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: 7581845
• 负责人: GREGORY CROSBY
• 金额: $ 36.24万
• 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/7581845
• 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; 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; improved; in vitro Model; in vivo; in vivo Model; indexing; interest; nerve stem cell; neurogenesis; neurotrophic factor; newborn neuron; preconditioning; prevent; public health relevance; 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（由申请人提供）：全身麻醉通常被认为是一种快速且完全可逆的状态。然而，针对缺血的麻醉预处理的证明清楚地表明，麻醉剂可以在数天内改变中枢神经系统中的分子和突触事件。类似地，我们的研究表明，啮齿类动物的全身麻醉会产生持久的认知障碍，而老年人的恢复速度会更慢。这种麻醉后认知功能障碍的机制尚不清楚，但有证据表明突触可塑性过程发生了持久变化。我们有证据表明，挥发性麻醉剂异氟烷会产生深度和持久的drebrin（一种参与树突棘和兴奋性突触形成的F-肌动蛋白结合蛋白）的下调、树突棘的损失以及tPA（一种调节神经营养蛋白BDNF合成的酶）神经元释放的减少，这意味着异氟烷 干扰神经营养支持和突触发生。此外，异氟烷在体外和体内都能减少神经祖细胞的增殖，可能导致成熟大脑中细胞可塑性降低。因此，利用培养的成熟和未成熟神经元以及年轻和年老动物的海马切片的体外模型，以及行为良好表征的体内模型，我们建议系统地检查麻醉对树突棘形态发生、突触发生和神经发生的影响，以测试异氟烷而不是异丙酚1.导致机制持续破坏的假设 底层的脊柱和突触形成； 2. 降低突触和细胞重塑的能力，特别是在衰老的大脑中。以前很少有人关注麻醉作用的这些方面，阐明全身麻醉药如何剧烈而持久地干扰突触通讯的形态和功能指标可能为其对大脑功能的持久短期和长期影响提供形态学/分子基础。这一提议是我们之前努力的逻辑延伸，通过提高对全身麻醉药对老年大脑影响的理解，最终可能有助于改善老年人手术和全身麻醉后的认知结果，而老年人是最容易发生术后认知疾病的群体。公共健康相关性：这些研究旨在调查全身麻醉后老年大脑持续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术后认知功能障碍。