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性的和非威胁性的。 威胁性刺激。例如，表示危险的突然强烈声音应该触发声学惊吓 响应，但无害的声音不应该。这种行为阈值是一种基本机制 感觉运动过滤，适当设置此阈值的重要性通过惊吓凸显出来 在自闭症、焦虑症和精神分裂症等神经精神疾病中观察到的超敏反应。尽管其 重要性，并且与我们对依赖于经验的惊吓调节的了解相反，分子和 建立和维持先天惊吓阈值的细胞途径尚未得到很好的表征。经过 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。该项目将利用强大的 幼虫斑马鱼模型系统研究惊吓的分子遗传和神经回路基础 临界点。这里有一个简单、保守且基因可访问的电路驱动刻板的惊吓反应， 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 最近的全基因组筛选，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 (cyfip2)。 cyfip2 突变体高度敏感且惊恐 低强度的声音很少惊吓野生类型。 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聚合 综合体（WRC）。在目标 1 中，我们将系统地测试 cyfip2 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 cyfip2 的细胞基础- 首先通过光遗传学和钙定位初级电路缺陷的位置来介导阈值控制 成像方法，然后识别正常惊吓敏感性需要 cyfip2 的细胞类型。 最后，我们的数据表明，肌动蛋白细胞骨架的急性操作会显着改变惊吓阈值 同时还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，但没有 兴奋性谷氨酸能神经元。在目标 3 中，我们将测试 cyfip2 细胞自主作用的假设 将行为记录与神经元实时成像相结合，维持兴奋/抑制性突触平衡 活动和突触支架来定义 cyfip2、电路结构和功能以及行为之间的直接联系。 总体而言，这项工作的结果将生成控制分子和细胞途径的详细模型 惊吓行为阈值，并为理解这些行为如何影响人类奠定基础 疾病。