Department of Psychiatry, University of California, Los Angeles, California, United States of America.
Department of Biology, Institute of Zoology, Albertus-Magnus University of Cologne, Cologne, Germany.
PLoS Genet. 2022 Nov 21;18(11):e1010289. doi: 10.1371/journal.pgen.1010289. eCollection 2022 Nov.
The Serotonin Transporter (SERT) regulates extracellular serotonin levels and is the target of most current drugs used to treat depression. The mechanisms by which inhibition of SERT activity influences behavior are poorly understood. To address this question in the model organism Drosophila melanogaster, we developed new loss of function mutations in Drosophila SERT (dSERT). Previous studies in both flies and mammals have implicated serotonin as an important neuromodulator of sleep, and our newly generated dSERT mutants show an increase in total sleep and altered sleep architecture that is mimicked by feeding the SSRI citalopram. Differences in daytime versus nighttime sleep architecture as well as genetic rescue experiments unexpectedly suggest that distinct serotonergic circuits may modulate daytime versus nighttime sleep. dSERT mutants also show defects in copulation and food intake, akin to the clinical side effects of SSRIs and consistent with the pleomorphic influence of serotonin on the behavior of D. melanogaster. Starvation did not overcome the sleep drive in the mutants and in male dSERT mutants, the drive to mate also failed to overcome sleep drive. dSERT may be used to further explore the mechanisms by which serotonin regulates sleep and its interplay with other complex behaviors.
5-羟色胺转运体（SERT）调节细胞外 5-羟色胺水平，是目前大多数用于治疗抑郁症的药物的作用靶点。SERT 活性抑制如何影响行为的机制还知之甚少。为了在模式生物黑腹果蝇中解决这个问题，我们在果蝇 SERT（dSERT）中开发了新的功能丧失突变。先前在果蝇和哺乳动物中的研究表明，5-羟色胺是睡眠的重要神经调节剂，我们新生成的 dSERT 突变体表现出总睡眠时间增加和睡眠结构改变，这类似于给予 SSRI 西酞普兰的作用。白天和夜间睡眠结构的差异以及遗传拯救实验出人意料地表明，不同的 5-羟色胺能回路可能调节白天和夜间的睡眠。dSERT 突变体还表现出交配和摄食缺陷，类似于 SSRIs 的临床副作用，与 5-羟色胺对黑腹果蝇行为的多态影响一致。饥饿并没有克服突变体中的睡眠驱动，在雄性 dSERT 突变体中，交配的驱动也未能克服睡眠驱动。dSERT 可能被用于进一步探索 5-羟色胺调节睡眠及其与其他复杂行为相互作用的机制。
