Division of Biology & Biological Engineering, California Institute of Technology, 1200 E California Boulevard, Pasadena, CA 91125, USA.
Division of Biology & Biological Engineering, California Institute of Technology, 1200 E California Boulevard, Pasadena, CA 91125, USA.
Curr Biol. 2022 Aug 8;32(15):3365-3373.e6. doi: 10.1016/j.cub.2022.05.048. Epub 2022 Jun 8.
Secreted neuromodulators, like biogenic amines and neuropeptides, can reconfigure circuit functions both locally and at a distance and establish global brain states that alter circuit outputs over prolonged timescales. Despite their diversity and ubiquitous presence, many studies on neuromodulation tend to focus on dissecting the function and site of action of individual neuropeptides. Here, we take a different approach by conducting a systems-level investigation of neuropeptide receptor signaling function and cell-type-specific distribution in the context of the Caenorhabditis elegans diapause entry developmental decision. C. elegans diapause entry is controlled by sensory perception of external factors and is regulated by neuropeptide signaling. We performed a comprehensive functional screen of neuropeptide receptor mutants for pheromone-induced diapause entry phenotypes and integrated these results with published C. elegans single-cell RNA-seq data to reveal that almost all neuron classes expressed at least one receptor with a role in diapause entry. Our receptor expression analysis also identified four highly modulated neural hubs with no previously reported roles in diapause entry that are distributed throughout the animal's body, possibly as a means of synchronizing the whole-organism transition into the appropriate larval morph. Furthermore, most neuron classes expressed unique neuropeptide receptor repertoires that have opposing effects on the diapause entry decision. We propose that brain-wide antagonistic neuropeptide modulation of individual neuron classes by distinct neuropeptide receptor subsets could serve as a strategy against overmodulation and that this motif might generalize to other decision-making paradigms in other organisms.
分泌的神经调质，如生物胺和神经肽，可以在局部和远距离重新配置电路功能，并建立全局脑状态，从而在长时间尺度上改变电路输出。尽管它们具有多样性和普遍存在性，但许多关于神经调制的研究往往侧重于剖析单个神经肽的功能和作用部位。在这里，我们采取了一种不同的方法，通过对秀丽隐杆线虫休眠进入发育决策中的神经肽受体信号转导功能和细胞类型特异性分布进行系统水平的研究。秀丽隐杆线虫休眠进入是由对外界因素的感觉感知控制的，受神经肽信号的调节。我们对神经肽受体突变体进行了全面的功能筛选，以研究其在信息素诱导的休眠进入表型中的作用，并将这些结果与已发表的秀丽隐杆线虫单细胞 RNA-seq 数据整合，揭示了几乎所有神经元类群都至少表达了一种在休眠进入中起作用的受体。我们的受体表达分析还确定了四个高度调节的神经中枢，它们在休眠进入中没有先前报道的作用，分布在动物的全身，可能是作为一种使整个生物体进入适当的幼虫形态的同步化手段。此外，大多数神经元类群表达了独特的神经肽受体库，这些受体对休眠进入决策有相反的影响。我们提出，通过不同的神经肽受体亚群对单个神经元类群进行广泛的拮抗神经肽调节，可能是一种对抗过度调节的策略，而且这种模式可能会推广到其他生物体的其他决策模式中。
