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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

基本信息

批准号：
10669082
负责人：
Zijun Wang
金额：
$ 13.21万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
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/10669082
关键词：
Abstinence Adolescence Adult Affect Affinity Chromatography Amphetamines Attenuated Behavior Behavioral Bioinformatics Candidate Disease Gene Chronic Chronic stress Cues Data Development Drug Regulations Drug abuse Drug usage Early identification Electrophysiology (science)Evaluation Exposure to Functional disorder Gene Expression Gene Mutation Gene Transfer Genes Genetic 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 Behavior Social Controls Social Interaction Social isolation Stress Synapses Synaptic Transmission Technology Testing Therapeutic Training Transgenic Mice Translating Viral addiction behavioral study career cocaine seeking comparative craving designer receptors exclusively activated by designer drugs differential expression drug relapse early life adversity early life stress genetic approach genome-wide insight mouse model nerve supply neurobiological mechanism neuron development neuronal circuitry pre-clinical research preclinical study relapse prevention stressor synaptic function tool transcriptome sequencing

项目摘要

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.

摘要海洛因成瘾的特征是强迫性渴望、寻求毒品和复吸，被认为是最有问题的公共卫生问题之一。海洛因复吸受到以下因素的显著影响：应力人类研究表明，暴露于生活压力与强迫性药物滥用有关，在戒毒期间重新吸毒。更重要的是，生命早期的环境压力与更大的成瘾风险和更高的复发风险有关。早期社会隔离（在青春期，ESI），作为早期生活压力的广泛使用的模型之一，导致许多行为与心理健康问题有关的异常，包括复发的脆弱性增加。我的初步数据证实，ESI增强了海洛因自我强迫戒断后线索诱导的海洛因寻求，给药（SA）。然而，潜在的神经生物学机制在很大程度上是研究不足。前额叶皮层（PFC）参与药物复吸的调节。前额叶皮层功能减退阿片类药物滥用者临床前研究表明，投射到皮质下区域如NAc和腹侧被盖区是海洛因复发的关键。由于ESI会诱导前额叶皮质不可逆转的突触功能障碍，因此很可能 ESI通过加重PFC功能障碍来增强海洛因寻求。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），海洛因复吸脆弱性的神经回路特异性分子机制尚不清楚。因此，我的中心假设是PFC（PFC-VTA/PFC-NAc）投射神经元功能减退是由于参与ESI-增强海洛因寻求，这种作用伴随着基因转录的变化在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（DREADDs）和投射特异性分子分析（TRAP [翻译核糖体亲和纯化]）技术到我的研究。我建议测量PFC-NAc和PFC-VTA的兴奋性突触传递投射神经元后，从海洛因SA强制戒毒。化学发生工具将用于测试 PFC-VTA和PFC-NAc投射神经元在ESI强化的海洛因寻求中的功能作用TRAP方法（使用GFPL 10转基因小鼠）将被应用于分离投射特异性神经元用于RNA-seq以鉴定潜在的分子机制ESI增强海洛因寻求。完成我的研究计划，培训计划将使我能够独立地追求我的长期职业目标：研究神经元回路特异性海洛因的分子机制，寻求最终有助于药物治疗的发展，海洛因复吸