Genetic and circuit control of visuo-acoustic behavior and integration

功能紊乱的AP2S1等位基因最近被认为与学习障碍和自闭症有关 疾病(ASD)，尽管该基因影响人类行为的潜在机制尚不清楚。 了解这种基因如何、何时和在哪里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的，然而存活的脊椎动物模型是缺乏的。我们的实验室有 分离出活的斑马鱼ap2s1突变体，并已开始表征ap2s1在S等认知过程中的作用 如整合多感官信息、适当选择行为、习惯性学习等。考虑到 信息处理和行为选择方面的缺陷是许多神经精神病学家的共同特征 疾病，包括自闭症和精神分裂症，我们的基因可及模型可以被用来确定 这些疾病背后的分子和神经机制以及更广泛的特征是ap2s1‘S 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ap2s1调节视觉和 声音行为和感觉整合。在目标1中，我们将确定视觉指导学习的哪些方面， 视觉行为选择和视听整合需要ap2s1。我们的结果将检验这一假设 AP2s1除了在声学行为中的作用外，还直接调节视觉处理和视-声整合。 在目标2中，我们将确定ap2s1在视觉和听觉上调节的时间和空间需求。 使用可诱导和细胞特异性转基因的诱发行为。我们的结果将检验这样的假设： Ap2s1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ap2s1是否通过不同的或共享的电路来调节视觉和听觉反应。 在目标3中，我们将重点放在一对类似命令的毛特纳神经元上，它们整合了视觉和听觉 驱动逃逸行为的信息，并确定ap2s1如何调节其功能。通过亚细胞 在行为鱼中的钙成像，我们的结果将检验ap2s1调节逃逸行为的假设 通过空间上特定的影响对莫特纳树突整合的选择，揭示了视觉的动态 以及这些中枢神经元的声学信息整合。总的来说，这些目标将对人类产生积极影响 通过提高我们对控制多感官的遗传和神经机制的知识来促进健康 信息处理和行为选择，以及ASD连锁基因AP2S1的直接作用。 此外，我们建议的工作将验证这些行为分析作为斑马鱼模型的使用 脊椎动物的多感官整合，当其他基因变得与临床相关时，它将被用来描述它们的特征。

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.