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

基本信息

批准号：
9225239
负责人：
Guang Yang
金额：
$ 32.21万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/9225239
关键词：
AMPA Receptors Acids Adult Adverse effects Affect Age 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 Impairment Infant Interneurons Ketamine Lead Learning Length Life Link Measures Microscopy Monkeys Motor Cortex Mus N-Methyl-D-Aspartate Receptors Neurons Operative Surgical Procedures Pharmacology Pharmacotherapy Phase Play Recovery Rodent Role Serine Signal Transduction Somatostatin Synapses Synaptic plasticity Techniques Testing Therapeutic aspartate receptor awake base behavioral impairment behavioral study calmodulin-dependent protein kinase II design effective therapy experimental study high resolution imaging hippocampal pyramidal neuron imaging approach in vivo in vivo two-photon imaging inhibitory neuron insight neural circuit neurotransmission novel novel therapeutic intervention operation postnatal prevent public health relevance restoration sensor sevoflurane synaptic function synaptogenesis treatment strategy two-photon

项目摘要

DESCRIPTION (provided by applicant): 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 α-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.

描述（由申请人提供）：该项目的目标是阐明全身麻醉剂对突触发育和功能的长期影响，并制定治疗策略以防止早期接触麻醉剂引起的突触和学习缺陷。用于婴儿和幼儿的外科手术。最近的研究表明，在广泛的突触发生期间，反复和长时间的麻醉可能会导致以后的学习和行为障碍。麻醉剂会导致神经回路的长期缺陷和学习障碍仍然未知。在本应用中，我们将通过使用体内双光子研究单次和重复接触麻醉剂对大脑发育特定阶段的突触可塑性和功能的影响。显微镜结合新生成的谷氨酸和钙传感器，我们将确定在出生后早期发育过程中反复接触麻醉剂是否会对以后的学习依赖性突触可塑性和功能产生长期的拮抗影响。此外，我们将检验这样的假设：氯胺酮或七氟醚等麻醉剂的不良反应是由于谷氨酸能神经传递功能持续低下，以及药物活性增强的结果。 α-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能够获得重要的机制见解。过早接触麻醉会导致学习和行为障碍，它们还将有助于建立旨在挽救麻醉对发育中的大脑的疼痛影响的新治疗策略。