Malki Karim, Du Rietz Ebba, Crusio Wim E, Pain Oliver, Paya-Cano Jose, Karadaghi Rezhaw L, Sluyter Frans, de Boer Sietse F, Sandnabba Kenneth, Schalkwyk Leonard C, Asherson Philip, Tosto Maria Grazia
King's College London, Social, Genetic and Developmental Psychiatry Centre (MRC), Institute of Psychiatry, Psychology and Neuroscience, United Kingdom.
University of Bordeaux, Aquitaine Institute for Cognitive and Integrative Neuroscience, Bordeaux, France.
Am J Med Genet B Neuropsychiatr Genet. 2016 Sep;171(6):827-38. doi: 10.1002/ajmg.b.32451. Epub 2016 Apr 19.
Despite moderate heritability estimates, the molecular architecture of aggressive behavior remains poorly characterized. This study compared gene expression profiles from a genetic mouse model of aggression with zebrafish, an animal model traditionally used to study aggression. A meta-analytic, cross-species approach was used to identify genomic variants associated with aggressive behavior. The Rankprod algorithm was used to evaluated mRNA differences from prefrontal cortex tissues of three sets of mouse lines (N = 18) selectively bred for low and high aggressive behavior (SAL/LAL, TA/TNA, and NC900/NC100). The same approach was used to evaluate mRNA differences in zebrafish (N = 12) exposed to aggressive or non-aggressive social encounters. Results were compared to uncover genes consistently implicated in aggression across both studies. Seventy-six genes were differentially expressed (PFP < 0.05) in aggressive compared to non-aggressive mice. Seventy genes were differentially expressed in zebrafish exposed to a fight encounter compared to isolated zebrafish. Seven genes (Fos, Dusp1, Hdac4, Ier2, Bdnf, Btg2, and Nr4a1) were differentially expressed across both species 5 of which belonging to a gene-network centred on the c-Fos gene hub. Network analysis revealed an association with the MAPK signaling cascade. In human studies HDAC4 haploinsufficiency is a key genetic mechanism associated with brachydactyly mental retardation syndrome (BDMR), which is associated with aggressive behaviors. Moreover, the HDAC4 receptor is a drug target for valproic acid, which is being employed as an effective pharmacological treatment for aggressive behavior in geriatric, psychiatric, and brain-injury patients. © 2016 Wiley Periodicals, Inc.
尽管有适度的遗传度估计，但攻击行为的分子结构仍未得到充分表征。本研究将攻击性遗传小鼠模型的基因表达谱与斑马鱼（一种传统上用于研究攻击行为的动物模型）进行了比较。采用元分析、跨物种方法来识别与攻击行为相关的基因组变异。使用Rankprod算法评估三组选择性培育的低攻击行为和高攻击行为小鼠品系（N = 18）（SAL/LAL、TA/TNA和NC900/NC100）前额叶皮质组织的mRNA差异。采用相同方法评估暴露于攻击性或非攻击性社交遭遇的斑马鱼（N = 12）的mRNA差异。比较结果以揭示两项研究中始终与攻击行为相关的基因。与非攻击性小鼠相比，76个基因在攻击性小鼠中差异表达（PFP < 0.05）。与隔离的斑马鱼相比，70个基因在经历打斗遭遇的斑马鱼中差异表达。7个基因（Fos、Dusp1、Hdac4、Ier2、Bdnf、Btg2和Nr4a1）在两个物种中均差异表达，其中5个基因属于以c-Fos基因中心的基因网络。网络分析揭示了与MAPK信号级联的关联。在人类研究中，HDAC4单倍体不足是与短指智力发育迟缓综合征（BDMR）相关的关键遗传机制，该综合征与攻击行为有关。此外，HDAC4受体是丙戊酸的药物靶点，丙戊酸正被用作老年、精神病和脑损伤患者攻击行为的有效药物治疗。© 2016威利期刊公司
