Applied Biology, CSIR-Indian Institute of Chemical Technology (IICT), Tarnaka, Uppal Road, Hyderabad 500007, India; Academy of Scientific and Industrial Research, Ghaziabad 201002, India.
CSIR-Centre for Cellular and Molecular Biology (CCMB), Habsiguda, Uppal Road, Hyderabad 500007, India.
Pharmacol Biochem Behav. 2021 May;204:173170. doi: 10.1016/j.pbb.2021.173170. Epub 2021 Mar 5.
Debilitating mental illness like depression and related mood disorders is due to the disruption in circuitry that controls emotion, motivation, and reward, characterized by disparate phenotypes like decrease in socialization, motivation, threshold for threat apprehension, etc. Chronic stress is a major factor in the etiology of these disorders. Here, using a chronic unpredictable stress (CUS) paradigm the characterization of an array of mood disorder phenotypes in adult zebrafish, in comparison to normal control unstressed fish, was achieved using a battery of behavioral assays including novel ones comprising social interaction test, feed approach test, threat response test and novel tank test. For the predictive validity of the model for mood disorders, the mitigative role of a slow (imipramine) and fast (ketamine) acting antidepressant was assessed. The molecular changes associated with CUS-induced mood disorder phenotype was investigated utilizing a high throughput method called isobaric tag for relative and absolute quantification (iTRAQ) in telencephalon, the region critically associated with the processing of emotional information in the fish brain. Out of 222 proteins identified to be significantly altered, 58 were differentially expressed across the stress and antidepressant-treatment groups at more than one fold (in log2) change. Of these proteins, some were implicated in earlier studies on mood disorders such as CABP1, PER2, mTOR, etc. The enrichment of altered proteins by Ingenuity Pathway Analysis (IPA) led us to mTOR and opioid signaling pathways, the top canonical pathways affected in the fish telencephalon. Interestingly, most of the pathways affected converge at the one controlling cell proliferation thus indicating altered neurogenesis, which was validated using immunohistochemistry for cell proliferation markers BrdU, SOX2, and BLBP. The study concludes that molecules that regulate telencephalon neural progenitor cell proliferation or neurogenesis are crucially involved in chronic stress-induced mood disorders by affecting the circuitry that controls emotion and reward.
使人衰弱的精神疾病，如抑郁症和相关的情绪障碍，是由于控制情绪、动机和奖励的电路中断所致，其特征是表现型不同，如社交减少、动机降低、对威胁感知的阈值等。慢性应激是这些疾病发病的一个主要因素。在这里，我们使用慢性不可预测应激 (CUS) 范式，在一系列行为测试中，包括包括社交互动测试、摄食接近测试、威胁反应测试和新鱼缸测试，比较了正常对照组未应激的鱼类，对成年斑马鱼的一系列情绪障碍表型进行了特征描述。为了评估该模型对情绪障碍的预测有效性，我们评估了一种慢（丙咪嗪）和快（氯胺酮）作用抗抑郁药的缓解作用。利用一种称为等重同位素标签相对和绝对定量 (iTRAQ) 的高通量方法，我们研究了与 CUS 诱导的情绪障碍表型相关的分子变化，该方法在端脑（fish brain）中与情绪信息处理密切相关的区域中使用。在鉴定出的 222 种显著改变的蛋白质中，有 58 种在应激和抗抑郁治疗组中以超过一个倍（在 log2）的变化水平发生差异表达。在这些蛋白质中，有些与情绪障碍的早期研究有关，如 CABP1、PER2、mTOR 等。IPA 对改变的蛋白质进行富集分析，导致 mTOR 和阿片样物质信号通路成为受影响最大的鱼类端脑经典通路。有趣的是，受影响的大多数通路都集中在控制细胞增殖的一个通路上，这表明神经发生发生了改变，这通过增殖标志物 BrdU、SOX2 和 BLBP 的免疫组织化学验证。该研究得出的结论是，调节端脑神经祖细胞增殖或神经发生的分子通过影响控制情绪和奖励的电路，在慢性应激诱导的情绪障碍中起着至关重要的作用。
