Loss or disrupted expression of the FMR1 gene causes fragile X syndrome (FXS), the most common monogenetic form of autism in humans. Although disruptions in sensory processing are core traits of FXS and autism, the neural underpinnings of these phenotypes are poorly understood. Using calcium imaging to record from the entire brain at cellular resolution, we investigated neuronal responses to visual and auditory stimuli in larval zebrafish, using fmr1 mutants to model FXS. The purpose of this study was to model the alterations of sensory networks, brain-wide and at cellular resolution, that underlie the sensory aspects of FXS and autism. Combining functional analyses with the neurons’ anatomical positions, we found that fmr1−/− animals have normal responses to visual motion. However, there were several alterations in the auditory processing of fmr1−/− animals. Auditory responses were more plentiful in hindbrain structures and in the thalamus. The thalamus, torus semicircularis, and tegmentum had clusters of neurons that responded more strongly to auditory stimuli in fmr1−/− animals. Functional connectivity networks showed more inter-regional connectivity at lower sound intensities (a − 3 to − 6 dB shift) in fmr1−/− larvae compared to wild type. Finally, the decoding capacities of specific components of the ascending auditory pathway were altered: the octavolateralis nucleus within the hindbrain had significantly stronger decoding of auditory amplitude while the telencephalon had weaker decoding in fmr1−/− mutants. We demonstrated that fmr1−/− larvae are hypersensitive to sound, with a 3–6 dB shift in sensitivity, and identified four sub-cortical brain regions with more plentiful responses and/or greater response strengths to auditory stimuli. We also constructed an experimentally supported model of how auditory information may be processed brain-wide in fmr1−/− larvae. Our model suggests that the early ascending auditory pathway transmits more auditory information, with less filtering and modulation, in this model of FXS.

中文翻译：

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脆性 X 综合征斑马鱼模型中全脑听觉网络的改变。


FMR1 基因表达缺失或破坏会导致脆性 X 综合征 (FXS)，这是人类最常见的单基因型自闭症。尽管感觉处理中断是 FXS 和自闭症的核心特征，但这些表型的神经基础却知之甚少。我们使用钙成像以细胞分辨率记录整个大脑，研究了斑马鱼幼虫对视觉和听觉刺激的神经元反应，并使用 fmr1 突变体来模拟 FXS。本研究的目的是模拟全脑和细胞分辨率的感觉网络的变化，这是 FXS 和自闭症感觉方面的基础。将功能分析与神经元的解剖位置相结合，我们发现 fmr1−/− 动物对视觉运动有正常的反应。然而，fmr1−/− 动物的听觉处理发生了一些变化。后脑结构和丘脑的听觉反应更为丰富。 fmr1−/− 动物的丘脑、半圆环和被盖具有对听觉刺激反应更强烈的神经元簇。与野生型相比，fmr1−/− 幼虫的功能连接网络在较低声音强度（a − 3 至 − 6 dB 变化）下显示出更多的区域间连接。最后，上行听觉通路特定组成部分的解码能力发生了改变：在 fmr1−/− 突变体中，后脑内的八外侧核对听觉幅度的解码能力明显更强，而端脑的解码能力较弱。我们证明了 fmr1−/− 幼虫对声音高度敏感，敏感性发生了 3-6 dB 的变化，并确定了四个皮层下大脑区域，对听觉刺激有更丰富的反应和/或更强的反应强度。 我们还构建了一个实验支持的模型，说明 fmr1−/− 幼虫如何在全脑范围内处理听觉信息。我们的模型表明，在 FXS 模型中，早期上行听觉通路传输更多听觉信息，而过滤和调制较少。