Dissecting the role of the gut microbiome on striatal chromatin conformation and drug-seeking behavior

剖析肠道微生物组对纹状体染色质构象和药物寻求行为的作用

基本信息

批准号：
10319289
负责人：
Katherine Meckel
金额：
$ 4.54万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2021-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319289
关键词：
Abstinence Acute Affect Animal Model Animals Antibiotics Bacteria Behavior Behavioral Biological Assay Blood - brain barrier anatomy Brain Chromatin Chromatin Structure Chronic Cocaine Complement Complex Corpus striatum structure Coupled Cues DNA Binding Data Development Disease Drug Controls Drug Modelings Drug usage Epigenetic Process Exhibits Exposure to FDA approved Faculty Fellowship Fiber Fostering Future Gastrointestinal tract structure Gene Expression Genes Genetic Transcription Goals Health Histone Acetylation Homeostasis Image Imaging Techniques Immune system Injections Intravenous Laboratories Learning Long-Term Depression Long-Term Potentiation Mental disorders Mentors Modeling Molecular Molecular Conformation Morbidity - disease rate Mus Neurons Nuclear Nucleus Accumbens Overdose Pathogenesis Pathologic Patients Pattern Pharmaceutical Preparations Pharmacotherapy Phase Photometry Play Population Positioning Attribute Public Health Publishing Regulation Regulator Genes Relapse Research Research Personnel Rewards Rodent Model Role Signal Pathway Signal Transduction Societies Sorting - Cell Movement Substance Use Disorder Synapses Synaptic plasticity Techniques Testing Training Transcriptional Regulation Transposase Vagus nerve structure Withdrawal Work XCL1 gene brain behavior cell type cocaine exposure cocaine self-administration cocaine use cost disability drug craving drug of abuse drug reward drug seeking behavior epigenome experimental study gut microbiome gut microbiota gut-brain axis human subject in vivo calcium imaging insight loved ones microbial microbiome mortality mouse model neurotransmission novel patient population post-doctoral training pre-doctoral prevent psychostimulant response skills stimulant use stimulant use disorder tenure track therapeutic target transcriptome sequencing transcriptomics

项目摘要

Project Summary Pathological substance use disorders are devastating psychiatric illnesses characterized by patterns of escalating and out of control drug use. These disorders account for profound disability, morbidity and mortality among patients, while also inflicting incalculable costs on their loved ones and society at large. Pathological use of stimulants, including cocaine, accounts for a significant proportion of morbidity and fatal overdose nationwide. Despite tremendous advances in elucidating the molecular changes underlying stimulant use disorders, there are no FDA-approved pharmacotherapies for their treatment. The largest obstacle to overcome in treating patients with psychostimulant use disorder is preventing relapse. In recent years, there has been a growing understanding that the resident population of bacteria in the gastrointestinal tract – collectively referred to as the gut microbiome – plays a critical role in regulating brain function and behavior. Extensive research now demonstrates that changes to the gut microbiome can support healthy brain function and also drive the development of pathological states. In our own lab, we have previously published that acute depletion of the microbiome can enhance the rewarding effects of cocaine and alter gene expression changes in the brain. In this proposal, I will investigate how antibiotic-induced depletion of the microbiome affects the persistence of drug-seeking behaviors in a mouse model of relapse, taking an integrative multi-level approach to examine changes in striatal reward centers at the epigenetic, transcriptional, and circuit levels. Preliminary data in Aim 1 (F99) demonstrate that microbiome-depleted mice exhibit increased cocaine-seeking behaviors following a period of prolonged abstinence. Full transcriptomic RNA-sequencing analysis from the nucleus accumbens demonstrates that these animals exhibit marked changes in gene expression in important gene networks known to affect DNA binding, synaptic plasticity, and behavior. Additional analyses demonstrate decreased permissive histone acetylation in microbiome-depleted mice following cocaine administration, suggesting that the microbiome affects chromatin structure. Aim 2 (F99) will delve more deeply into the microbial regulation of the epigenome in response to drugs of abuse by examining chromatin conformation in specific populations of striatal neurons. This will be accomplished via training in and application of Fluorescent- Activated Nuclear Sorting (FANS) and Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq). These studies will be coupled with behavioral analyses to provide mechanistic insight into epigenetic remodeling underlying drug-seeking behaviors. For Aim 3 (K00) I will identify a postdoctoral mentor to support my professional development as well as my research examining the effects of the microbiome on firing activity in striatal neuronal subpopulations using in vivo calcium imaging techniques. These studies will provide important mechanistic insight into gut-brain signaling in a model of cocaine use disorder while simultaneously fostering my development into a successful independent investigator ready for a tenure-track faculty position.

项目摘要病理性物质使用障碍是精神科精神疾病这些疾病导致严重的残疾和发病。和患者的死亡，同时也给他们的亲人和整个社会造成难以估量的损失。包括可卡因在内的兴奋剂的病理性使用在发病率和死亡率中占很大比例尽管在阐明兴奋剂分子变化方面取得了巨大进展。使用障碍，没有 FDA 批准的药物疗法是其治疗的最大障碍。近年来，治疗精神兴奋剂使用障碍患者所克服的困难是防止复发。人们越来越认识到胃肠道中常驻的细菌种群—— 统称为肠道微生物组，在调节大脑功能和行为方面发挥着关键作用。现在广泛的研究表明，肠道微生物组的变化可以支持健康的大脑功能并推动病理状态的发展，我们之前曾在我们自己的实验室发表过这种急性研究。微生物组的消耗可以增强可卡因的奖励效果并改变基因表达变化在这个提案中，我将研究抗生素引起的微生物组消耗如何影响采取综合多层次方法，在复发小鼠模型中持续寻求药物行为检查纹状体奖励中心在表观遗传、转录和回路水平上的变化。目标 1 (F99) 中的数据表明，微生物组耗尽的小鼠表现出增加的可卡因寻求行为经过一段时间的长期戒断后，从细胞核进行完整的转录组 RNA 测序分析。伏隔核表明这些动物在重要基因中的基因表达表现出显着变化已知影响 DNA 结合、突触可塑性和行为的网络。给予可卡因后微生物组耗尽的小鼠的允许组蛋白乙酰化减少，表明微生物组影响染色质结构。目标 2 (F99) 将更深入地研究染色质结构。通过检查染色质构象来响应滥用药物对表观基因组的微生物调节这将通过荧光的训练和应用来实现。激活核分选 (FANS) 和转座酶可及染色质测序 (ATAC-seq) 分析。这些研究将与行为分析相结合，以提供对表观遗传学的机制见解重塑潜在的药物寻求行为对于目标 3 (K00)，我将确定一位博士后导师来支持。我的专业发展以及我的研究检查微生物组对放电活动的影响这些研究将提供使用体内钙成像技术的纹状体神经元亚群的结果。对可卡因使用障碍模型中肠脑信号传导的重要机制洞察，同时促进我发展成为一名成功的独立调查员，为获得终身教职做好准备。