Neuronal Circuits and Molecular Mechanisms Underlying Early Social Isolation-Potentiated Heroin Seeking

早期社会孤立强化海洛因寻求背后的神经元回路和分子机制

• 批准号: 10456987
• 负责人: Zijun Wang
• 金额: $ 10.67万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456987
• 关键词: Abstinence; Adolescence; Affect; Affinity Chromatography; Attenuated; Behavior; Behavioral; Bioinformatics; Candidate Disease Gene; Chronic; Chronic stress; Cues; Data; Development; Drug Regulations; Drug abuse; Electrophysiology (science); Evaluation; Exposure to; Functional disorder; Gene Expression; Gene Mutation; Gene Transfer; Genes; Genetic Transcription; Glutamates; Goals; Heroin; Heroin Dependence; Human; Immunofluorescence Immunologic; Life; Locomotion; Measures; Medial; Mediating; Mental Health; Mental disorders; Methods; Modeling; Molecular; Molecular Profiling; Motivation; Mus; Neurons; Opioid abuser; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Play; Prefrontal Cortex; Procedures; Public Health; Regulation; Relapse; Research; Ribosomes; Risk; Role; Self Administration; Social Controls; Social Interaction; Social isolation; Stress; Synapses; Synaptic Transmission; Technology; Testing; Therapeutic; Training; Transgenic Mice; Translating; Viral; addiction; behavioral study; career; comparative; craving; designer receptors exclusively activated by designer drugs; differential expression; disorder later incidence prevention; drug relapse; early life adversity; early life stress; genome-wide; insight; mouse model; nerve supply; neurobiological mechanism; neuronal circuitry; pre-clinical research; preclinical study; social; stressor; synaptic function; tool; transcriptome sequencing

Abstract Heroin addiction is characterized by compulsive craving, drug seeking and re-occurrence of relapse, and is considered to be one of the most problematic public health concerns. Heroin relapse is significantly affected by stress. Human studies suggest that exposure to life stressors is correlated with compulsive drug abuse and relapse to drugs during periods of abstinence. More importantly, environmental stress during early life is related to bigger risk for developing addiction and increased relapse vulnerability. Early social isolation (during adolescence, ESI), as one of the widely used models for early life stress, causes many behavioral abnormalities that related to mental health issues including increased vulnerability for relapse. My preliminary data confirmed that ESI potentiates cue-induced heroin seeking after forced abstinence from heroin self- administration (SA). However, the underlying neurobiological mechanisms are largely understudied. Prefrontal cortex (PFC) is involved in the regulation of drug relapse. PFC hypofunction has been identified in opioid abusers. Preclinical studies indicate that PFC, which projects to subcortical regions such as NAc and VTA, is critical for heroin relapse. As ESI induces irreversible synaptic dysfunction in the PFC, it is likely that ESI potentiates heroin seeking by exacerbating PFC malfunction. Moreover, due to the heterogeneous of PFC projecting neurons (PFC-VTA and PFC-NAc projection have distinct distribution and molecular signatures), it remains unclear what are the neuronal circuit-specific molecular mechanisms for heroin relapse vulnerability. Therefore, my central hypothesis is that hypofunction of PFC (PFC-VTA/PFC-NAc) projecting neurons is involved in ESI-potentiates heroin seeking, and this effect is accompanied by gene transcriptional changes within the PFC-VTA and/or PFC-NAc projecting neurons. To test my hypothesis, I will incorporate state-of-the-art electrophysiology, chemogenetic strategies (DREADDs), and projection-specific molecular profiling (TRAP [translating ribosome affinity purification]) technologies into my study. I propose to measure excitatory synaptic transmission in PFC-NAc and PFC-VTA projecting neurons after forced abstinence from heroin SA. Chemogenetic tools will be used to test the functional role of PFC-VTA and PFC-NAc projecting neurons in ESI-intensified heroin seeking. TRAP methods (using GFPL10 transgenic mice) will be applied to isolate projection-specific neurons for RNA-seq to identify potential molecular mechanisms for ESI-potentiated heroin seeking. Fulfillment of my Research Plan and Training Plan will allow me to independently pursue my long-term career goals: study neuronal circuit-specific molecular mechanisms for heroin seeking to ultimately contribute to the development of pharmacotherapies for heroin relapse.

抽象的 海洛因成瘾的特征是强迫性渴望，寻求药物和复发的重新出现，并且是 被认为是最有问题的公共卫生问题之一。海洛因复发受到显着影响 压力。人类研究表明，暴露于生命压力源与强迫性滥用药物和 在禁欲期间复发到药物。更重要的是，早期的环境压力是 与更大的成瘾风险和增加复发脆弱性有关。早期的社会隔离（在 青春期，ESI）是一种广泛使用的早期生活压力模型之一，导致许多行为 与心理健康问题有关的异常，包括增加复发的脆弱性。我的初步 数据证实，ESI增强了提示引起的海洛因寻求海洛因自我戒酒后的寻求海洛因 管理（SA）。但是，基本的神经生物学机制在很大程度上被研究了。 前额叶皮层（PFC）参与药物复发的调节。已鉴定出PFC功能障碍 在阿片类药物滥用者中。临床前研究表明，PFC投射到皮质下区域，例如NAC和NAC和 VTA，对于海洛因复发至关重要。由于ESI在PFC中引起了不可逆的突触功能障碍，因此很可能 ESI通过加剧PFC故障而增强海洛因。而且，由于PFC的异质性 投射神经元（PFC-VTA和PFC-NAC投影具有独特的分布和分子特征）， 尚不清楚海洛因复发脆弱性的神经元电路特异性分子机制是什么。 因此，我的核心假设是PFC（PFC-VTA/PFC-NAC）投射神经元的功能是 参与寻求海洛因的Esi-Potentiat，这种效果伴随基因转录变化 在PFC-VTA和/或PFC-NAC投射神经元中。 为了检验我的假设，我将结合最先进的电生理学，化学遗传学策略 （Dreadds）和投影特异性分子分析（TRAP [翻译核糖体亲和力纯化]） 我的研究技术。我建议测量PFC-NAC和PFC-VTA中的兴奋性突触传播 强迫海洛因SA戒酒后投射神经元。化学发生工具将用于测试 PFC-VTA和PFC-NAC投射神经元在寻求大量密集的海洛因中的功能作用。陷阱方法 （使用GFPL10转基因小鼠）将应用于分离的RNA-Seq投射特异性神经元以识别 ESI启用海洛因寻求的潜在分子机制。履行我的研究计划和 培训计划将使我能够独立追求自己的长期职业目标：研究特定于神经元电路 海洛因的分子机制，试图最终有助于开发药物疗法 海洛因复发。