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，麻醉预处理对缺血的证明表明，麻醉剂可以在数天内改变中枢神经系统的分子和突触事件。与此类似，我们的研究表明，在啮齿类动物中，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，但有证据表明，与突触可塑性有关的过程发生了持久的变化。我们有证据表明，挥发性麻醉剂异氟醚会导致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）的持续下调，树突棘的丧失，以及tPA（一种调节神经营养因子BDNF合成的酶）的神经元释放减少，这意味着异氟醚会干扰神经营养支持和突触发生。此外，异氟醚在体外和体内都降低了神经祖细胞的增殖，可能导致成熟大脑中细胞可塑性的降低。因此，利用体外培养的成熟和未成熟神经元模型以及来自年轻和年老动物的海马切片，以及行为特征良好的体内模型，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，以验证异氟醚而非异丙酚1的假设。导致脊柱和突触形成机制的持续破坏；和2。降低突触和细胞重塑的能力，特别是在老年大脑中。以前很少关注麻醉作用的这些方面，阐明全麻如何急性和持续地干扰突触通信的形态学和功能指标，可能为其对脑功能的持续短期和长期影响提供形态学/分子基础。这一建议是我们之前努力的合理延伸，通过提高对全麻对老年人大脑影响的理解，可能最终有助于改善老年人手术后和全麻后的认知结果，老年人是最容易发生术后认知疾病的群体。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持续神经可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.