Combinatorial Targeting of Distributed Forebrain Networks Reverses Noise Hypersensitivity in a Model of Autism Spectrum Disorder
Combinatorial Targeting of Distributed Forebrain Networks Reverses Noise Hypersensitivity in a Model of Autism Spectrum Disorder
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DOI：
10.1016/j.neuron.2019.09.040
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发表时间：
2019-11-06
期刊：
影响因子：
16.2
通讯作者：
Halassa, Michael M.
中科院分区：
文献类型：
--
作者：
Nakajima, Miho;Schmitt, L. Ian;Halassa, Michael M.
自闭症谱系障碍（ASD）与噪声超敏反应有关，噪声超敏反应是在噪声环境中对有意义信号的次优提取。然而，由于感觉过滤可能涉及不同的自动和执行回路机制，因此开发针对ASD噪声过敏症的回路特异性治疗策略可能具有挑战性。在这里，我们发现，这两个过程是单独扰动在一个单基因形式的ASD，Ptchd1缺失。虽然Ptchd 1在发育过程中优先在丘脑网状核中表达，但敲除（KO）小鼠中丘脑扰动的药理学救援仅使自动感觉过滤正常化。通过在这些动物中发现单独的前额叶扰动，并采用组合药理学方法，也挽救了其相关的目标导向的噪声过滤缺陷，我们在该模型中实现了噪声超敏性的完全正常化。总的来说，我们的工作突出了识别大规模功能电路架构并将其用作行为疾病矫正的接入点的重要性。
Autism spectrum disorder (ASD) is associated with noise hypersensitivity, the suboptimal extraction of meaningful signals in noisy environments. Because sensory filtering can involve distinct automatic and executive circuit mechanisms, however, developing circuit-specific therapeutic strategies for ASD noise hypersensitivity can be challenging. Here, we find that both of these processes are individually perturbed in one monogenic form of ASD, Ptchd1 deletion. Although Ptchd1 is preferentially expressed in the thalamic reticular nucleus during development, pharmacological rescue of thalamic perturbations in knockout (KO) mice only normalized automatic sensory filtering. By discovering a separate prefrontal perturbation in these animals and adopting a combinatorial pharmacological approach that also rescued its associated goal-directed noise filtering deficit, we achieved full normalization of noise hypersensitivity in this model. Overall, our work highlights the importance of identifying large-scale functional circuit architectures and utilizing them as access points for behavioral disease correction.