Imaging Dynamics in Anxiogenic Serotonin Circuitry

致焦虑血清素回路的成像动力学

• 批准号: 10464898
• 负责人: Emily Clarissa Wright
• 金额: $ 7.48万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464898
• 关键词: Acute; Address; Adult; Androgen Receptor; Animals; Anti-Anxiety Agents; Anxiety; Behavior; Behavioral; Biosensor; Brain region; Chronic; Communities; Consensus; Data; Data Analyses; Development; Dorsal; Elements; Endocrine; Engineering; Ensure; Exposure to; Fellowship; Fiber; Gonadal Steroid Hormones; Guidelines; Image; Imaging technology; Knock-out; Knowledge; Light; Link; Maps; Measures; Microdialysis; Moods; Mus; Neurons; Neurosecretory Systems; Optics; Outcome; Pathway interactions; Pattern; Performance; Pharmacology; Photometry; Physiological; Population; Protocols documentation; Reaction; Research; Resolution; Role; STEM career; Scientist; Selective Serotonin Reuptake Inhibitor; Series; Serotonin; Signal Transduction; Site; Specificity; Stimulus; Stress; Structure of terminal stria nuclei of preoptic region; Testing; Testosterone; Time; Training; Transgenic Mice; Transgenic Organisms; Up-Regulation; Work; anxious; attenuation; awake; base; behavior measurement; behavior test; behavioral response; biological adaptation to stress; conditioned fear; deprivation; dorsal raphe nucleus; experimental study; in vivo; insight; male; millisecond; mouse model; neural circuit; novel; optogenetics; response; sensor; sensor technology; serotonin transporter; skills; social defeat; social stress; social stressor; stressor; success; temporal measurement

PROJECT SUMMARY Serotonin has been long been recognized as an important modulator of mood and behavior, yet it projection- specific dynamics are little understood. While serotonin has been well studied in anxiolytic contexts, activity of certain serotonin projections works to increase stress behaviors. In particular, serotonergic projections from dorsal raphe to the anterodorsal bed nucleus of the stria terminalis have been shown to be anxiogenic. Despite decades of targeting serotonin, a consensus on serotonin function and release dynamic is lacking. Pharmacological approaches, microdialysis, and chemogenetic manipulations have produced key insights, but none provide millisecond resolution for serotonin release and correlates of specific reactions and behaviors until recently. The Tian lab is in the final stages of developing two serotonin specific biosensors (sLight and iSeroSnFR) that open the door for new possibilities in serotonin research. I will these sensors combined with fiber-photometry to optically measure behaviorally driven serotonin release in an anxiogenic serotonin circuit with high temporal and spatial resolution. The series of experiments outlined in this proposal are significant because they will: Aim 1) rigorously demonstrate the in vivo utility of serotonin sensors in dissecting anxiety circuit, providing end users important protocols and guidelines for fast technological implementation; Aim2) map dynamics of serotonin release in anxiogenic circuits to stress behavior, and discover how activity in this circuit is impacted in anxious animals and determine the mechanistic impacts of acute vs. chronic SSRI administration on anxiogenic serotonin signaling; Aim 3) determine the developmental effects of pubertal testosterone on the maturation of anxiogenic serotonin activity and SSRI efficacy.

项目摘要 长期以来，5-羟色胺被认为是情绪和行为的重要调节剂，但它投影 - 具体的动态几乎没有理解。虽然5-羟色胺在抗焦虑环境中进行了很好的研究，但 某些5-羟色胺的投影有助于增加压力行为。特别是，血清素能预测来自 末端的脊骨前床核的背侧raphe已被证明是焦虑的。尽管 几十年来靶向5-羟色胺，缺乏对5-羟色胺功能和释放动态的共识。 药理学方法，微透析和化学发生操作已经产生了关键见解，但 没有人提供5-羟色胺释放和特定反应和行为相关的毫秒分辨率 直到最近。天实验室处于开发两个5-羟色胺特异性生物传感器的最后阶段（轻微和 Iserosnfr）为5-羟色胺研究的新可能性打开了大门。我将这些传感器与 纤维光度法在焦虑症5-羟色胺回路中的光学测量以行为驱动的5-羟色胺释放 具有高时空和空间分辨率。 该提案中概述的一系列实验非常重要，因为它们将：目标1）严格 证明5-羟色胺传感器在解剖焦虑电路时的体内实用性，使最终用户很重要 快速技术实施的协议和指南； AIM2）在5-羟色胺释放的动力学中 焦虑的电路压力行为，并发现该电路中的活动在焦虑的动物中如何影响 并确定急性与慢性SSRI给药对抗焦虑症的机械影响 信号传导；目标3）确定青春期睾丸激素对焦虑症的成熟的发育影响 5-羟色胺活性和SSRI功效。