Mechanisms of Developmental Anesthesia Toxicity

发育麻醉毒性机制

• 批准号: 9159240
• 负责人: Cyrus David Mintz
• 金额: $ 38.77万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9159240
• 关键词: Address; Adverse effects; Anesthesia procedures; Anesthetics; Animal Model; Behavioral; Behavioral Assay; Biological Assay; Brain; Cell Transplants; Cells; Child; Childhood; Cognition; Cognitive deficits; Data; Dendrites; Dendritic Spines; Development; Dose; Electrophysiology (science); Employee Strikes; Epidemiologic Studies; Exposure to; FDA approved; FRAP1 gene; Fragile X Syndrome; General anesthetic drugs; Growth; Hippocampus (Brain); Human; Human Biology; Immunofluorescence Immunologic; Impairment; Injury; Isoflurane; Learning; Life; Link; Long-Term Potentiation; Measures; Microscopy; Modality; Modeling; Molecular; Mus; Neurocognitive; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Parahippocampal Gyrus; Pathologic; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phosphorylation; Prevention strategy; Risk; Signal Transduction; Sirolimus; Structure; Synapses; System; Testing; Toxic effect; Translations; Transplantation; Virus; base; behavior test; clinical practice; clinically relevant; cognitive function; cohort; dentate gyrus; fluorophore; in vivo; mTOR Inhibitor; mTOR inhibition; member; mouse model; nerve stem cell; neuron development; neuronal circuit disruption; neuronal circuitry; neurotoxicity; newborn neuron; nonhuman primate; prevent; synaptic function; synaptogenesis

PROJECT SUMMARY Epidemiologic studies of human patients have shown a correlation between childhood exposure to general anesthetic agents and subsequent cognitive deficits. This association is supported by data from animal models, which shows that developmental exposure to anesthetics causes lasting impairments in learning. The mechanism by which anesthetic exposure during childhood could impair subsequent brain function is unknown and no strategies currently exist in clinical practice to protect patients from the putative risk of anesthetic neurotoxicity. We hypothesize that developmental exposure to general anesthetics causes a disruption in brain circuit formation by interfering with dendrite growth and synapse formation, and further that this form of toxicity is caused by activation of the mTOR pathway, a signaling system associated with neurodevelopmental disorders. To test this hypothesis we will employ in vivo structural and functional analysis of mouse and human neurons in the dentate gyrus of the hippocampus. To address this hypothesis, we will determine the conditions in which commonly used anesthetics cause pathologic overgrowth of developing dendrites (Aim I); we will determine whether anesthetics alter the structure and function of synapses on the dendrites of exposed neurons in vivo (Aim II); finally, we will determine whether anesthetic induced activation of the mTOR pathway causes a disruption of neuronal circuits and deficits in learning that can be reversed with a pharmacologic mTOR inhibitor. (Aim III). The proposed studies will not only link pediatric anesthetic neurotoxicity to a well characterized mechanism of injury that is common to neurodevelopmental disorders, but it will also explore both a treatment modality, in the form of the mTOR inhibitor rapamycin, and a prevention strategy, in the form of differential effects anesthetic choice and dose. The findings will be established in vivo at the single cell level, both in terms of structure and function, in a well-defined brain circuit in the intact mouse and via the use using behavioral learning assays that are highly specific for the circuit under study. Key findings will be verified in human neurons in an in vivo setting, thus establishing relevance to human biology that is critical for translation. This proposal will explore the broader hypothesis that pediatric anesthetic neurotoxicity arises from disruptions of brain circuit formation, and more generally it will contribute to our understanding of neurodevelopmental disorders.

项目总结 对人类患者的流行病学研究表明，儿童时期的接触与 全身麻醉剂和随后的认知缺陷。支持此关联 来自动物模型的数据表明，发育过程中接触麻醉剂会导致 学习上的持久障碍。儿童时期麻醉剂暴露的机制 是否会损害后续的脑功能尚不清楚，目前尚无临床策略 实践以保护患者免受麻醉神经毒性的假定风险。我们假设 发育过程中接触全身麻醉药会导致大脑回路中断 通过干扰树突生长和突触形成而形成，而且这种形式的 毒性是由mTOR通路激活引起的，mTOR通路是一种与 神经发育障碍。为了验证这一假设，我们将在体内使用结构和 小鼠和人类海马齿状回神经元的功能分析。至 为了解决这一假设，我们将确定常用麻醉药的条件 导致发育中的树突病理性过度生长(目标I)；我们将确定 麻醉药改变暴露神经元树突上突触的结构和功能 活体(AIM II)；最后，我们将确定麻醉剂是否诱导mTOR的激活 通路导致神经元回路中断和学习障碍，这是可以逆转的 使用一种药理上的mTOR抑制剂。(目标III)。拟议的研究不仅将儿科 麻醉性神经毒性对一种具有明确特征的损伤机制的影响 神经发育障碍，但它也将探索一种治疗方式，形式为 MTOR抑制剂雷帕霉素，以及以不同效果形式出现的预防策略 麻醉药物的选择和剂量。这一发现将在体内建立在单细胞水平上，两者 在结构和功能方面，在完好的小鼠的大脑回路中，通过 使用对正在研究的电路具有高度特异性的行为学习分析。钥匙 这些发现将在活体环境中在人类神经元中得到验证，从而确定与 对翻译至关重要的人类生物学。这项提议将探索更广泛的假设 儿科麻醉剂的神经毒性是由大脑回路形成中断引起的，还有更多 一般来说，这将有助于我们对神经发育障碍的理解。