Anesthetic Suppression of Memory through disinhibitory circuits in Hippocampus

通过海马体的去抑制回路麻醉性抑制记忆

• 批准号: 9082006
• 负责人: ROBERT A PEARCE
• 金额: $ 43.92万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9082006
• 关键词: Action Potentials; Amnesia; Anesthesia procedures; Anesthetics; Awareness; Behavioral; Brain; Cells; Cholecystokinin; Development; Disease; Dissociation; Drug effect disorder; Etomidate; Event; Excision; Feedback; General Anesthesia; General anesthetic drugs; Genetic Recombination; Goals; Hippocampus (Brain); Hypnosis; In Vitro; Interneurons; Knockout Mice; Learning; Long-Term Potentiation; Measures; Mediating; Memory; Memory impairment; Methods; Modeling; Molecular; Mus; Mutation; Patients; Play; Process; Property; Pyramidal Cells; Research; Role; Sedation procedure; Stimulus; Synaptic plasticity; System; Testing; genetic manipulation; hippocampal pyramidal neuron; improved; in vivo; optogenetics; public health relevance; receptor; relating to nervous system; research study

 DESCRIPTION (provided by applicant): The long-term objective of the research is to understand the mechanism of general anesthesia, relating specific molecular- and cellular-level targets to their network- and behavioral-level consequences. This proposal focuses on the role of hippocampal GABAA receptors in the suppression of learning and memory by the general anesthetic etomidate. Three specific aims test the hypothesis that etomidate blocks synaptic plasticity and memory by targeting interneurons in the hippocampus, interrupting disinhibitory circuits that are essential to these processes. Aim 1) Test the role of GABAAR β2 subunits in suppression of synaptic plasticity and memory by etomidate, studying mice that carry the β2-N265M mutation and measuring the effects of etomidate on LTP in vitro and memory in vivo. Aim 2) Determine whether removing α5-GABAARs from specific classes of interneurons interferes with the ability of etomidate to suppress synaptic plasticity and memory, using Cre-driver lines targeting all interneurons (GAD65) or specific subsets of interneurons (VIP, CR, PV, CCK, SOM, O-LM). Aim 3) Measure the effects of etomidate on disinhibitory circuits in wild type and genetically modified mice, recording from specific interneurons to identify relevant inhibitory processes (i.e. those that incorporate α5- and β2-GABAARs), focusing our experiments on those classes of interneurons that are found to contribute most strongly, and manipulating disinhibitory circuits directly using optogenetic methods to reproduce or counteract the effects of etomidate on LTP in vitro and learning in vivo. The information that we will learn will aid in the development of improved methods for detecting and treating undesired events such as awareness with recall or persistent memory impairment that sometimes follows anesthesia. It also will help us understand the neural systems that are in place to control learning and memory in the healthy brain, how these systems are altered in certain disease states, and how they might be manipulated to improve memory in patients.

 描述（由适用提供）：研究的长期目标是了解全身麻醉的机理，将特定的分子和细胞级靶标与其网络和行为层面的后果相关。该提案的重点是海马GABAA受体在全身麻醉症中抑制学习和记忆中的作用。三个特定的目的检验了一个假设，即突然蛋白通过靶向海马中的中间神经元来阻止突触可塑性和记忆力，从而中断了这些过程必不可少的抑制性电路。目标1）测试GABAARβ2亚基在抑制合成可塑性和记忆中的作用，研究携带β2-N265M突变的小鼠，并测量体外体外LTP对LTP的影响。目标2）确定是否从特定类别的中间神经元干扰的α5-GABAAR与AIM中删除α5-GABAARs 3）测量弹性蛋白对野生类型和转基因小鼠的抗抑制性电路的影响，从特定的神经元记录以识别相关的抑制性抑制 过程（即那些结合了α5-和β2-Gabaar的过程），将我们的实验集中在那些发现最强烈贡献的中间神经元上，并使用光学遗传学方法直接操纵抑制性电路，以使用光学遗传学来复制或抵消 在体外LTP上脱氧于体内学习。我们将学习的信息将有助于开发改进的方法，用于检测和治疗未介绍事件，例如有时会随着麻醉的意识或持续记忆障碍的意识或持续记忆障碍。它还将帮助我们了解可以控制健康大脑学习和记忆的神经系统，在某些疾病状态中如何改变这些系统以及如何被操纵以改善患者的记忆力。