Targeting gut brain-signaling to reduce cocaine seeking behaviors

针对肠道大脑信号传导以减少可卡因寻求行为

基本信息

批准号：
10733638
负责人：
Drew Kiraly
金额：
$ 67.16万
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：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733638
关键词：
Abstinence Acute Affect Animal Model Animals Antibiotics Automobile Driving Bacteria Behavior Behavioral Behavioral Assay Biological Assay Brain CREB1 gene Cell Nucleus Chromatin Structure Cocaine Cocaine use disorder Complex Corpus striatum structure Coupled Crossover Design Cues Data Development Disease Distant Dose Drug Modelings Drug usage Epigenetic Process FDA approved Family Foundations Gene Expression Genes Genetic Transcription Grant Health Histone Acetylation Homeostasis Immune system Incubated Individual Intestines Laboratories Mediating Modeling Molecular Molecular Analysis Morbidity - disease rate Neurobiology Nucleus Accumbens Paper Pathologic Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacotherapy Phase Play Population Production Public Health Publications Publishing Relapse Research Rewards Risk Reduction Role Signal Transduction Societies Specificity Structure Substance Use Disorder Synaptic plasticity System Testing Translational Research Vagus nerve structure Volatile Fatty Acids Withdrawal Work behavioral study brain shape cocaine seeking cocaine use cost drug abstinence drug craving drug development drug of abuse drug relapse drug seeking behavior experimental study gene network genome-wide gut microbiome gut-brain axis human subject insight loved ones microbiome microbiome alteration microbiome analysis microbiome composition mortality neural circuit neuropsychiatry permissiveness preference prevent prolonged abstinence psychostimulant receptor reconstitution reduced substance use relapse risk response small molecule stimulant dependence stimulant use stimulant use disorder substance use transcription factor transcriptome sequencing translational approach translational study

项目摘要

Project Summary Pathological substance use disorders are devastating psychiatric conditions that lead to patterns of increasing and out of control substance use. These disorders account for significant morbidity and mortality amongst patients and inflict untold costs on their families and loved ones as well as society at large. Of these disorders, pathological use of cocaine and other psychostimulants accounts for a significant proportion of morbidity and mortality. Despite tremendous advances in understanding of the neurobiology of stimulant use disorders, there are no FDA-approved pharmacotherapies for stimulant use disorders. In treating patients with stimulant use disorder, the largest hurdle to overcome is in preventing drug relapse. In recent years there has been a growing understanding that a number of systems outside of the brain can play a critical role in shaping brain and behavior. Among these is the resident population of bacteria in the intestinal tract – collectively referred to as the gut microbiome. Extensive research now demonstrates that changes in the gut microbiome play a critical role in both normal brain function, as well as in the development of pathological states. In our own lab we have previously published that acute depletion of the microbiome can alter the rewarding effects of cocaine and affect gene expression changes in the brain. More recently, we have begun investigating how depleting the microbiome with antibiotics affects the persistence of behavioral and brain gene expression changes in animal models of relapse. We find that animals that lack a complex microbiome have increased cocaine seeking behaviors after a prolonged period of abstinence. Genome-wide RNA-sequencing analyses demonstrate that these animals have robust changes in gene expression in important striatal gene networks that affect synaptic plasticity and behavior. Additional analyses demonstrate epigenetic changes in chromatin structure. Importantly, behavioral and molecular effects of microbiome depletion can be largely reversed by replenishment of specific bacterially derived small molecules. In this grant we will work in two comprehensive Aims to clarify the specificity and mechanisms of these effects and will work to further targeting the gut microbiome and its molecular byproducts. Aim 1 will define temporal specificity of microbiome depletion effects on drug seeking behaviors with targeted microbiome depletions and reconstitutions at different phases of behavior. Behavioral studies will be coupled with molecular analyses of synaptic plasticity related transcriptional and epigenetic effects. Additional analyses of microbiome composition will define bacterial populations associated with increased drug seeking. Aim 2 will further clarify the role of individual microbiome- derived small molecules in driving these behavioral and molecular changes. These studies will provide critical mechanistic insight into gut-brain signaling in a model of cocaine use disorder and will lay the foundation for tractable translational research going forward.

项目概要病理性物质使用障碍是一种破坏性的精神疾病，会导致精神疾病的增加这些疾病导致了显着的发病率和死亡率。这些疾病给患者的家人和亲人以及整个社会造成了难以估量的损失，可卡因和其他精神兴奋剂的病理性使用在发病率和发病率中占很大比例尽管对兴奋剂使用障碍的神经生物学的理解取得了巨大进展，但仍然存在。不是 FDA 批准的用于治疗兴奋剂使用障碍的药物疗法。近年来，要克服的最大障碍是防止药物复发。人们越来越认识到大脑外部的许多系统可以在塑造大脑方面发挥关键作用其中包括肠道内常驻的细菌群——统称为细菌群。现在，广泛的研究表明肠道微生物组的变化起着重要作用。在我们自己的实验室中，它在正常大脑功能以及病理状态的发展中发挥着关键作用。我们之前发表过，微生物组的急性耗竭可以改变可卡因的奖励效果最近，我们开始研究如何消耗基因。含有抗生素的微生物群会影响行为和大脑基因表达变化的持久性我们发现缺乏复杂微生物组的动物模型中可卡因含量增加。寻求长期禁欲的行为。全基因组 RNA 测序分析。证明这些动物的重要纹状体基因网络中的基因表达发生了剧烈变化影响突触可塑性和行为的其他分析表明染色质的表观遗传变化。重要的是，微生物组耗竭的行为和分子效应可以在很大程度上逆转在这笔赠款中，我们将开展两项全面的工作。旨在阐明这些作用的特异性和机制，并将致力于进一步针对肠道微生物组及其分子副产物将定义微生物组消耗效应的时间特异性。关于在不同阶段进行有针对性的微生物组消耗和重建的药物寻求行为行为研究将与突触可塑性相关的分子分析相结合。对微生物组组成的额外分析将定义细菌。目标 2 将进一步阐明个体微生物组的作用。这些研究将为驱动这些行为和分子变化提供关键的衍生小分子。对可卡因使用障碍模型中肠脑信号传导的机制洞察，将为易于处理的转化研究正在进行中。