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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.

项目摘要病理性物质使用障碍是毁灭性的精神状况，导致增加的模式，以及滥用药物这些疾病占显著的发病率和死亡率，这不仅对患者造成了巨大的伤害，而且给他们的家庭和亲人以及整个社会造成了难以估量的代价。在这些疾病中，可卡因和其他精神兴奋剂的病理性使用占发病率的很大比例， mortality.尽管对兴奋剂使用障碍的神经生物学理解有了巨大的进步，没有FDA批准的兴奋剂使用障碍的药物治疗。在治疗使用兴奋剂的患者时要克服的最大障碍是防止复吸。近年来，越来越多的人认识到，大脑以外的一些系统在塑造大脑方面发挥着关键作用。和行为。其中包括肠道中的常驻细菌群-统称为作为肠道微生物组。广泛的研究现在表明，肠道微生物组的变化起着重要作用。在正常的大脑功能以及病理状态的发展中起着关键作用。在我们自己的实验室里我们之前已经发表过，微生物组的急性消耗可以改变可卡因的奖励作用。并影响大脑中基因表达的变化。最近，我们开始研究抗生素的微生物组影响行为和大脑基因表达变化的持续性，复发的动物模型。我们发现，缺乏复杂微生物组的动物会增加可卡因在长期禁欲后寻求行为。全基因组RNA测序分析表明这些动物在重要的纹状体基因网络中的基因表达发生了强烈的变化，影响突触的可塑性和行为。其他分析表明染色质的表观遗传变化结构重要的是，微生物组消耗的行为和分子效应可以通过以下方式在很大程度上逆转：补充特定细菌衍生的小分子。在这一补助金，我们将在两个全面的工作目的是阐明这些作用的特异性和机制，并将致力于进一步靶向肠道微生物组及其分子副产物。目标1将定义微生物组消耗效应的时间特异性在不同阶段的药物寻求行为与目标微生物组消耗和重建行为行为研究将与突触可塑性相关的分子分析相结合。转录和表观遗传效应。对微生物组组成的其他分析将确定细菌与寻求毒品有关的人口增加。目标2将进一步阐明个体微生物组的作用- 衍生小分子来驱动这些行为和分子变化。这些研究将提供关键的在可卡因使用障碍模型中对肠脑信号传导的机械见解，并将为可操作的转化研究。