Oliver R J, Brigman J L, Bolognani F, Allan A M, Neisewander J L, Perrone-Bizzozero N I
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico.
Roche Pharma Research and Early Development; Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center, Basel, Switzerland.
Genes Brain Behav. 2018 Apr;17(4):e12454. doi: 10.1111/gbb.12454. Epub 2018 Jan 26.
The neuronal RNA-binding protein HuD is involved in synaptic plasticity and learning and memory mechanisms. These effects are thought to be due to HuD-mediated stabilization and translation of target mRNAs associated with plasticity. To investigate the potential role of HuD in drug addiction, we first used bioinformatics prediction algorithms together with microarray analyses to search for specific genes and functional networks upregulated within the forebrain of HuD overexpressing mice (HuD ). When this set was further limited to genes in the knowledgebase of addiction-related genes database (KARG) that contains predicted HuD-binding sites in their 3' untranslated regions (3'UTRs), we found that HuD regulates networks that have been associated with addiction-like behavior. These genes included Bdnf and Camk2a, 2 previously validated HuD targets. Since addiction is hypothesized to be a disorder stemming from altered gene expression causing aberrant plasticity, we sought to test the role of HuD in cocaine conditioned placed preference (CPP), a model of addiction-related behaviors. HuD mRNA and protein were upregulated by CPP within the nucleus accumbens of wild-type C57BL/6J mice. These changes were associated with increased expression of Bdnf and Camk2a mRNA and protein. To test this further, we trained HuD and wild-type mice in CPP and found that HuD mice showed increased cocaine CPP compared with controls. This was also associated with elevated expression of HuD target mRNAs and proteins, CaMKIIα and BDNF. These findings suggest HuD involvement in addiction-related behaviors such as cocaine conditioning and seeking, through increased plasticity-related gene expression.
神经元RNA结合蛋白HuD参与突触可塑性以及学习和记忆机制。这些作用被认为是由于HuD介导了与可塑性相关的靶mRNA的稳定性和翻译。为了研究HuD在药物成瘾中的潜在作用，我们首先使用生物信息学预测算法并结合微阵列分析，来寻找在过表达HuD的小鼠（HuD+）前脑内上调的特定基因和功能网络。当将这一组基因进一步限定为成瘾相关基因数据库（KARG）知识库中的基因，这些基因在其3'非翻译区（3'UTR）含有预测的HuD结合位点时，我们发现HuD调节与成瘾样行为相关的网络。这些基因包括Bdnf和Camk2a，这是2个先前已验证的HuD靶标。由于成瘾被假设为一种源于基因表达改变导致异常可塑性的疾病，我们试图测试HuD在可卡因条件性位置偏爱（CPP）中的作用，CPP是一种成瘾相关行为的模型。在野生型C57BL/6J小鼠的伏隔核内，CPP使HuD的mRNA和蛋白上调。这些变化与Bdnf和Camk2a的mRNA及蛋白表达增加有关。为了进一步验证，我们在CPP实验中训练HuD+和野生型小鼠，发现与对照组相比，HuD+小鼠表现出更强的可卡因CPP。这也与HuD靶标mRNA和蛋白、CaMKIIα和BDNF的表达升高有关。这些发现表明，HuD通过增加与可塑性相关的基因表达，参与了成瘾相关行为，如可卡因条件反射和觅药行为。
