Genetic and circuit control of visuo-acoustic behavior and integration

视声行为和整合的遗传和电路控制

• 批准号: 10439217
• 负责人: Roshan A Jain
• 金额: $ 41.97万
• 依托单位: HAVERFORD COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439217
• 关键词: Acoustics; Acute; Address; Alleles; Animals; Automobile Driving; Behavior; Behavioral; Behavioral Assay; Behavioral Paradigm; Calcium; Cells; Characteristics; Clathrin Adaptors; Cognitive deficits; Complex; Cues; Dendrites; Development; Elements; Endocytosis; Environment; Fishes; Functional disorder; Genes; Genetic; Head; Health; Human; Image; Immunofluorescence Immunologic; Interneurons; Knowledge; Lateral; Lead; Learning; Learning Disabilities; Link; Location; Mauthner' s neuron; Measures; Membrane Proteins; Mental Health; Modality; Modeling; Molecular; Neurons; Neurophysiology - biologic function; Output; Pathway interactions; Process; Public Health; Regulation; Research; Role; Schizophrenia; Sensory; Siblings; Sigma Factor; Stimulus; Stream; Substance abuse problem; Tail; Testing; Tissues; Transgenes; Transgenic Organisms; Variant; Visual; Visual system structure; Work; Zebrafish; addiction; autism spectrum disorder; behavioral response; calcium indicator; cell type; clinically relevant; cognitive process; effective therapy; enhancer-binding protein AP-2; experimental study; habituation; hindbrain; in vivo; information processing; learned behavior; multisensory; mutant; neural circuit; neuromechanism; neuronal cell body; neuropsychiatry; relating to nervous system; response; sensory integration; visual processing; visual stimulus

Function-disrupting AP2S1 alleles have recently been linked to learning disabilities and autism spectrum disorders (ASD), though the mechanisms underlying this gene’s impact on human behavior are unknown. Understanding how, when, and where this gene regulates vertebrate behavior is key to addressing deficits observed in these and other neuropsychiatric conditions, yet viable vertebrate models are lacking. Our lab has isolated viable zebrafish ap2s1 mutants and has begun to characterize AP2S1’s role in cognitive processes such as integrating multisensory information, appropriate selection of behaviors, and habituation learning. Given that deficits in information processing and behavioral selection are characteristics shared by many neuropsychiatric conditions, including ASD and schizophrenia, our genetically-accessible model can be leveraged to determine the molecular and neural mechanisms underlying these conditions as well as more broadly characterize ap2s1’s role in multisensory integration, behavior selection, and learning. We will use our zebrafish model to reveal the neural mechanisms by which ap2s1 modulates visual and acoustic behavior and sensory integration. In Aim 1, we will determine what aspects of visually guided learning, visual behavior selection, and visuo-acoustic integration require ap2s1. Our results will test the hypothesis that ap2s1 directly modulates visual processing and visuo-acoustic integration, beyond its role in acoustic behavior. In Aim 2, we will determine the temporal and spatial requirements for ap2s1 to modulate visually and acoustically evoked behavior using inducible and cell-specific transgenes. Our results will test the hypotheses that the behavioral role of ap2s1 is 1) to regulate appropriate circuit development, and/or 2) to regulate acute neuronal function, and will distinguish if ap2s1 regulates visual and acoustic responses through distinct or shared circuits. In Aim 3, we will focus on the pair of command-like Mauthner neurons that integrate visual and acoustic information to drive escape behavior, and determine how its function is modulated by ap2s1. Through subcellular calcium imaging in behaving fish, our results will test the hypothesis that ap2s1 modulates escape behavior selection through a spatially-specific impact on Mauthner dendritic integration, revealing the dynamics of visual and acoustic information integration in these central neurons. Overall, these Aims will positively impact human health initiatives by advancing our knowledge of the genetic and neural mechanisms governing multisensory information processing and behavioral selection, and the direct roles of the ASD-linked gene AP2S1. Furthermore, our proposed work will validate the use of these behavioral assays as a zebrafish model for vertebrate multisensory integration that will be used to characterize other genes as they become clinically relevant.

Distrupt的AP2S1等位基因最近与学习障碍和自闭症谱系有关 疾病（ASD），尽管该基因对人类行为的影响的基础机制尚不清楚。 了解该基因调节脊椎动物行为的如何，何时和位置是解决缺陷的关键 在这些和其他神经精神疾病中观察到，缺乏可行的脊椎动物模型。我们的实验室有 孤立的可行斑马鱼AP2S1突变体，并开始表征AP2S1在认知过程中的作用 作为整合多感官信息，适当的行为选择和习惯学习。鉴于 信息处理和行为选择的缺陷是许多神经精神病学共享的特征 包括ASD和精神分裂症在内的条件，我们的一般访问模型可以利用以确定 这些条件下的分子和神经元机制，以及更广泛的AP2S1的特征 在多感官整合，行为选择和学习中的作用。 我们将使用斑马鱼模型来揭示AP2S1调节视觉和的神经机制 声学行为和感觉整合。在AIM 1中，我们将确定视觉指导学习的哪些方面， 视觉行为选择和视觉声音整合需要AP2S1。我们的结果将检验以下假设 AP2S1直接调节视觉处理和视觉声音整合，超出了其在声学行为中的作用。 在AIM 2中，我们将确定AP2S1在视觉和声学上调节的临时和空间要求 使用诱导和细胞特异性翻译引起的行为。我们的结果将检验以下假设 AP2S1的行为作用为1）调节适当的电路发展，/或2）调节急性神经元 功能，并将区分AP2S1是否通过不同或共享电路来调节视觉和声学响应。 在AIM 3中，我们将重点放在一对类似命令的Mauthner神经元上，这些神经元整合了视觉和声学 信息以推动逃生行为，并确定其功能如何由AP2S1调节。通过亚细胞 在行为鱼类中的钙成像，我们的结果将检验AP2S1调节逃生行为的假设 通过对Mauthner树突整合的空间特异性影响进行选择，揭示了视觉的动力学 这些中心神经元中的声学信息整合。总体而言，这些目标将对人类产生积极影响 通过促进我们对管理多感官的遗传和神经机制的了解，可以采取健康计划 信息处理和行为选择，以及ASD连接基因AP2S1的直接作用。 此外，我们提出的工作将验证这些行为测定作为斑马鱼模型的使用 脊椎动物多感官整合将在临床上相关时用来表征其他基因。