Transcriptional reprogramming of drug-associated memories in the nucleus accumbens

伏隔核中药物相关记忆的转录重编程

• 批准号: 10282201
• 负责人: Freddyson J Martinez-Rivera
• 金额: $ 17.84万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10282201
• 关键词: Abstinence; Attenuated; Award; Behavior; Behavior Therapy; Behavioral; Brain; Brain region; Cells; Clinic; Clinical; Cocaine; Code; Conflict (Psychology); Cues; Data Set; Decision Making; Dopamine; Drug usage; Enterobacteria phage P1 Cre recombinase; Event; Exposure to; Extinction (Psychology); Faculty; Failure; Gene Transfer; Genes; Genetic Transcription; Hippocampus (Brain); Home; Individual; Individual Differences; Learning; Life; Link; Mediating; Memory; Mentored Research Scientist Development Award; Mentors; Modeling; Molecular; Neurobiology; Neuronal Plasticity; Neurons; Nucleus Accumbens; Outcome; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Procedures; Process; Punishment; Rattus; Recurrence; Relapse; Research; Resistance; Rewards; Rodent Model; Self Administration; Self-control as a personality trait; Shock; Signal Transduction; Substance Use Disorder; Testing; Training; Transgenic Organisms; Viral; Viral Vector; Withdrawal; addiction; adverse outcome; base; cell type; clinically relevant; cocaine self-administration; cost; design; drug seeking behavior; genome-wide; knock-down; learning extinction; neurobehavioral; novel; paired stimuli; pre-clinical; prevent; relating to nervous system; response; success; transcription factor; transcriptional reprogramming; transcriptome; transcriptome sequencing; transcriptomics; translational model

Project Summary Substance use disorder (SUD) is characterized by recurrent drug-taking behaviors that often resemble the renewal-induced relapse after a successful extinction-based therapy. This inability of transferring the learned extinction as the subjects are re-exposed to the original drug context (i.e., their homes) is associated with deficits in neural regions such as the nucleus accumbens (NAc), which regulates the extinction of drug-associated memories and its ability to maintain voluntary abstinence. For instance, addicts developing addiction in a particular context “A” may extinguish the responses for drug-associated cues in a clinical context “B”, but when re-exposed to the same cues in context “A”, fail to transfer the learned extinction to suppress the context-induced renewal/relapse. Thus, because the ability to cease drug-seeking relies on overcoming drug-associated memories, extinction represents a preclinical opportunity to characterize and manipulate the molecular substrates underlying drug-seeking behavior to overcome the renewal-associated relapse. While drug self-administration (SA) leads to numerous neuroplasticity changes in the reward circuit, little is known about the impact of extinction training in reprogramming the addiction-relevant behavioral and transcriptomic codes/outcomes of the brain reward circuit. Together, these research questions pose a platform to delineate my current personal and professional training plan, which will be applied as I transition to a faculty position. Under the tutelage of my primary mentors (Drs. Eric Nestler: sponsor and Paul Kenny: co-sponsor) and my mentoring committee (Drs. Mary Kay Lobo, Yavin Shaham, Li Shen and Fabricio Do Monte), I will use RNA-sequencing of NAc subregions (core and shell) of rats receiving cocaine-SA and contextual extinction (AAA vs ABA) or withdrawal (no extinction) procedures, to characterize the drug-associated memories (phenotypes; renewal vs. extinction), at the transcriptional level (Aim 1). Subsequently, to manipulate the resulting behaviors, I will be targeting the transcriptome of NAc subregions and cell types. Specifically, I will design novel viral vectors to perform viral-mediated gene transfer to manipulate a top hub gene (i.e., transcription factor) previously proven or newly deduced as a main driver of renewal-induced relapse (failure of extinction transfer) in a subregion and cell-specific manner in NAc. As for the cell-specific manipulations, I will be utilizing the novel transgenic rat model expressing Cre-recombinase in dopamine D1 or D2 medium spiny neurons (MSNs) (Aim 2). Purposely, because life situations involving conflict between abstaining from or taking a drug due to adverse consequences are a key feature of relapse, I will test the impact of extinction training on restoring adaptive decisions in a conflict-based model (Aim 3), where drug seeking leads to punishable outcomes (i.e., footshocks), to delve deeper into the neurobiology of extinction/renewal that is most relevant to people.

项目摘要 药物使用障碍（SUD）的特征是复发性吸毒行为，这些行为通常类似于成功基于扩展的治疗后续签诱导的救济。由于受试者被重新暴露于原始药物环境（即其房屋），因此无法转移学习的延伸与神经区域（例如伏抗核）（NAC）等神经区域的缺陷有关，该神经区域（NAC）调节了与药物相关的记忆的灭绝及其戒烟。例如，在特定语境“ A”中发展成瘾的成瘾者可能会在临床环境中熄灭对药物相关线索的反应“ B”，但是当在“ A”上下文中重新暴露于相同的线索时，未能转移学习的扩展以抑制上下文引起的诱导的更新/复发。这是因为停止寻求药物的能力取决于克服与药物相关的记忆，因此扩展代表了临床前的机会，可以表征和操纵寻求药物的行为的分子底物来克服续签相关的继电器。尽管药物自我管理（SA）会导致奖励电路的许多神经可塑性变化，但对于扩展训练在重编程中的影响与成瘾相关的行为和转录组代码/大脑奖励电路的结果鲜为人知。这些研究问题共同构成了一个平台来描述我当前的个人和专业培训计划，当我过渡到教师职位时，该计划将被应用。在我的主要导师的指导下（Eric Nestler博士：赞助商和Paul Kenny：共同赞助者）和我的心理委员会（Mary Kay Lobo博士扩展程序，以在转录水平（AIM 1）处表征与药物相关的记忆（表型；更新与扩展）。随后，为了操纵所产生的行为，我将针对NAC子区域和细胞类型的转录组。具体而言，我将设计新颖的病毒载体，以执行病毒介导的基因转移，以操纵先前证明或新推导的顶部集线器基因（即转录因子），作为在NAC中的子调和细胞特异性方式中以更新诱导的复发（扩展转移失败）的主要驱动力。至于细胞特异性的操作，我将使用在多巴胺D1或D2培养基神经元（MSNS）中表达CRE聚合酶的新型转基因大鼠模型（AIM 2）。目的，因为由于不利后果而弃权或服用药物之间的生活状况是继电器的关键特征，所以我将测试扩展培训对基于冲突的模型中恢复适应性决策的影响（AIM 3），在这种模型中，寻求药物会导致可惩罚的结果（即，脚圈）深入到iS erention to the Greemer to the Meyer oferemoloby/rene nerene ineriention rene inene rene rene rene。