Behavioral and Gene Regulatory Responses to Developmental Drug Exposures in Zebrafish.
Behavioral and Gene Regulatory Responses to Developmental Drug Exposures in Zebrafish.
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DOI：
10.3389/fpsyt.2021.795175
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发表时间：
2021
影响因子：
4.7
通讯作者：
Busch-Nentwich EM
中科院分区：
文献类型：
--
作者：
Mech AM;Merteroglu M;Sealy IM;Teh MT;White RJ;Havelange W;Brennan CH;Busch-Nentwich EM
在许多人类队列和动物研究中，已经报道了产前药物暴露的发育后果。对后代的长期影响--包括运动和认知障碍、颅脑和心脏异常以及ADHD患病率增加--是世界范围内的社会经济负担。确定导致发育后果的分子变化可能有助于改善缺陷并限制影响。在这项研究中，我们使用斑马鱼，一个成熟的行为和遗传模型，具有保守的药物反应和奖励途径，以确定行为和细胞途径的变化，以响应发育过程中暴露于苯丙胺、尼古丁或羟考酮。在药物存在的情况下，接触该药物的动物表现出与哺乳动物系统中看到的效果一致的行为变化，包括行动能力受损和对声音惊吓的习惯性改变。急性和慢性暴露后的不同反应表明对药物的存在有适应。对暴露的幼虫的转录分析表明，许多基因的差异表达和许多途径的变化，包括与细胞死亡、免疫和昼夜节律调节有关的途径。昼夜节律基因的差异表达与幼虫的行为变化无关，但两个昼夜节律基因arntl2和per2在发育后期也有差异表达，表明发育暴露对昼夜节律基因表达的长期影响。与突触可塑性相关的即刻早期基因Egr1、egr4、Fosab和Junbb都被这三种药物下调，原位杂交显示，所有四种基因在所有神经解剖区域的表达都降低了，包括与奖赏处理、成瘾和其他精神疾病有关的大脑区域。我们预计，这些对药物暴露做出反应的基因表达的早期变化可能会导致产前暴露的后果，他们的发现可能为治疗干预铺平道路，以改善长期的缺陷。
Developmental consequences of prenatal drug exposure have been reported in many human cohorts and animal studies. The long-lasting impact on the offspring—including motor and cognitive impairments, cranial and cardiac anomalies and increased prevalence of ADHD—is a socioeconomic burden worldwide. Identifying the molecular changes leading to developmental consequences could help ameliorate the deficits and limit the impact. In this study, we have used zebrafish, a well-established behavioral and genetic model with conserved drug response and reward pathways, to identify changes in behavior and cellular pathways in response to developmental exposure to amphetamine, nicotine or oxycodone. In the presence of the drug, exposed animals showed altered behavior, consistent with effects seen in mammalian systems, including impaired locomotion and altered habituation to acoustic startle. Differences in responses seen following acute and chronic exposure suggest adaptation to the presence of the drug. Transcriptomic analysis of exposed larvae revealed differential expression of numerous genes and alterations in many pathways, including those related to cell death, immunity and circadian rhythm regulation. Differential expression of circadian rhythm genes did not correlate with behavioral changes in the larvae, however, two of the circadian genes, arntl2 and per2, were also differentially expressed at later stages of development, suggesting a long-lasting impact of developmental exposures on circadian gene expression. The immediate-early genes, egr1, egr4, fosab, and junbb, which are associated with synaptic plasticity, were downregulated by all three drugs and in situ hybridization showed that the expression for all four genes was reduced across all neuroanatomical regions, including brain regions implicated in reward processing, addiction and other psychiatric conditions. We anticipate that these early changes in gene expression in response to drug exposure are likely to contribute to the consequences of prenatal exposure and their discovery might pave the way to therapeutic intervention to ameliorate the long-lasting deficits.
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