Molecular and Cellular Mechanisms of Acoustic Startle Threshold Regulation

声惊吓阈值调节的分子和细胞机制

• 批准号: 10599887
• 负责人: Kurt C. Marsden
• 金额: $ 37.37万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599887
• 关键词: Acoustics; Actins; Acute; Affect; Anxiety; Architecture; Auditory; Behavior; Behavior Disorders; Behavioral; Binding; Biological; Biological Models; Brain; Bypass; Calcium; Cells; Cellular Morphology; Clinical; Complex; Critical Pathways; Cytoplasm; Cytoskeleton; DLG4 gene; Data; Defect; Detection; Development; Disease; Electrophysiology (science); Enabling Factors; Epilepsy; Equilibrium; Esthesia; Excitatory Synapse; FMR1; Fiber; Foundations; Genetic; Glutamates; Goals; Hair Cells; Hypersensitivity; Image; Inhibitory Synapse; Interneurons; Label; Laboratories; Link; Measures; Mediating; Molecular; Molecular Genetics; Motor Neurons; Movement; Mutagenesis; Nervous System; Nervous System Physiology; Neurologic Dysfunctions; Neurons; Neurophysiology - biologic function; Optics; Pathway interactions; Peripheral; Phenotype; Polymers; Population; RNA; Regulation; Reproducibility; Research; Role; Schizophrenia; Sensory; Site; Startle Reaction; Stereotyping; Stimulus; Structure; Synapses; Testing; Therapeutic Intervention; Transgenic Organisms; Translational Repression; Translations; Variant; Work; Zebrafish; addiction; auditory stimulus; autism spectrum disorder; base; behavioral phenotyping; behavioral response; cell type; density; experience; genome wide screen; gephyrin; hindbrain; human disease; imaging approach; in vivo imaging; molecular modeling; mutant; neural; neural circuit; neuronal circuitry; neuropsychiatric disorder; novel; optogenetics; polymerization; programs; promoter; protein protein interaction; response; scaffold; sensory processing disorder; sensory stimulus; sound; tool

Project Summary. A fundamental function of the nervous system is to distinguish between threatening and non- threatening stimuli. For example, a sudden intense sound that indicates danger should trigger an acoustic startle response, but an innocuous sound should not. This type of behavioral threshold is a basic mechanism for sensorimotor filtering, and the importance of setting this threshold appropriately is highlighted by the startle hypersensitivity observed in neuropsychiatric diseases such as autism, anxiety, and schizophrenia. Despite its importance, and in contrast to our knowledge of experience-dependent startle modulation, the molecular and cellular pathways that establish and maintain the innate startle threshold are not well characterized. By developing a more complete understanding of the biological mechanisms that govern the startle threshold, we can generate new hypotheses about the neural bases for these diseases. This project will leverage the powerful larval zebrafish model system to investigate the molecular-genetic and neural circuit bases of the startle threshold. Here a simple, conserved, and genetically accessible circuit drives a stereotyped startle response, with auditory afferents triggering reticulospinal neurons to activate motor neurons and initiate movement. In a recent genome-wide screen, we identified a novel regulator of the innate startle threshold: cytoplasmic Fragile X mental retardation protein (FMRP) interacting protein 2 (cyfip2). cyfip2 mutants are hypersensitive and startle to low intensity sounds that rarely startle wild-types. Cyfip2 acts through FMRP and eIF4E to regulate RNA translation, but it can also control actin polymerization through interactions with Rac1 and the WAVE regulatory complex (WRC). In Aim 1 we will systematically test which of these molecular pathways cyfip2 uses to establish the startle threshold and to maintain it through development. In Aim 2 we will define the cellular basis for cyfip2- mediated threshold control by first locating the site of the primary circuit defect with optogenetic and calcium imaging approaches and then identifying the cell types in which cyfip2 is needed for normal startle sensitivity. Finally, our data show that acute manipulation of the actin cytoskeleton substantially alters the startle threshold while also decreasing the number and size of excitatory synapses in inhibitory glycinergic neurons but not excitatory glutamatergic neurons. In Aim 3 we will test the hypothesis that cyfip2 acts cell-autonomously to maintain excitatory/inhibitory synaptic balance, combining behavioral recording with live imaging of neuronal activity and synaptic scaffolds to define direct links between cyfip2, circuit structure and function, and behavior. Overall, the results of this work will generate a detailed model of molecular and cellular pathways that control the startle behavior threshold and lay a foundation for understanding how these may be affected in human disease.

项目摘要。神经系统的一个基本功能是区分威胁性和非威胁性。 威胁性的刺激例如，一个突然的强烈的声音，表明危险应该触发一个声学惊吓 一个无害的声音不应该。这种行为阈值是一种基本机制， 感觉运动过滤，设置这个阈值适当的重要性是突出的惊吓 在神经精神疾病如自闭症、焦虑症和精神分裂症中观察到的超敏反应。尽管 重要性，与我们对经验依赖性惊吓调节的知识相反，分子和 建立和维持先天惊吓阈值的细胞途径还没有得到很好的表征。通过 为了更全面地了解控制惊吓阈值的生物机制，我们 可以产生关于这些疾病的神经基础的新假设。这个项目将利用强大的 斑马鱼幼鱼模型系统研究惊跳的分子遗传和神经回路基础 阈值在这里，一个简单的，保守的，遗传上可访问的电路驱动着一个刻板的惊吓反应， 听觉传入触发网状脊髓神经元以激活运动神经元并启动运动。中 在最近的全基因组筛选中，我们发现了一种新的先天惊吓阈值调节因子：细胞质脆性X 精神发育迟滞蛋白（FMRP）相互作用蛋白2（cyfip 2）。cyfip 2突变体是高度敏感的， 低强度的声音很少惊吓野生动物Cyfip 2通过FMRP和eIF 4 E调节RNA 翻译，但它也可以通过与Rac 1和WAVE调节蛋白的相互作用来控制肌动蛋白聚合。 复合物（WRC）。在目标1中，我们将系统地测试cyfip 2使用哪些分子途径来建立 惊吓阈值，并通过发展来维持它。在目标2中，我们将定义cyfip 2的细胞基础。 介导的阈值控制，首先用光遗传学和钙离子标记定位初级回路缺陷的位点， 成像方法，然后鉴定其中正常惊吓敏感性需要CyFIP 2的细胞类型。 最后，我们的数据表明，急性操纵肌动蛋白细胞骨架大大改变了惊吓阈值 同时减少抑制性甘氨酸能神经元兴奋性突触的数量和大小， 兴奋性神经元在目标3中，我们将检验cyfip 2细胞自主作用的假设， 维持兴奋性/抑制性突触平衡，将行为记录与神经元的实时成像相结合 活性和突触支架来定义cyfip 2、电路结构和功能以及行为之间的直接联系。 总的来说，这项工作的结果将产生一个详细的分子和细胞途径的模型，控制 并为理解这些在人类中如何受到影响奠定了基础 疾病