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: 10458058
• 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/10458058
• 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; Persons; 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.

项目总结