展，并且通过提高对全身麻醉对老年大脑的影响的理解，最终可能有助于改善长者手术和全身麻醉后的认知结果，这是该小组最容易受到术后认知发病率的影响。公共卫生相关性：这些研究旨在调查全身麻醉后老年大脑持续性神经塑性和认知变化的原因。这项工作可能有助于预防或治疗老年人的术后认知功能障碍。