The function of the ZFP189 transcription factor in the nucleus accumbens facilitates cocaine-specific transcriptional and behavioral adaptations

Here, we explore the function of a drug-associated repressive transcription factor (TF), ZFP189, whose expression in the nucleus accumbens (NAc) facilitates cocaine-induced molecular and behavioral adaptations. To uncover the molecular action of ZFP189, we created synthetic ZFP189 TFs of distinct transcriptional function, including ZFP189VPR, which activates the expression of target genes and exerts opposite transcriptional control to the endogenously repressive ZFP189. By virally delivering synthetic ZFP189 TFs to the NAc of mice, we discover that the molecular control exerted by synthetic or endogenous ZFP189 solely alters behavioral response to cocaine but not morphine or palatable food. Transcriptional adaptation occurred in response to cocaine, but not morphine. We demonstrate that NAc ZFP189 function drives the cocaine self-administration behaviors, whereas NAc ZFP189VPR impedes this worsening of cocaine taking behaviors. Collectively, this research illuminates the mechanisms through which a drug-associated TF specifically coordinates the brain adaptations necessary for the increasing of cocaine self-administration behaviors. Overall design: To investigate the function of ZFP189 TF in driving drug-response, we surgically delivered HSV-ZFP189 TFs within mouse NAc tissue and perform drug-induced locomotor testing, followed by NAc tissue extraction and RNA seqencing.

本研究旨在探究一种与药物相关的阻遏型转录因子（Transcription Factor, TF）ZFP189的功能——该因子在伏隔核（nucleus accumbens, NAc）中的表达可介导可卡因诱导的分子与行为适应性改变。为揭示ZFP189的分子作用机制，我们构建了具备不同转录调控功能的人工合成ZFP189转录因子，其中包括ZFP189VPR：该变体可激活靶基因表达，与内源性阻遏型ZFP189发挥截然相反的转录调控作用。通过病毒递送方式将合成型ZFP189转录因子导入小鼠伏隔核，我们发现，合成型或内源性ZFP189所介导的分子调控，仅会改变小鼠对可卡因的行为响应，而不会影响其对吗啡或适口性食物的行为响应。转录适应性改变仅在可卡因给药后出现，吗啡给药后并未观察到此现象。我们证实，伏隔核中的ZFP189功能可驱动可卡因自身给药行为，而伏隔核中的ZFP189VPR则可抑制这种可卡因摄取行为的恶化。综上，本研究阐明了一类与药物相关的转录因子，如何通过特异性协调大脑适应性改变，介导可卡因自身给药行为的增强。整体实验设计：为探究ZFP189转录因子在药物响应中的功能，我们通过外科手术将携带ZFP189转录因子的单纯疱疹病毒（Herpes Simplex Virus, HSV）递送至小鼠伏隔核组织，随后开展药物诱导的运动活性检测，再提取伏隔核组织并进行RNA测序（RNA Sequencing）。