Lim Patrick Henry, Shi Guang, Wang Tengfei, Jenz Sophia T, Mulligan Megan K, Redei Eva E, Chen Hao
Department of Psychiatry and Behavioral Science, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
Liaoning Provincial People's Hospital, Liaoning Sheng, China.
Front Genet. 2018 Nov 27;9:566. doi: 10.3389/fgene.2018.00566. eCollection 2018.
Posttraumatic Stress Disorder (PTSD) is a complex illness, frequently co-morbid with depression, caused by both genetics, and the environment. Alcohol Use Disorder (AUD), which also co-occurs with depression, is often co-morbid with PTSD. To date, very few genes have been identified for PTSD and even less for PTSD comorbidity with AUD, likely because of the phenotypic heterogeneity seen in humans, combined with each gene playing a relatively small role in disease predisposition. In the current study, we investigated whether a genetic model of depression-like behavior, further developed from the depression model Wistar Kyoto (WKY) rat, is a suitable vehicle to uncover the genetics of co-morbidity between PTSD and AUD. The by-now inbred WKY More Immobile (WMI) and the WKY Less Immobile (WLI) rats were generated from the WKY via bidirectional selective breeding using the forced swim test, a measure of despair-like behavior, as the functional selector. The colonies of the WMIs that show despair-like behavior and the control strain showing less or no despair-like behavior, the WLI, are maintained with strict inbreeding over 40 generations to date. WMIs of both sexes intrinsically self-administer more alcohol than WLIs. Alcohol self-administration is increased in the WMIs without sucrose fading, water deprivation or any prior stress, mimicking the increased voluntary alcohol-consumption of subjects with AUD. Prior Stress-Enhanced Fear Learning (SEFL) is a model of PTSD. WMI males, but not females, show increased SEFL after acute restraint stress in the context-dependent fear conditioning paradigm, a sexually dimorphic pattern similar to human data. Plasma corticosterone differences between stressed and not-stressed WLI and WMI male and female animals immediately prior to fear conditioning predict SEFL results. These data demonstrate that the WMI male and its genetically close, but behaviorally divergent control the WLI male, would be suitable for investigating the underlying genetic basis of comorbidity between SEFL and alcohol self-administration.
创伤后应激障碍（PTSD）是一种复杂的疾病，常与抑郁症共病，由遗传因素和环境因素共同导致。酒精使用障碍（AUD）也与抑郁症同时出现，且常与PTSD共病。迄今为止，针对PTSD确定的基因非常少，而与AUD共病的PTSD相关基因更少，这可能是由于人类中观察到的表型异质性，以及每个基因在疾病易感性中所起的作用相对较小。在当前的研究中，我们调查了一种从抑郁症模型Wistar Kyoto（WKY）大鼠进一步发展而来的类似抑郁行为的遗传模型，是否是揭示PTSD和AUD共病遗传学的合适载体。目前通过双向选择性育种从WKY大鼠中培育出了近交系的WKY多动（WMI）大鼠和WKY少动（WLI）大鼠，使用强迫游泳试验（一种绝望样行为的测量方法）作为功能选择指标。表现出绝望样行为的WMI大鼠群体和表现出较少或没有绝望样行为的对照品系WLI大鼠，至今已通过严格的近亲繁殖维持了40代。无论雌雄，WMI大鼠自身摄入的酒精都比WLI大鼠多。在没有蔗糖消退、禁水或任何先前应激的情况下，WMI大鼠的酒精自我给药量增加，这模拟了AUD患者自愿饮酒量的增加。先前应激增强恐惧学习（SEFL）是一种PTSD模型。在情境依赖性恐惧条件范式中，急性束缚应激后，WMI雄性大鼠（而非雌性大鼠）表现出增强的SEFL，这是一种与人类数据相似的性别差异模式。在恐惧条件训练前，应激和未应激的WLI和WMI雄性及雌性动物之间的血浆皮质酮差异可预测SEFL结果。这些数据表明，WMI雄性大鼠及其遗传关系密切但行为不同的对照品系WLI雄性大鼠，适合用于研究SEFL与酒精自我给药共病的潜在遗传基础。
