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和完全可逆的状态。然而，麻醉剂预处理对抗缺血的证明清楚地表明，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。沿着类似的思路，我们的研究表明，啮齿动物全身麻醉会产生持久的认知障碍，老年人恢复得更慢。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过程中的持久变化。我们有证据表明，挥发性麻醉剂异氟烷可显著和持续下调drepletin（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）、树突棘丢失和tPA（一种调节神经营养因子BDNF合成的酶）神经元释放减少，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均降低神经祖细胞的增殖，可能导致成熟脑中细胞可塑性降低。因此，使用体外培养的成熟和未成熟的神经元和海马切片的模型，从年轻和年老的动物，以及行为良好的特点在体内模型，我们建议系统地检查麻醉剂对树突棘形态发生，突触发生和神经发生的影响，以测试的假设，异氟烷，但不是丙泊酚1。导致脊椎和突触形成的基础机制的持续破坏;以及2.降低了突触和细胞重塑的能力，特别是在老年大脑中。以前很少有人关注麻醉作用的这些方面，阐明全身麻醉剂如何急性和持续地干扰突触通讯的形态和功能指标，可能为它们对脑功能的长期和短期影响提供形态/分子基础。这项建议是我们以前努力的逻辑延伸，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，老年人是最容易发生术后认知发病的群体。公共卫生相关性：这些研究旨在调查全身麻醉后老年人大脑中持续性神经可塑性和认知变化的原因。这一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.