Molecular genetics of sensory modulation of motor programs

项目总结 5-羟色胺和神经肽等神经调节剂可以对神经产生广泛和持久的影响。 电路和行为。这种信号模式对大脑功能至关重要。神经调质信号转导功能障碍 引起宿主神经和精神疾病，而神经调节剂信号通路是靶点 临床上重要的治疗方法和滥用药物。这个项目的目标是增进对 调节神经调节系统的发育和功能的分子机制 行为。为此，我们研究了线虫，它的小而易接近的神经系统被赋予 人类大脑中发现的大多数神经调节剂。线虫的许多行为需要特定的 神经调节剂，并服从基因分析，允许无偏见地发现所需的因素 用于神经调节信号或神经调节系统的发展。我们已经找到了一个电路 结合两种类型的神经调节来控制线虫简单而刻板的行为。化学感官 BAG神经元释放的神经肽可以有效地抑制生殖系统中的一对5-羟色胺能神经元 线虫两性的神经肌肉系统--HSNS。通过对所产生的行为的基因研究 通过这个回路，我们已经发现了肽能袋的发育和功能所需的基因和 神经肽调节HSN功能和生殖行为所需的因子。除了服务之外 作为神经调节的模型，这个回路使我们能够研究动物微生物的神经生物学。 互动。袋状神经元检测微生物呼吸产生的二氧化碳，它们在 一种评估环境微生物质量的电路，允许线虫区分 营养微生物和病原体。我们已经将我们对宿主-微生物相互作用的兴趣与我们对 通过研究微生物代谢物作为5-羟色胺的激动剂来影响神经调节 动物的行为。到目前为止，我们的研究已经揭示了在发育和功能中的功能 Toll样受体及其相关信号通路的神经调节系统，胰岛素信号， 进化上保守的转录因子，以及神经元兴奋性的调节。生化和遗传学 基于这些发现的屏幕继续产生新的因素，我们预计这条赛道将继续 为了解神经调节的分子机制提供了一个强大的平台。

PROJECT SUMMARY Neuromodulators such as serotonin and neuropeptides can exert widespread and lasting effects on neural circuits and behavior. This mode of signaling is critical for brain function. Dysfunctional neuromodulator signaling causes a host neurological and psychiatric disorders, and neuromodulator signaling pathways are targets of clinically important therapeutics and drugs of abuse. The goal of this project is to advance understanding of molecular mechanisms that regulate the development and function of neuromodulatory systems that control behavior. For this, we study the roundworm C. elegans, whose small and accessible nervous system is endowed with most of the neuromodulators found in the human brain. Many behaviors of C. elegans require specific neuromodulators and are amenable to genetic analysis, which permits unbiased discovery of factors required for neuromodulator signaling or the development of neuromodulatory systems. We have found a circuit that combines two types of neuromodulation to control a simple and stereotyped C. elegans behavior. Chemosensory BAG neurons release neuropeptides that potently inhibit a pair of serotonergic neurons in the reproductive neuromusculature of the C. elegans hermaphrodite - the HSNs. Through genetic studies of behaviors generated by this circuit we have discovered genes required for the development and function of peptidergic BAGs and factors required for neuropeptides to modulate HSN function and reproductive behavior. In addition to serving as a model for neuromodulation, this circuit allows us to investigate the neurobiology of animal-microbe interactions. BAG neurons detect the carbon dioxide generated by microbial respiration, and they function in a circuit that evaluates the quality of environmental microbes and that allows C. elegans to discriminate between nutritive microbes and pathogens. We have linked our interest in host-microbe interactions to our interest in neuromodulation through a study of microbial metabolites that function as agonists of serotonin signaling to affect animal behavior. To date our studies have revealed functions in the development and function of neuromodulatory systems for a Toll-like receptor and its associated signaling pathway, insulin signaling, evolutionarily conserved transcription factors, and regulators of neuronal excitability. Biochemical and genetic screens based on these discoveries continue to yield new factors, and we expect that this circuit will continue to serve as a powerful platform for understanding molecular mechanisms of neuromodulation.