Mechanisms of Developmental Anesthesia Toxicity

发育麻醉毒性机制

• 批准号: 9335979
• 负责人: Cyrus David Mintz
• 金额: $ 40.88万
• 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/9335979
• 关键词: Address; Adverse effects; Anesthesia procedures; Anesthetics; Animal Model; Autistic Disorder; Behavioral; Behavioral Assay; Biological Assay; Brain; Cell Transplants; Cells; Child; Childhood; Cognition Disorders; Cognitive deficits; Data; Dendrites; Dendritic Spines; Development; Dose; Electrophysiology (science); Employee Strikes; 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; Pharmacology; Phosphorylation; Prevention strategy; Risk; Signal Transduction; Sirolimus; Structure; Synapses; System; Testing; Toxic effect; Translations; Transplantation; Virus; animal data; behavior test; clinical practice; clinically relevant; cognitive function; cohort; dentate gyrus; epidemiology study; 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.

项目摘要 人类患者的流行病学研究表明儿童暴露之间存在相关性 通用麻醉剂和随后的认知缺陷。支持该协会 通过来自动物模型的数据，这表明发育性暴露于麻醉剂原因 学习的持久障碍。儿童时期麻醉暴露的机制 可能会损害随后的大脑功能是未知的，目前在临床中没有策略 练习以保护患者免受麻醉神经毒性的推定风险。我们假设 这种发育性暴露于全身麻醉剂会导致脑电路中断 通过干扰树突生长和突触形成，进一步形成这种形式 毒性是由MTOR途径激活引起的，MTOR途径是与 神经发育障碍。为了检验该假设，我们将采用体内结构和 海马齿状回中小鼠和人神经元的功能分析。到 解决这一假设，我们将确定通常使用麻醉药的条件 导致发育树突的病理过度生长（AIM I）；我们将确定是否 麻醉药改变了突触在暴露神经元树突上的结构和功能 Vivo（AIM II）；最后，我们将确定麻醉诱导MTOR的激活是否 途径会导致神经元电路的破坏和学习的缺陷可以逆转 用药理学MTOR抑制剂。 （AIM III）。拟议的研究不仅将连接小儿 麻醉神经毒性，具有良好特征的损伤机制，这是常见的 神经发育障碍，但它也将以 MTOR抑制剂雷帕霉素和预防策略以差异作用的形式 麻醉选择和剂量。这些发现将在单细胞级的体内建立，两者都 在结构和功能方面，在完整的小鼠中定义明确的脑电路中 使用对所研究电路高度特定的行为学习测定法。钥匙 在体内环境中，将在人类神经元中验证发现的结果，从而建立与 对翻译至关重要的人类生物学。该提议将探讨更广泛的假设 小儿麻醉神经毒性源于脑电路形成的中断，更多 通常，它将有助于我们对神经发育障碍的理解。