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: 9244817
• 负责人: ROBERT A PEARCE
• 金额: $ 42.59万
• 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/9244817
• 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; Impairment; In Vitro; Interneurons; Interruption; Intuition; 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; experimental study; genetic manipulation; hippocampal pyramidal neuron; improved; in vivo; optogenetics; public health relevance; receptor; relating to nervous system

 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：大麻醉的长期目标是对其网络和行为海马GABA受体在全身麻醉效果中的靶标的，通过靶向塑料和记忆。过程。 Etomide抑制所有神经元中的突触塑料和记忆中的所有神经元或特定子集（VIP，CR，PV，CCK，SOM，O-LM）。抑制相关的抑制作用 过程（即那些结合了α5和β2-Gabaar的过程），将我们的实验集中在要强烈贡献OST的类中的类别上，并使用光学遗传学方法直接操纵diasublibitaly电路，以复制或抵消 在体外进行LTP的eTom，I将学习有助于开发改进的方法，以探测不受欢迎的事件，例如召回或持续的记忆障碍，有时会遵循以下的神经系统。健康脑中的记忆可能会被操纵以改善患者的记忆力。