Mechanisms of Developmental Anesthesia Toxicity

项目摘要 对人类患者的流行病学研究表明，儿童期接触 全身麻醉剂和随后的认知缺陷。支持此关联 通过动物模型的数据，这表明发育暴露于麻醉剂会导致 学习上的持久障碍。儿童时期麻醉剂暴露的机制 可能会损害随后的脑功能是未知的，目前没有策略存在于临床 保护患者免受麻醉剂神经毒性假定风险的实践。我们假设 发育期接触全身麻醉剂会导致大脑回路中断 通过干扰树突生长和突触形成，进一步地，这种形式的 毒性是由mTOR通路的激活引起的，mTOR通路是一种与 神经发育障碍为了验证这一假设，我们将采用体内结构和 小鼠和人类海马齿状回神经元的功能分析。到 解决这个假设，我们将确定常用麻醉剂的条件， 导致发育中树突的病理性过度生长（目的I）;我们将确定是否 麻醉剂改变暴露神经元树突上突触的结构和功能， 体内（目的II）;最后，我们将确定麻醉剂是否诱导mTOR激活 这一通路会导致神经元回路的中断和学习能力的缺陷， 药物mTOR抑制剂(Aim III）。这项研究不仅将儿童 麻醉神经毒性是一种常见的损伤机制， 神经发育障碍，但它也将探索两种治疗方式，以 mTOR抑制剂雷帕霉素和预防策略，以差异效应的形式 麻醉剂的选择和剂量。这些发现将在体内单细胞水平上建立， 在结构和功能方面，在完整小鼠的明确脑回路中， 使用对所研究的电路具有高度特异性的行为学习测定。关键 研究结果将在体内环境中的人类神经元中得到验证，从而建立与 人类生物学对翻译至关重要。本提案将探讨更广泛的假设 小儿麻醉剂神经毒性是由脑回路形成的中断引起的，等等。 一般来说，它将有助于我们了解神经发育障碍。

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.