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The Unfolding Role of Microglia in Alcohol Withdrawal

小胶质细胞在酒精戒断中的作用

基本信息

批准号：
10314628
负责人：
John F Neumaier
金额：
$ 19.58万
依托单位：
SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10314628
关键词：
Abstinence Address Air Alcohol Withdrawal Delirium Alcohol abuse Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcohols Animals Apoptosis Area Behavior Behavior Therapy Behavioral Biology Brain Cell Death Cells Cellular Stress Response Cessation of life Characteristics Chronic Code Complication Corpus striatum structure Cre driver Data Development Enterobacteria phage P1 Cre recombinase Ethanol Ethanol toxicity Exploratory/Developmental Grant Exposure to Filopodia Gene Expression Genes Genetic Transcription Genotype Goals Immune Induction of Apoptosis Inflammatory Knock-out Lead Life LoxP-flanked allele Measures Mediating Medical emergency Messenger RNA Methods Microglia Microscopic Microscopy Modeling Molecular Morphology Motivation Mouse Protein Mus Negative Reinforcements Neuroimmune Neuronal Plasticity Neurons Oxidative Stress Pathway interactions Pharmaceutical Preparations Process Protein Biosynthesis Proteins RNA Regulation Relapse Reporter Research RiboTag Ribosomes Risk Role Seizures Severities Signal Transduction Structure Substance Withdrawal Syndrome Surveys Synapses Testing Time Toxic effect Transgenic Mice Transgenic Organisms Translations Withdrawal Withdrawal Symptom alcohol abstinence alcohol abuse therapy alcohol consequences alcohol exposure alcohol measurement alcohol relapse alcohol use disorder base cell motility cohort conditional knockout cytokine endoplasmic reticulum stress experience experimental study in vivo innovation neuroinflammation next generation sequencing novel protein expression response transcription factor transcription factor CHOP transcriptome sequencing two photon microscopy two-photon vapor

项目摘要

Abstract Alcohol withdrawal is a medical emergency and a behavioral barrier to reducing alcohol abuse. Unlike withdrawal to other drugs, there is ample evidence that withdrawal to alcohol becomes worse after multiple cycles of alcohol consumption and abstinence, increasing the risks for serious adverse complications including seizures, delirium tremens, and death. Furthermore, the negative reinforcement inherent to cycles of alcohol abstinence and relapse to alcohol consumption complicates any behavioral interventions to reduce alcohol abuse. Many clues suggest that neuroinflammation is involved in both alcohol tolerance as well as withdrawal, but this realization has not led to new treatments for alcohol use disorder. The purpose of this proposal is to develop our hypothesis that chronic, intermittent alcohol exposure alters the way microglia, the innate immune cells that reside in the brain, modulate neuroimmune as well as neuronal synaptic signaling. In pilot experiments using RNA sequencing of ribosome-associated RNA from microglia after multiple cycles of alcohol exposure and abstinence, we found that alcohol withdrawal causes oxidative stress in microglia and activates the “unfolded protein response” (UPR), a mechanism that is involved in cellular stress responses leading to neuroinflammatory signaling and derangements in microglia function that can lead to cell death. We propose to block the full activation of the microglial UPR by knocking out CHOP, a key transcription factor involved in this pathway that was dramatically upregulated in microglia during withdrawal, using a recently developed, selective cre-driver mouse line, Tmem119-2A-Cre-ERT2/TdTomato, crossed with commercially available floxed CHOP mice to investigate this biology. We will examine how blunting UPR signaling alters the signs of alcohol withdrawal by testing if CHOP knockout alters several behavioral manifestations and reduces microglia morphological and gene expression changes associated with withdrawal. Using in vivo two-photon time lapse microscopy, we will examine if CHOP knockout from microglia changes morphology and motility associated during alcohol withdrawal. We will also test whether microglial CHOP impacts the motivation to drink alcohol in a model of voluntary alcohol drinking after multiple cycles of ethanol vapor exposure and withdrawal. Together, these experiments examine the role of neuroinflammation in the mechanisms of alcohol dependence and withdrawal from a new angle that has not been previously considered and is well matched to the R21 mechanism due to its high novelty and potential to develop new treatments.

摘要