Neuron-Astrocyte Interactions in Developmental Lead Exposure

发育铅暴露中的神经元-星形胶质细胞相互作用

• 批准号: 10226572
• 负责人: Maureen McGuirk Sampson
• 金额: $ 8.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226572
• 关键词: Acute; Address; Adult; Affect; Analytical Chemistry; Astrocytes; Bathing; Behavioral; Biophysics; Calcium; Cell physiology; Cells; Chronic; Communities; Coupled; Data; Detection; Development; Drosophila genus; Drosophila melanogaster; Gap Junctions; Gene Expression; Genetic Transcription; Human; Image; Individual; Institution; Invertebrates; Label; Lead; Life; Light; Literature; Mammals; Maps; Measures; Mental disorders; Mentors; Modeling; Molecular; Molecular Biology; Molecular Toxicology; Moods; Motion; Nervous system structure; Neuromodulator; Neurons; Neurosciences; Optic Lobe; Pathway interactions; Pattern; Pharmacology; Phase; Photic Stimulation; Photoreceptors; Physiological; Postdoctoral Fellow; Process; Research; Role; Sensory; Serotonin; Serotonin Receptor 5-HT2B; Signal Transduction; Site; Stimulus; Stream; System; Technical Expertise; Testing; Toxic Environmental Substances; Toxicokinetics; Training; Visual; Visual system structure; Work; animal tissue; career; cellular targeting; combinatorial; desensitization; early life exposure; experimental study; extracellular; flexibility; fly; human tissue; insight; interest; lead exposure; monoamine; nervous system disorder; neural circuit; neurochemistry; neuroregulation; neurotoxic; neurotoxicology; programs; receptor; receptor expression; response; serotonin receptor; skills; toxicant; transcriptomics; visual processing; visual stimulus

Abstract Serotonergic neurons extensively innervate the visual system of the fruit fly Drosophila melanogaster, yet the role of serotonin signaling in visual processing is unknown. Identification of individual cells expressing serotonin receptors in visual system circuits will allow us to determine the contribution of serotonergic modulation to visual processing computations. Five genetically distinct serotonin receptors are expressed throughout the optic lobe and we identified specific neurons and visual processing pathways targeted by serotonin neuromodulation. Single-cell labeling mapped serotonin receptors to specific visual processing neurons: L2, L4, L5, T1, Lawf1, and Lawf2. Lamina monopolar cell 2 (L2) receives direct input from photoreceptors and expresses the serotonin receptor 5-HT2B. Calcium imaging confirmed an increase in baseline calcium in response to bath-applied serotonin in L2 and its electrically coupled partner, L1. L1 and L2 are the first-order neurons in the light-ON and light-OFF pathways, respectively, and both information streams feed into motion detection circuits. L1 neurons do not express serotonin receptors, demonstrating that indirect mechanisms such as gap junctions enable neuromodulators to influence cells in the absence of receptors. We tested whether serotonin modulates visual responses in L2 neurons and found that serotonin increased the magnitude of visually induced calcium transients. This suggests that neuromodulation may regulate salience to specific visual stimuli in the light-OFF pathway. In this work we tested acute effects of serotonin signaling and I propose to advance these findings by measuring physiological and transcriptomic changes in L2 neurons following chronic increases in serotonin signaling. Together, these data will allow us to compare serotonin modulation over multiple timescales. Additionally, these experiments will reveal molecular pathways and transcriptional programs downstream of serotonin signaling cascades that are important for long-term neuromodulation and may be relevant to mood elevation in humans. This work explores the molecular mechanisms of neuromodulation and will contribute to the understanding of how neuromodulatory signaling is integrated into sensory circuits.

摘要 5-羟色胺能神经元广泛支配果蝇的视觉系统， 然而，血清素信号在视觉处理中的作用尚不清楚。表达的单个细胞的鉴定 视觉系统回路中的5-羟色胺受体将使我们能够确定多巴胺能神经元的作用。 调制到视觉处理计算。五种基因上不同的血清素受体表达 在整个视叶，我们确定了特定的神经元和视觉处理通路的目标， 血清素神经调节单细胞标记将5-羟色胺受体映射到特定的视觉处理 神经元：L2、L4、L5、T1、Lawf 1和Lawf 2。板层单极单元2（L2）接收来自 光感受器并表达5-羟色胺受体5-HT 2B。钙成像证实， L2及其电偶联伴侣L1对浴用5-羟色胺反应的基线钙。L1和L2 分别是光开和光关通路中的一级神经元，两种信息流 输入运动检测电路L1神经元不表达5-羟色胺受体，这表明， 诸如间隙连接的机制使得神经调质能够在受体不存在的情况下影响细胞。我们 测试了血清素是否调节L2神经元的视觉反应，发现血清素增加了L2神经元的视觉反应。 视觉诱导钙瞬变的幅度。这表明，神经调节可能会调节显著性， 特定的视觉刺激在光关闭路径。在这项工作中，我们测试了血清素信号的急性效应， 我建议通过测量L2神经元的生理和转录组学变化来推进这些发现 这是因为血清素信号长期增加。这些数据将使我们能够比较血清素 在多个时间尺度上的调制。此外，这些实验将揭示分子途径， 5-羟色胺信号级联下游的转录程序， 神经调节，并且可能与人类的情绪升高有关。这项工作探讨了分子 神经调节的机制，并将有助于了解神经调节信号是如何 集成到感知电路中。