Genetic and circuit control of visuo-acoustic behavior and integration

功能破坏AP 2S 1等位基因最近与学习障碍和自闭症谱系有关 自闭症（ASD），尽管该基因对人类行为的影响机制尚不清楚。 了解这种基因如何、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，但缺乏可行的脊椎动物模型。我们的实验室 分离出可行的斑马鱼ap 2s 1突变体，并已开始表征AP 2S 1在认知过程中的作用， 整合多感官信息，适当的行为选择和习惯化学习。鉴于 信息处理和行为选择的缺陷是许多神经精神病患者共有的特征， 条件，包括ASD和精神分裂症，我们的遗传模型可以用来确定 这些病症的分子和神经机制以及更广泛地表征AP 2S 1 在多感官整合、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ap 2s 1调节视觉和 听觉行为和感觉统合。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-声学集成需要AP 2S 1。我们的研究结果将验证以下假设： AP 2S 1直接调节视觉处理和视觉-声学整合，超出其在声学行为中的作用。 在目标2中，我们将确定ap 2s 1在视觉和听觉上进行调制的时间和空间要求 诱发行为使用诱导型和细胞特异性转基因。我们的研究结果将检验假设， ap 2s 1的行为作用是1）调节适当的回路发育，和/或2）调节急性神经元 功能，并将区分AP 2S 1是否通过不同的或共享的电路调节视觉和听觉反应。 在目标3中，我们将重点关注整合视觉和听觉的一对命令式Mauthner神经元 驱动逃逸行为的信息，并确定其功能如何被AP 2S 1调节。通过亚细胞 钙成像行为的鱼，我们的结果将测试的假设，ap 2s 1调节逃避行为 通过对Mauthner树突整合的空间特异性影响的选择，揭示了视觉的动态 和声音信息的整合。总的来说，这些目标将对人类产生积极影响。 通过推进我们对控制多感官的遗传和神经机制的了解， 信息处理和行为选择，以及ASD连锁基因AP 2S 1的直接作用。 此外，我们提出的工作将验证使用这些行为测定作为斑马鱼模型， 脊椎动物多感觉整合，将用于表征其他基因，因为它们成为临床相关的。

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.