Molecular genetics of sensory modulation of motor programs

项目摘要 神经调节剂如5-羟色胺和神经肽可以对神经系统产生广泛而持久的影响， 电路和行为。这种信号模式对大脑功能至关重要。功能障碍性神经调质信号 引起宿主神经和精神疾病，神经调节剂信号通路是 临床上重要的治疗药物和滥用药物。该项目的目标是促进对 调节神经调节系统的发育和功能的分子机制， 行为为此，我们研究了蛔虫C。秀丽线虫，其小而易接近的神经系统被赋予 与人类大脑中发现的大多数神经调质结合。C. elegans需要特定的 神经调节剂，并服从遗传分析，这允许公正的发现所需的因素， 神经调节信号或神经调节系统的发展。我们发现了一个电路， 结合了两种类型的神经调节来控制一个简单而刻板的C。优雅的行为化学感受 BAG神经元释放神经肽，有效地抑制生殖系统中的一对多巴胺能神经元。 神经肌肉系统的C。秀丽线虫雌雄同体--HSN。通过对行为的遗传研究， 通过这个电路，我们发现了肽能BAGs的发育和功能所需的基因， 神经肽调节HSN功能和生殖行为所需的因子。除了服务 作为神经调节的模型，该回路允许我们研究动物-微生物的神经生物学。 交互. BAG神经元检测微生物呼吸产生的二氧化碳， 评估环境微生物质量并允许C.优雅地区分 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-羟色胺信号传导的激动剂， 动物行为到目前为止，我们的研究已经揭示了功能的发展和功能， Toll样受体的神经调节系统及其相关的信号通路，胰岛素信号， 进化上保守的转录因子和神经元兴奋性调节因子。生化和遗传 基于这些发现的筛选继续产生新的因子，我们预计这一循环将继续下去， 作为理解神经调节分子机制的强大平台。

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.