权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
8245821
负责人：
GREGORY CROSBY
金额：
$ 35.77万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8245821
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

项目摘要

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)：全身麻醉通常被认为是一种快速且完全可逆的状态。然而，针对缺血的麻醉剂预适应的证明清楚地表明，麻醉剂可以改变中枢神经系统中的分子和突触事件数天。沿着类似的思路，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，而老年人的恢复速度更慢。这种麻醉后认知功能障碍的机制尚不清楚，但有证据表明，涉及突触可塑性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对Drebrin产生了深刻而持久的下调，Drebrin是一种F-肌动蛋白结合蛋白，参与树突棘和兴奋性突触的形成，树突棘的丢失，以及tPA的神经元释放减少，tPA是一种调节神经营养因子BDNF合成的酶，这意味着异氟烷干扰了神经营养支持和突触发生。此外，异氟醚在体外和体内都会减少神经前体细胞的增殖，可能会导致成熟大脑的细胞可塑性降低。因此，使用体外培养的成熟和未成熟神经元以及年轻和老年动物的海马片模型，以及行为特征良好的体内模型，我们建议系统地检测麻醉对树突棘形态发生、突触发生和神经发生的影响，以检验以下假设：异氟醚而不是异丙酚1.导致脊柱和突触形成的机制持续中断；2.降低突触和细胞重塑的能力，特别是在老年大脑中。以往对麻醉作用的这些方面的关注很少，阐明全麻药如何强烈而持久地干扰突触通讯的形态和功能指标，可能为它们对脑功能持续的短期和长期影响提供一个形态/分子基础。这项建议是我们之前努力的合乎逻辑的延伸，通过提高对全麻药对老年大脑影响的了解，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障碍的群体。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。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Oxytocin alters cell fate selection of rat neural progenitor cells in vitro.

催产素在体外改变大鼠神经祖细胞的细胞命运选择。

DOI：
10.1371/journal.pone.0191160
发表时间：
2018
期刊：
PloS one
影响因子：
3.7
作者：
Palanisamy,Arvind;Kannappan,Ramaswamy;Xu,Zhiqiang;Martino,Audrey;Friese,MatthewB;Boyd,JustinD;Crosby,Gregory;Culley,DeborahJ
通讯作者：
Culley,DeborahJ

Prolonged Treatment with Propofol Transiently Impairs Proliferation but Not Survival of Rat Neural Progenitor Cells In Vitro.