CONSTRUCT AND FACE VALIDITY OF A NEW MODEL FOR THE THREE-HIT THEORY OF DEPRESSION USING PACAP MUTANT MICE ON CD1 BACKGROUND
CONSTRUCT AND FACE VALIDITY OF A NEW MODEL FOR THE THREE-HIT THEORY OF DEPRESSION USING PACAP MUTANT MICE ON CD1 BACKGROUND
复制标题
DOI：
10.1016/j.neuroscience.2017.04.019
复制
发表时间：
2017-06-23
期刊：
影响因子：
3.3
通讯作者：
Gaszner, Balazs
中科院分区：
文献类型：
--
作者：
Farkas, Jozsef;Kovacs, Laszlo A.;Gaszner, Balazs
重度抑郁症是慢性残疾的常见原因。尽管几十年的努力，没有明确接受的动物模型可用于研究抑郁症。我们测试了一个新的模型的有效性的基础上的脆弱性和弹性的三击概念。将遗传易感性（击中1，垂体腺苷酸环化酶激活多肽，PACAP基因突变），早期生活逆境（击中2，180分钟母亲剥夺，MD 180）和慢性可变轻度应激（击中3，CVMS）相结合。物理，内分泌，行为和功能形态学的工具来验证模型。体重和肾上腺重量的变化以及皮质酮滴度证明CVMS是有效的。强迫游泳试验表明，在CVMS PACAP杂合子（Hz）小鼠与MD 180历史的抑郁症增加，伴随着在大理石掩埋试验中的焦虑水平升高。终纹床核卵圆区的促肾上腺皮质激素释放因子神经元显示FosB表达增加，这与野生型和Hz小鼠的CVMS暴露有关。在具有MD 180病史的CMVS暴露PACAP敲除（KO）小鼠中，尿皮质素1神经元变得过度活跃，这表明中央投射的Edinger-Westphal核对应激KO小鼠抑郁和焦虑水平降低的贡献。MD 180小鼠中缝背核5-羟色胺能神经元丧失对CVMS的适应能力。总之，构建和表面有效性标准表明，CVMS后CD 1背景下的MD 180 PACAP HZ小鼠可用作三击理论的可靠模型。(C)2017年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Major depression is a common cause of chronic disability. Despite decades of efforts, no equivocally accepted animal model is available for studying depression. We tested the validity of a new model based on the three-hit concept of vulnerability and resilience. Genetic predisposition (hit 1, mutation of pituitary adenylate cyclaseactivating polypeptide, PACAP gene), early-life adversity (hit 2, 180-min maternal deprivation, MD180) and chronic variable mild stress (hit 3, CVMS) were combined. Physical, endocrinological, behavioral and functional morphological tools were used to validate the model. Body-and adrenal weight changes as well as corticosterone titers proved that CVMS was effective. Forced swim test indicated increased depression in CVMS PACAP heterozygous (Hz) mice with MD180 history, accompanied by elevated anxiety level in marble burying test. Corticotropin-releasing factor neurons in the oval division of the bed nucleus of the stria terminalis showed increased FosB expression, which was refractive to CVMS exposure in wild-type and Hz mice. Urocortin1 neurons became over-active in CMVS-exposed PACAP knock out (KO) mice with MD180 history, suggesting the contribution of centrally projecting Edinger-Westphal nucleus to the reduced depression and anxiety level of stressed KO mice. Serotoninergic neurons of the dorsal raphe nucleus lost their adaptation ability to CVMS in MD180 mice. In conclusion, the construct and face validity criteria suggest that MD180 PACAP HZ mice on CD1 background upon CVMS may be used as a reliable model for the three-hit theory. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.