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: 10237136
• 负责人: Zijun Wang
• 金额: $ 10.21万
• 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/10237136
• 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 海洛因成瘾的特点是强迫性渴望、寻求毒品和反复复发， 被认为是最成问题的公共卫生问题之一。海洛因复吸受到以下因素的显着影响 压力。人类研究表明，暴露于生活压力源与强迫性药物滥用和 戒毒期间再次吸毒。更重要的是，早年的环境压力 与更大的成瘾风险和增加的复发风险有关。早期社会隔离（期间 青春期（ESI）作为广泛使用的早期生活压力模型之一，会导致许多行为 与心理健康问题相关的异常，包括复发的可能性增加。我的初步 数据证实，ESI 会增强提示诱导的海洛因寻求，强制戒除海洛因后 管理（SA）。然而，潜在的神经生物学机制在很大程度上尚未得到充分研究。 前额皮质（PFC）参与药物复发的调节。已发现 PFC 功能减退 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 VTA 对海洛因复吸至关重要。由于 ESI 会导致 PFC 中不可逆的突触功能障碍，因此很可能 ESI 通过加剧 PFC 故障来增强海洛因寻求。此外，由于PFC的异质性 投射神经元（PFC-VTA 和 PFC-NAc 投射具有不同的分布和分子特征）， 目前尚不清楚海洛因复吸易感性的神经元回路特异性分子机制是什么。 因此，我的中心假设是 PFC (PFC-VTA/PFC-NAc) 投射神经元功能减退是 参与 ESI 增强海洛因寻找，这种效应伴随着基因转录变化 在 PFC-VTA 和/或 PFC-NAc 投射神经元内。 为了验证我的假设，我将结合最先进的电生理学、化学遗传学策略 （DREADD）和投影特异性分子分析（TRAP [翻译核糖体亲和纯化]） 技术融入我的学习。我建议测量 PFC-NAc 和 PFC-VTA 中的兴奋性突触传递 强制戒除海洛因 SA 后投射的神经元。化学遗传学工具将用于测试 PFC-VTA 和 PFC-NAc 投射神经元在 ESI 强化海洛因寻找中的功能作用。陷阱方法 （使用 GFPL10 转基因小鼠）将用于分离投射特异性神经元，用于 RNA-seq 来识别 ESI 增强海洛因寻找的潜在分子机制。我的研究计划的完成情况 培训计划将使我能够独立追求我的长期职业目标：研究神经元回路特定 海洛因的分子机制寻求最终促进药物疗法的发展 海洛因复发。