Crosby_Gregory_Mechanisms of Post-Anesthetic CNS Dysfunction in Aging

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，啮齿类动物全身麻醉会产生持久的认知障碍，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导致 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）的深度和持续下调、树突棘的损失以及 tPA（一种调节神经营养蛋白 BDNF 合成的酶）的神经元释放减少，这意味着异氟烷会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.导致树突棘和突触形成机制持续破坏的假设； 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长期和短期影响提供形态学/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。

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.