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Mechanisms of Alcohol Withdrawal

戒酒机制

基本信息

批准号：
10661556
负责人：
DWAYNE W GODWIN
金额：
$ 42.98万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-10 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661556
关键词：
Action Potentials Alcohol withdrawal syndrome Alcohols Animal Model Apical Behavior Behavioral Benzodiazepines Binding Brain Chronic Clinical Complex Coupled Dangerousness Data Dendrites Dependence Development Diagnosis Dose Drug Metabolic Detoxication Drug Targeting Epilepsy Ethanol FRAP1 gene Grant Hippocampus In Vitro Incidence Invaded Ion Channel Protein Knock-out Knowledge Longevity Mediating Membrane Messenger RNA Midline Thalamic Nuclei Mission Modeling Molecular Mouse Strains Nature Neurons Organism Outcome Pathway interactions Pattern Pharmaceutical Preparations Population Potassium Channel Predisposition Preparation Prevention Procedures Property Protein Synthesis Inhibitors Proteins Public Health Pyramidal Cells Repression Research Seizures Signal Transduction Sirolimus Structure Substance Withdrawal Syndrome Substance abuse problem Symptoms Synapses T-Type Calcium Channels Testing Thalamic structure Time Toxic effect Translational Repression Translations United States National Institutes of Health Up-Regulation Withdrawal Withdrawal Symptom Work addiction liability alcohol abuse therapy alcohol effect alcohol exposure alcohol related problem alcohol use disorder comparison control drinking epileptiform experience experimental study gain of function improved in vivo nervous system disorder network models neural circuit neuronal cell body novel optogenetics permissiveness pharmacologic prevent response success transmission process voltage voltage clamp

项目摘要

PROJECT SUMMARY Alcohol withdrawal (WD) produces a range of dangerous clinical symptoms, including intense seizures. Hyperexcitability underlying seizures is produced by an array of intrinsic membrane properties that are disrupted by ethanol (EtOH). Prior work has demonstrated that chronic EtOH exposure and WD produce an up-regulation of ion channel proteins and a gain of function that promotes WD seizure. A remaining gap in our understanding of WD-related seizure is a testable model that places cellular changes in a network context. WD produces upregulation and increased bursting in midline thalamic nuclei. In hippocampus, mammalian target of rapamycin Complex 1 (mTORC1) is activated in CA1 neurons during WD, represses translation of Kv1.1, and results in reduced inhibition that we hypothesize will allow invasion of thalamic bursts and increased epileptiform population discharges. We have developed a new model of network excitability that will allow us to study the emergence, time course and molecular underpinnings of EtOH WD hyperexcitability and seizure. We will address the following aims: In Aim 1, we will determine the intrinsic properties contributing to membrane hyperexcitability in midline thalamus and CA1 due to ethanol WD seizure. Using voltage clamp recordings in an in vitro preparation coupled with pharmacological approaches, we will determine whether epileptiform discharges in WD are ultimately dependent on a progressive imbalance between excitatory burst discharges in thalamus (which depend on PKC), and reduced K+ currents in CA1 pyramidal cells (which are controlled by mTOR). In Aim 2, we will Determine important regulators of dendritic excitability in thalamus and CA1 in EtOH WD seizure. mTOR signaling is implicated in the development of spontaneous seizures in epilepsy, and we show data that it is active during WD. Using molecular approaches, we will toggle mTOR activity in the presence and absence of protein synthesis inhibitors. We will test whether mTORC represses translation of Kv1.1, as suggested by our preliminary data. In Aim 3, we bring together the cellular and molecular findings to determine the effects of WD-mediated changes to network excitability and seizure susceptibility in vivo. Using a novel optogenetic approach, we will test whether stimulation of the thalamo-HC pathway during WD will elicit enhanced epileptiform activity compared to controls that will depend on patterned activity at facilitated CA1 synapses. We expect that disruptions of mTORC1 will modify or reverse WD-mediated excitability. Seizure threshold is significantly reduced during repeated EtOH WD and we will use this fact to test the hypothesis that drugs effective against WD-induced hyper-excitability will also be effective at raising seizure thresholds to baseline levels. Success in these experiments will provide a more comprehensive understanding of how brief spindle episodes and spike wave complexes promote or support tonic-clonic WD seizures – which could lead to the identification of novel pathways and associated drug targets that will provide a means to prevent WD seizure, and to more effectively treat it.

项目总结戒酒(WD)会产生一系列危险的临床症状，包括剧烈的癫痫发作。癫痫发作背后的超兴奋性是由一系列固有的膜特性产生的，这些特性是被乙醇(Etoh)破坏。先前的研究表明，长期接触乙醇和WD会产生一种上调离子通道蛋白，获得促进WD癫痫发作的功能。一个剩余的缺口我们对WD相关癫痫的理解是一个可测试的模型，它将细胞变化置于网络中背景。WD导致丘脑中线核团表达上调和爆发量增加。在海马体中，哺乳动物雷帕霉素复合体靶标1(MTORC1)在WD期间激活CA1神经元，抑制翻译Kv1.1，并导致抑制减少，我们假设将允许丘脑入侵癫痫样放电的爆发和增加。我们开发了一种新的网络模型兴奋性，使我们能够研究Etoh WD的出现、时间进程和分子基础过度兴奋和癫痫。我们将解决以下目标：在目标1中，我们将确定内在的乙醇WD引起丘脑中线和CA1细胞膜高兴奋性的特性癫痫发作。在结合药理学方法的体外制剂中使用电压钳记录，我们将确定WD的癫痫样放电是否最终依赖于进行性丘脑兴奋性猝发放电(依赖于PKC)和K+电流减少之间的失衡在CA1锥体细胞中(受mTOR控制)。在目标2中，我们将确定重要的监管机构 Etoh WD癫痫患者丘脑和CA1区树突状细胞的兴奋性MTOR信号与癫痫自发性发作的发展，我们的数据显示，它在WD期间是活跃的。vbl.使用分子方法，我们将在存在和不存在蛋白质合成的情况下切换mTOR活性抑制剂。我们将测试mTORC是否像我们的初步数据所建议的那样抑制Kv1.1的翻译。在目标3中，我们结合细胞和分子的发现来确定WD介导的效应体内网络兴奋性和癫痫易感性的变化。使用一种新的光遗传学方法，我们将测试在WD期间刺激丘脑-HC通路是否会引起癫痫样活动增强与依赖于促进的CA1突触的模式活动的对照相比。我们期待着 MTORC1的破坏将改变或逆转WD介导的兴奋性。癫痫发作阈值显著我们将利用这一事实来检验药物对以下疾病有效的假设 WD诱导的高兴奋性也将有效地将癫痫阈值提高到基线水平。在以下方面取得成功这些实验将提供一个更全面的了解如何短暂的纺锤波发作和尖峰波复合体促进或支持强直-克隆性WD发作-这可能导致识别新的途径和相关的药物靶点，将提供一种手段，以防止WD发作，并更有效地治疗它。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rich Club Characteristics of Alcohol-Naïve Functional Brain Networks Predict Future Drinking Phenotypes in Rhesus Macaques.

DOI：
10.3389/fnbeh.2021.673151
发表时间：
2021
期刊：
Frontiers in behavioral neuroscience
影响因子：
3
作者：
Rowland JA;Stapleton-Kotloski JR;Alberto GE;Davenport AT;Epperly PM;Godwin DW;Daunais JB
通讯作者：
Daunais JB

Role of FMRP in rapid antidepressant effects and synapse regulation.

DOI：
10.1038/s41380-020-00977-z
发表时间：
2021-06
期刊：
Molecular psychiatry
影响因子：
11
作者：
Heaney CF;Namjoshi SV;Uneri A;Bach EC;Weiner JL;Raab-Graham KF
通讯作者：
Raab-Graham KF

Research Needs for Inpatient Management of Severe Alcohol Withdrawal Syndrome: An Official American Thoracic Society Research Statement.

DOI：
10.1164/rccm.202108-1845st
发表时间：
2021-10-01
期刊：
American journal of respiratory and critical care medicine
影响因子：
24.7
作者：
Steel TL;Afshar M;Edwards S;Jolley SE;Timko C;Clark BJ;Douglas IS;Dzierba AL;Gershengorn HB;Gilpin NW;Godwin DW;Hough CL;Maldonado JR;Mehta AB;Nelson LS;Patel MB;Rastegar DA;Stollings JL;Tabakoff B;Tate JA;Wong A;Burnham EL
通讯作者：
Burnham EL

Functional dynamics of primate cortico-striatal networks during volitional movements.

自愿运动过程中灵长类皮质 - 纹状体网络的功能动力学。