Dopaminergic mechanisms of sensorimotor gating in larval zebrafish

斑马鱼幼虫感觉运动门控的多巴胺能机制

• 批准号: 9536271
• 负责人: ADAM D DOUGLASS
• 金额: $ 37.88万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9536271
• 关键词: Acoustic Stimulation; Acute; Affect; Anabolism; Anatomy; Animals; Area; Atlases; Auditory; Behavior; Behavioral; Behavioral inhibition; Biological; Brain; Brain region; Calcium; Calcium Signaling; Cell Nucleus; Cells; Cues; Data; Defect; Disease; Dopamine; Dopamine Antagonists; Dopaminergic Cell; Drug Targeting; Environment; Exhibits; Fire - disasters; Gilles de la Tourette syndrome; Goals; Image; Location; Locomotion; Mammals; Mediating; Methods; Modeling; Neuroanatomy; Neurons; Neurophysiology - biologic function; Obsessive-Compulsive Disorder; Pathology; Pattern; Phase; Population; Recording of previous events; Reflex action; Schizophrenia; Sensorimotor functions; Sensory; Sensory Process; Shapes; Signal Transduction; Source; Stimulus; Swimming; System; Testing; Time; Tyrosine 3-Monooxygenase; Work; Zebrafish; auditory stimulus; base; cell type; common treatment; diencephalon; dopaminergic neuron; endophenotype; experimental study; human disease; mutant; nervous system disorder; neural circuit; neuromechanism; neuroregulation; optogenetics; prepulse inhibition; relating to nervous system; response; sensory input; spatiotemporal

Project Summary A fundamental requirement of normal brain function is to filter relevant from irrelevant sensory information using criteria that change depending on the immediate behavioral context. One example is a sensorimotor gating phenomenon known as prepulse inhibition (PPI), in which the startle reflex that would normally be evoked by an intense stimulus is inhibited by a weaker preceding cue. Deficits in PPI are a common feature of neurological disorders that entail more general problems with sensory filtering, including schizophrenia, Tourette’s, and obsessive-compulsive disorder. The neuronal mechanisms of PPI are incompletely characterized, though it is known to be critically dependent on dopamine, and a common treatment for all of the disorders mentioned above is the administration of drugs that target dopaminergic systems. Developing a more complete understanding of the basic biological mechanisms that drive PPI, and particularly those that involve dopamine, will generate hypotheses for the neural bases of these and other diseases. This project will exploit the experimental leverage offered by the larval zebrafish to investigate the means by which a genetically-defined population of dopamine neurons located throughout the diencephalon mediates audiomotor PPI. By combining behavioral recordings with calcium imaging, optogenetics, whole-brain activity mapping, and neuroanatomy, the project will achieve three goals: (1) Identify the specific dopaminergic nuclei within the population that participate in audiomotor processing; (2) Test the hypothesis that rapid modulation of activity within these neurons is essential for behavioral inhibition; (3) Assess the anatomical and likely functional targets of dopamine release from these cells in the context of PPI. The results of this work will be a detailed model for how distributed activity within a specific population of dopaminergic neurons shapes sensorimotor gating, and a better understanding of how similar networks might be affected in human disease.

项目摘要 正常大脑功能的一个基本要求是从无关的感觉信息中过滤出相关的信息 使用根据即时行为环境而变化的标准。一个例子是感觉运动 门控现象被称为前脉冲抑制（PPI），其中惊吓反射，通常是 强烈的刺激所引起的反应会被较弱的先前提示所抑制。生产者价格指数的赤字是一个共同的特点， 神经系统疾病引起更普遍的感觉过滤问题，包括精神分裂症， 妥瑞症和强迫症PPI的神经机制尚不完全 特点，虽然它是已知的严重依赖于多巴胺，和一个共同的治疗所有的 上述疾病是靶向多巴胺能系统的药物的给药。开发一 更全面地了解驱动PPI的基本生物学机制，特别是那些 涉及多巴胺，将产生这些和其他疾病的神经基础的假设。 该项目将利用斑马鱼幼鱼提供的实验杠杆来研究 其中位于间脑的遗传定义的多巴胺神经元群体介导 听觉PPI。通过将行为记录与钙成像、光遗传学、全脑活动相结合， 该项目将实现三个目标：（1）识别特定的多巴胺能核团 在参与听觉加工的人群中;（2）测试快速调制的假设， 这些神经元内的活动对于行为抑制是必不可少的;（3）评估解剖学和可能的 在PPI的背景下，从这些细胞释放多巴胺的功能靶点。这项工作的结果将是一个 多巴胺能神经元特定群体内的分布活动如何形成的详细模型 感觉运动门控，以及更好地理解类似的网络如何在人类疾病中受到影响。