Impaired Pavlovian fear extinction is a common phenotype across genetic lineages of the 129 inbred mouse strain.
Impaired Pavlovian fear extinction is a common phenotype across genetic lineages of the 129 inbred mouse strain.
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DOI：
10.1111/j.1601-183x.2009.00519.x
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发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Holmes A
中科院分区：
文献类型：
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作者：
Camp M;Norcross M;Whittle N;Feyder M;D'Hanis W;Yilmazer-Hanke D;Singewald N;Holmes A
恐惧消退在精神疾病中受损，如创伤后应激障碍和精神分裂症，这有一个主要的遗传成分。然而，恐惧消退的个体差异性背后的遗传因素仍有待确定。通过比较一组近交系小鼠品系，我们最近确定了一种品系，129 S1/SvImJ（129 S1），与C57 BL/6 J相比，它在巴甫洛夫恐惧消退中表现出深刻的和选择性的缺陷，以及关键的前额叶杏仁核回路功能激活的相关异常。本研究的第一个目的是评估多个129个亚株的恐惧灭绝，这些亚株代表了菌株的四种不同的遗传谱系（亲本、钢铁、畸胎瘤、污染）。结果表明，129 P1/ReJ、129 P3/J、129 T2/SvEmsJ和129 X1/SvJ相对于C57 BL/6 J表现出较差的恐惧消退，而129 S1表现出恐惧潜伏的证据。基于这些结果，第二个目的是进一步表征129 S1中灭绝表型的性质和特异性，作为129个亚株的范例。结果表明，129 S1的消退缺陷既不是未能适应敏感的恐惧反应的结果，也不是对（无条件）音调本身的恐惧反应的人为因素。更强的调节方案（即，与C57 BL/6 J相比，5 ×更高强度的电击）导致129 S1的恐惧表达增加，这是由于在音调呈现期间冻结的快速上升。综上所述，这些数据表明，受损的恐惧消退是一个表型特征，共同跨越129个亚株，并提供初步证据表明，受损的恐惧消退在129 S1可能反映了亲恐惧孵化样的过程。
Fear extinction is impaired in psychiatric disorders such as posttraumatic stress disorder and schizophrenia, which have a major genetic component. However, the genetic factors underlying individual variability in fear extinction remain to be determined. By comparing a panel of inbred mouse strains, we recently identified a strain, 129S1/SvImJ (129S1), that exhibits a profound and selective deficit in Pavlovian fear extinction, and associated abnormalities in functional activation of a key prefrontal-amygdala circuit, as compared to C57BL/6J. The first aim of the present study was to assess fear extinction across multiple 129 substrains representing the strain’s four different genetic lineages (Parental, Steel, Teratoma, Contaminated). Results showed that 129P1/ReJ, 129P3/J, 129T2/SvEmsJ, and 129X1/SvJ exhibited poor fear extinction, relative to C57BL/6J, while 129S1 showed evidence of fear incubation. Based on these results, the second aim was to further characterize the nature and specificity of the extinction phenotype in 129S1, as an exemplar of the 129 substrains. Results showed that the extinction deficit in 129S1 was neither the result of a failure to habituate to a sensitized fear response, nor an artifact of a fear response to (unconditioned) tone per se. A stronger conditioning protocol (i.e., five × higher intensity shocks) produced an increase in fear expression in 129S1, relative to C57BL/6J, due to rapid rise in freezing during tone presentation. Taken together, these data demonstrate that impaired fear extinction is a phenotypic feature common across 129 substrains, and provide preliminary evidence that impaired fear extinction in 129S1 may be reflect a pro-fear incubation-like process.