Long-lasting effects of anesthetics on synapse development and plasticity

麻醉剂对突触发育和可塑性的长期影响

• 批准号: 8697774
• 负责人: Guang Yang
• 金额: $ 31.54万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-10 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697774
• 关键词: AMPA Receptors; Acids; Adult; Adverse effects; Affect; Age; Anesthesia Recovery Period; Anesthesia procedures; Anesthetics; Animals; Behavioral; Biochemical; Biochemistry; Biological Neural Networks; Brain; Calcium; Calcium Signaling; Child; Cognitive; Defect; Dendrites; Development; Distal; Exposure to; General Anesthesia; General anesthetic drugs; Glutamates; Goals; Image; Impairment; Infant; Interneurons; Ketamine; Lead; Learning; Length; Life; Link; Measures; Microscopy; Monkeys; Motor Cortex; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Operative Surgical Procedures; Pharmaceutical Preparations; Phase; Play; Recovery; Resolution; Rodent; Role; Serine; Signal Transduction; Somatostatin; Staging; Synapses; Synaptic plasticity; Techniques; Testing; Therapeutic; awake; base; behavioral impairment; calmodulin-dependent protein kinase II; design; effective therapy; hippocampal pyramidal neuron; in vivo; inhibitory neuron; insight; neural circuit; neurotransmission; novel; novel therapeutics; operation; postnatal; prevent; public health relevance; research study; restoration; sensor; sevoflurane; synaptic function; synaptogenesis; treatment strategy; two-photon

PROJECT SUMMARY / ABSTRACT The goal of this project is to elucidate the long-term consequences of general anesthetics on synapse development and function, and to develop therapeutic strategies to prevent synaptic and learning deficits caused by early exposure to anesthesia. Anesthetics are commonly used for surgical operations in infants and young children. Recent studies suggest that repeated and prolonged anesthetic exposure, during the period of extensive synaptogenesis, can lead to learning and behavioral impairments later in life. However, the mechanisms by which anesthetics cause long-lasting deficits in neural circuits and learning impairments remain unknown. In this application, we will investigate the effects of single and repeated exposure to anesthetics on synaptic plasticity and function at specific stages of brain development. By using in vivo two- photon microscopy in combination with newly-generated glutamate and calcium sensors, we will determine whether repeated exposure to anesthetics during early postnatal development has long-lasting detrimental impacts on learning-dependent synaptic plasticity and function later in life. In addition, we will test the hypothesis that the adverse effects of anesthetics such as ketamine or sevoflurane are due to persistent hypofunction of glutamatergic neurotransmission and that pharmacological enhancement of the activities of ¿- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or N-methyl-D-aspartate (NMDA) receptors would alleviate such effects. The proposed experiments will allow us to gain important mechanistic insights into how early exposure to anesthesia causes learning and behavioral impairments. They will also help establish novel treatment strategies directed at rescuing the detrimental effects of anesthesia on the developing brain.

项目概要/摘要 该项目的目标是阐明全身麻醉药对突触的长期影响 发育和功能，并制定治疗策略以预防突触和学习缺陷 由于早期接触麻醉而引起的，麻醉剂常用于婴儿和婴儿的外科手术。 最近的研究表明，在麻醉期间反复和长时间接触麻醉剂。 广泛的突触发生可能会导致以后的学习和行为障碍。 麻醉剂导致神经回路长期缺陷和学习障碍的机制 在此应用中，我们将研究单次和重复暴露的影响。 麻醉剂对大脑发育特定阶段的突触可塑性和功能的影响通过使用体内两种药物。 光子显微镜与新生成的谷氨酸和钙传感器相结合，我们将确定 产后早期发育过程中反复接触麻醉剂是否会导致持久疼痛 对以后学习依赖的突触可塑性和功能的影响此外，我们将测试 假设氯胺酮或七氟醚等麻醉剂的不良反应是由于持续性 谷氨酸能神经传递功能减退以及 ¿ 活性的药理增强- 氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 受体或 N-甲基-D-天冬氨酸 (NMDA) 受体将减轻这种影响。所提出的实验将使我们获得重要的机制。 了解早期接触麻醉如何导致学习和行为障碍也将有所帮助。 建立新的治疗策略，旨在挽救麻醉对患者的疼痛影响 正在发育的大脑。