Assali Dina R, Sidikpramana Michael, Villa Andrew P, Falkenstein Jeffrey, Steele Andrew D
Department of Biological Sciences, California State Polytechnic University Pomona, Pomona, CA, United States of America.
PLoS One. 2021 Feb 8;16(2):e0242897. doi: 10.1371/journal.pone.0242897. eCollection 2021.
Circadian rhythms are entrained by light and influenced by non-photic stimuli, such as feeding. The activity preceding scheduled mealtimes, food anticipatory activity (FAA), is elicited in rodents fed a limited amount at scheduled times. FAA is thought to be the output of an unidentified food entrained oscillator. Previous studies, using gene deletion and receptor pharmacology, implicated dopamine type receptor 1 (D1R) signaling in the dorsal striatum as necessary for FAA in mice. To further understand the role of D1R in promoting FAA, we utilized the Cre-lox system to create cell type-specific deletions of D1R, conditionally deleting D1R in GABA neurons using Vgat-ires-Cre line. This conditional deletion mutant had attenuated FAA, but the amount was higher than expected based on prior results using a constitutive knockout of D1R, D1R KODrago. This result prompted us to re-test the original D1R KODrago line, which expressed less FAA than controls, but only moderately so. To determine if genetic drift had diminished the effect of D1R deletion on FAA, we re-established the D1R KODrago knockout line from cryopreserved samples. The reestablished D1R KODrago-cryo had a clear impairment of FAA compared to controls, but still developed increased activity preceding mealtime across the 4 weeks of timed feeding. Finally, we tested a different deletion allele of D1R created by the Knockout Mouse Project. This line of D1R KOKOMP mice had a significant impairment in the acquisition of FAA, but eventually reached similar levels of premeal activity compared to controls after 4 weeks of timed feeding. Taken together, our results suggest that D1R signaling promotes FAA, but other dopamine receptors likely contribute to FAA given that mice lacking the D1 receptor still retain some FAA.
昼夜节律受光照调节,并受非光刺激(如进食)影响。在按计划进食有限量食物的啮齿动物中,会引发在预定用餐时间之前的活动,即食物预期活动(FAA)。FAA被认为是一个未知的食物调节振荡器的输出。先前的研究,通过基因敲除和受体药理学,表明小鼠背侧纹状体中的多巴胺1型受体(D1R)信号传导是FAA所必需的。为了进一步了解D1R在促进FAA中的作用,我们利用Cre-lox系统创建了D1R的细胞类型特异性缺失,使用Vgat-ires-Cre品系在GABA神经元中条件性删除D1R。这种条件性缺失突变体的FAA减弱,但数量高于基于先前使用D1R组成型敲除D1R KODrago的结果所预期的。这一结果促使我们重新测试原始的D1R KODrago品系,其FAA表达低于对照组,但只是适度降低。为了确定基因漂移是否削弱了D1R缺失对FAA的影响,我们从冷冻保存的样本中重新建立了D1R KODrago敲除品系。与对照组相比,重新建立的D1R KODrago-cryo的FAA明显受损,但在4周定时喂养期间,餐前活动仍有所增加。最后,我们测试了由基因敲除小鼠项目创建的D1R的另一个缺失等位基因。这一品系的D1R KOKOMP小鼠在FAA的获得方面有显著损伤,但在4周定时喂养后,最终与对照组相比达到了相似的餐前活动水平。综上所述,我们的结果表明D1R信号传导促进FAA,但鉴于缺乏D1受体的小鼠仍保留一些FAA,其他多巴胺受体可能也对FAA有贡献。