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 正常脑功能的基本要求是从无关的感觉信息中过滤相关 使用根据直接行为环境改变的标准。一个例子是感觉运动 门控现象称为预硫抑制（PPI），其中通常是惊吓反射 强烈刺激引起的刺激受到较弱的提示抑制。 PPI缺陷是 神经系统疾病会导致更普遍的感觉过滤，包括精神分裂症， 图雷特和强迫症。 PPI的神经元机制不完全 特征是，尽管众所周知，它依赖多巴胺，并且是所有的常见治疗方法 上面提到的疾病是针对多巴胺能系统的药物的给药。开发 对驱动PPI的基本生物学机制，尤其是那些的基本生物学机制，尤其是那些的基本生物学机制 涉及的多巴胺将为这些疾病和其他疾病的神经碱产生假设。 该项目将利用幼虫斑马鱼提供的实验杠杆来调查手段 整个diencephalon的多巴胺神经元的遗传定义的种群介导 Audiomotor PPI。通过将行为记录与钙成像，光遗传学，全脑活动相结合 映射和神经解剖学，该项目将实现三个目标：（1）确定特定的多巴胺能核 在参与有声益体处理的人群中； （2）检验快速调制的假设 这些神经元内的活性对于行为抑制至关重要。 （3）评估解剖学和可能 在PPI的背景下，多巴胺的功能靶标从这些细胞中释放出来。这项工作的结果将是 详细的模型，用于特定多巴胺能神经元中特定种群中的分布活动 感觉运动门控，以及更好地了解人类疾病中类似网络的影响。