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.

项目摘要病理药物使用障碍是毁灭性的精神病，导致增加的模式并失控的药物使用。这些疾病解释了大量的发病率和死亡率患者并为家人和亲人以及整个社会造成了无数的成本。在这些疾病中可卡因和其他心理刺激剂的病理使用占发病率的很大比例和死亡。尽管在理解刺激使用障碍的神经生物学方面取得了巨大进步，但没有用于FDA批准的用于刺激使用障碍的药物治疗。在治疗兴奋剂的患者中疾病，要克服的最大障碍是防止药物缓解。近年来有一个越来越了解大脑以外的许多系统可以在塑造大脑中发挥关键作用和行为。其中包括肠道中细菌的居民人群 - 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播放在正常大脑功能以及病理状态的发展中的关键作用。在我们自己的实验室我们以前已经发表过，微生物组的急性耗竭会改变可卡因的奖励作用并影响基因表达在大脑中的变化。最近，我们已经开始研究如何耗尽具有抗生素的微生物组会影响行为和脑基因表达的持续性救济动物模型。我们发现缺乏复杂微生物组的动物增加了可卡因长期禁欲后寻求行为。全基因组的RNA序列分析证明这些动物在重要的纹状体基因网络中的基因表达有强大的变化影响合成的可塑性和行为。其他分析表明染色质的表观遗传变化结构。重要的是，微生物组耗竭的行为和分子效应可以在很大程度上逆转补充特定的细菌衍生的小分子。在这笔赠款中，我们将在两个全面工作旨在阐明这些影响的特异性和机制，并将努力进一步针对肠道微生物组及其分子副产品。 AIM 1将定义微生物组部署效果的临时特异性在针对性微生物组部署和重组的毒品寻求行为方面的不同阶段行为。行为研究将与合成可塑性相关的分子分析结合转录和表观遗传效应。微生物组组成的其他分析将定义细菌与吸毒增加有关的种群。 AIM 2将进一步阐明单个微生物组的作用驱动这些行为和分子变化时衍生的小分子。这些研究将提供关键在可卡因使用障碍模型中对肠脑信号传导的机械洞察力，并将为可拖动的翻译研究。