Holl K, He H, Wedemeyer M, Clopton L, Wert S, Meckes J K, Cheng R, Kastner A, Palmer A A, Redei E E, Solberg Woods L C
Department of pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
Internal Medicine, Molecular Medicine, Wake Forest Baptist Health, Winston Salem, NC, USA.
Genes Brain Behav. 2018 Feb;17(2):139-148. doi: 10.1111/gbb.12410. Epub 2017 Sep 26.
Major depressive disorder (MDD) is a complex illness caused by both genetic and environmental factors. Antidepressant resistance also has a genetic component. To date, however, very few genes have been identified for major depression or antidepressant resistance. In this study, we investigated whether outbred heterogeneous stock (HS) rats would be a suitable model to uncover the genetics of depression and its connection to antidepressant resistance. The Wistar Kyoto (WKY) rat, one of the eight founders of the HS, is a recognized animal model of juvenile depression and is resistant to fluoxetine antidepressant treatment. We therefore hypothesized that adolescent HS rats would exhibit variation in both despair-like behavior and response to fluoxetine treatment. We assessed heritability of despair-like behavior and response to sub-acute fluoxetine using a modified forced swim test (FST) in 4-week-old HS rats. We also tested whether blood transcript levels previously identified as depression biomarkers in adolescent human subjects are differentially expressed in HS rats with high vs. low FST immobility. We demonstrate heritability of despair-like behavior in 4-week-old HS rats and show that many HS rats are resistant to fluoxetine treatment. In addition, blood transcript levels of Amfr, Cdr2 and Kiaa1539, genes previously identified in human adolescents with MDD, are differentially expressed between HS rats with high vs. low immobility. These data demonstrate that FST despair-like behavior will be amenable to genetic fine-mapping in adolescent HS rats. The overlap between human and HS blood biomarkers suggest that these studies may translate to depression in humans.
重度抑郁症（MDD）是一种由遗传和环境因素共同导致的复杂疾病。抗抑郁药耐药性也有遗传因素。然而，迄今为止，很少有基因被确定与重度抑郁症或抗抑郁药耐药性有关。在本研究中，我们调查了远交系异质种群（HS）大鼠是否会是一个合适的模型，用于揭示抑郁症的遗传学及其与抗抑郁药耐药性的联系。Wistar Kyoto（WKY）大鼠是HS的八个奠基品系之一，是公认的青少年抑郁症动物模型，并且对氟西汀抗抑郁治疗有抗性。因此，我们假设青春期HS大鼠在绝望样行为和对氟西汀治疗的反应方面都会表现出差异。我们使用改良的强迫游泳试验（FST）评估了4周龄HS大鼠绝望样行为和对亚急性氟西汀反应的遗传力。我们还测试了先前在青少年人类受试者中被确定为抑郁症生物标志物的血液转录水平在FST不动时间高与低的HS大鼠中是否存在差异表达。我们证明了4周龄HS大鼠绝望样行为的遗传力，并表明许多HS大鼠对氟西汀治疗有抗性。此外，Amfr、Cdr2和Kiaa1539的血液转录水平，这些基因先前在患有MDD的青少年中被确定，在不动时间高与低的HS大鼠之间存在差异表达。这些数据表明，FST绝望样行为在青春期HS大鼠中适合进行基因精细定位。人类和HS血液生物标志物之间的重叠表明，这些研究可能适用于人类抑郁症。
