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: 10211396
• 负责人: Kurt C. Marsden
• 金额: $ 37.48万
• 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/10211396
• 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; Cytoskeleton; DLG4 gene; Data; Defect; Detection; Development; Disease; Electrophysiology (science); 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 Physiology; Nervous system structure; Neurologic Dysfunctions; Neurons; Neurophysiology - biologic function; Optics; Pathway interactions; Peripheral; Phenotype; Population; Proteins; RNA; Regulation; Reproducibility; Research; Role; Schizophrenia; Sensory; Site; Startle Reaction; Stereotyping; Stimulus; Structure; Synapses; Testing; Therapeutic Intervention; Transgenic Organisms; 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 circuit; neuropsychiatric disorder; novel; optogenetics; polymerization; programs; promoter; relating to nervous system; 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和非威胁 威胁性刺激。例如，表明危险的突然强烈的声音应该触发声学上的惊吓 反应，但无害的声音不应该。这种类型的行为阈值是 感觉运动过滤，适当设置这一阈值的重要性被惊吓突显出来 自闭症、焦虑症和精神分裂症等神经精神疾病中观察到的过敏反应。尽管它的 重要性，与我们对经验依赖的惊吓调制的知识相反，分子和 建立和维持先天惊吓阈值的细胞通路还没有得到很好的描述。通过 对控制惊吓阈值的生物机制有了更全面的了解，我们 可以产生关于这些疾病的神经基础的新假说。该项目将利用强大的 斑马鱼幼体模型系统研究斑马鱼的分子遗传学和神经回路基础 临界点。在这里，一个简单的、保守的、可遗传的回路驱动着刻板的惊吓反应， 听觉传入触发网状脊髓神经元激活运动神经元并启动运动。在一个 最近的全基因组筛查，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 智力低下蛋白(FMRP)相互作用蛋白2(Cyfip2)。Cyfip2突变体对 低强度的声音很少吓到野人。Cyfip2通过FMRP和eIF4E调节RNA 翻译，但它也可以通过与rac1和Wave调节相互作用来控制肌动蛋白的聚合 复合体(WRC)。在目标1中，我们将系统地测试Cyfip2使用这些分子通路中的哪一个来建立 令人震惊的门槛，并在整个发展过程中保持它。在目标2中，我们将定义Cyfip2的细胞基础- 先用光生理学和钙离子定位初级电路缺陷部位的介导性阈值控制 成像方法，然后确定需要Cyfip2来实现正常惊吓敏感性的细胞类型。 最后，我们的数据显示，对肌动蛋白细胞骨架的急性操纵大大改变了惊吓阈值。 同时也减少了抑制性甘氨酸能神经元中兴奋性突触的数量和大小，但不 兴奋性谷氨酸能神经元。在目标3中，我们将测试Cyfip2细胞自主作用于 保持兴奋性/抑制性突触平衡，将行为记录与神经元实时成像相结合 活性和突触支架，以定义Cyfip2、电路结构和功能以及行为之间的直接联系。 总体而言，这项工作的结果将产生一个控制分子和细胞通路的详细模型 惊吓行为阈值，并为了解这些在人类中可能受到的影响奠定了基础 疾病。