Molecular and Cellular Mechanisms of Acoustic Startle Threshold Regulation

声惊吓阈值调节的分子和细胞机制

基本信息

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
项目类别：
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

项目摘要

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。神经系统的基本功能是区分威胁和非威胁和非威胁刺激。例如，突然的强烈声音表明危险应该触发声音惊吓响应，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滤波以及设置此阈值适当的重要性由惊吓突出显示在自闭症，焦虑和精神分裂症等神经精神疾病中观察到的高敏性。尽管有它重要性，与我们对经验依赖性惊吓调制的了解相反，分子和建立和维持先天惊吓阈值的蜂窝路径没有很好地表征。经过我们对控制惊吓阈值的生物学机制有了更完整的了解，我们可以产生有关这些疾病神经碱基的新假设。这个项目将利用强大的幼虫斑马鱼模型系统，以研究惊吓的分子遗传和神经回路碱基临界点。在这里，一个简单，保守和遗传上可访问的电路驱动了刻板的惊吓响应，带有听觉传入的传入触发网状脊髓神经元激活运动神经元并启动运动。在最近全基因组屏幕，我们确定了先天惊吓阈值的新型调节因子：细胞质脆弱x 智力低下蛋白（FMRP）相互作用蛋白2（CYFIP2）。 CYFIP2突变体是高敏的，惊吓低强度的声音很少惊人的野生型。 CYFIP2通过FMRP和EIF4E起作用以调节RNA 翻译，但还可以通过与Rac1的相互作用和波调节来控制肌动蛋白聚合复杂（WRC）。在AIM 1中，我们将系统地测试CYFIP2使用哪些分子途径惊吓阈值并通过开发维护。在AIM 2中，我们将定义Cyfip2-的细胞基础首先用光学遗传学和钙定位一级电路缺陷的位点，介导的阈值控制成像方法，然后识别需要CYFIP2的细胞类型，以使正常的惊吓敏感性。最后，我们的数据表明，肌动蛋白细胞骨架的急性操纵显着改变了惊吓阈值同时还减少了抑制性糖神经元中兴奋性突触的数量和大小，但不能兴奋性谷氨酸能神经元。在AIM 3中，我们将检验以下假设：Cyfip2用细胞自主作用至保持兴奋性/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，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，这项工作的结果将生成一个控制分子和细胞途径的详细模型惊吓行为阈值并为理解人类可能受到影响的基础疾病。