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.

最近发现功能破坏性 AP2S1 等位基因与学习障碍和自闭症谱系有关 障碍（ASD），尽管该基因对人类行为影响的机制尚不清楚。 了解该基因如何、何时、何地调节脊椎动物的行为是解决缺陷的关键 在这些和其他神经精神疾病中观察到，但我们的实验室缺乏可行的脊椎动物模型。 分离出可存活的斑马鱼 ap2s1 突变体，并开始表征 AP2S1 在认知过程中的作用，例如 鉴于此，整合多感官信息、适当的行为选择和习惯化学习。 信息处理和行为选择的缺陷是许多神经精神病学的共同特征 包括 ASD 和精神分裂症在内的疾病，我们的基因可访问模型可用于确定 这些条件下的分子和神经机制以及更广泛地表征 ap2s1 在多感觉统合、行为选择和学习中的作用。 我们将使用我们的斑马鱼模型来揭示 ap2s1 调节视觉和视觉的神经机制 在目标 1 中，我们将确定视觉引导学习的哪些方面。 视觉行为选择和视觉声学整合需要 ap2s1 我们的结果将检验以下假设： ap2s1 直接调节视觉处理和视声整合，超出其在声学行为中的作用。 在目标 2 中，我们将确定 ap2s1 调节视觉和听觉的时间和空间要求 使用诱导型和细胞特异性转基因诱发行为我们的结果将检验以下假设： ap2s1 的行为作用是 1) 调节适当的电路发育，和/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调节视觉和听觉反应。 在目标 3 中，我们将重点关注一对类似命令的 Mauthner 神经元，它们在视觉上与听觉上进行整合 驱动逃逸行为的信息，并确定 ap2s1 如何调节其功能。 对行为鱼类进行钙成像，我们的结果将检验 ap2s1 调节逃逸行为的假设 通过对 Mauthner 树突整合的空间特定影响进行选择，揭示视觉的动态 总体而言，这些目标将对人类产生积极影响。 通过增进我们对控制多感官的遗传和神经机制的了解来开展健康倡议 信息处理和行为选择，以及 ASD 相关基因 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用途 脊椎动物多感觉整合将用于表征其他基因，因为它们变得与临床相关。