Targeting gut brain-signaling to reduce cocaine seeking behaviors

项目摘要 病理性物质使用障碍是一种破坏性的精神疾病，会导致 和失控的物质使用。这些疾病造成了许多人的发病率和死亡率。 并给他们的家人和亲人以及整个社会带来难以估量的代价。在这些障碍中， 病理性使用可卡因和其他精神刺激剂占发病率和 死亡率。尽管对兴奋剂使用障碍的神经生物学的理解有了巨大的进步，但 没有FDA批准的兴奋剂使用障碍的药物疗法。在治疗使用兴奋剂的患者时 要克服的最大障碍是防止毒品复发。近年来，有一种 逐渐认识到大脑以外的许多系统可以在塑造大脑方面发挥关键作用 和行为。其中包括肠道中的常驻细菌数量--统称为 作为肠道微生物群。广泛的研究现在表明，肠道微生物群的变化对 在正常的大脑功能以及病理状态的发展中都起着关键的作用。在我们自己的实验室 我们之前已经发表过，微生物群的急性枯竭会改变可卡因的回报效应 并影响大脑中基因表达的变化。最近，我们已经开始调查如何耗尽 抗生素微生物群影响行为和脑基因表达变化的持续性 复发的动物模型。我们发现，缺乏复杂微生物群的动物增加了可卡因 在长期禁欲后寻求行为。全基因组RNA测序分析 证明这些动物在重要的纹状体基因网络中的基因表达有很大的变化 会影响突触的可塑性和行为。额外的分析表明染色质的表观遗传变化 结构。重要的是，微生物群枯竭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。在这笔赠款中，我们将在两个全面的 旨在阐明这些影响的特殊性和机制，并将致力于进一步针对肠道 微生物组及其分子副产物。目标1将定义微生物组耗竭效应的时间特异性 不同阶段靶向微生物群耗竭与重组的寻药行为研究 行为。行为学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。对微生物组组成的额外分析将定义细菌 与寻求毒品增加有关的人口。目标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的衍生小分子。这些研究将提供关键的 对可卡因使用障碍模型中肠道-大脑信号的机械性洞察，将为 易于处理的翻译研究将会继续下去。

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.