Neuron
Volume 104, Issue 3, 6 November 2019, Pages 488-500.e11
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Article
Combinatorial Targeting of Distributed Forebrain Networks Reverses Noise Hypersensitivity in a Model of Autism Spectrum Disorder

https://doi.org/10.1016/j.neuron.2019.09.040Get rights and content
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Highlights

  • ASD model (Ptchd1 KO) shows deficits in automatic and goal-directed noise filtering

  • Automatic filtering is explained by sensory thalamic deficits

  • Goal-directed filtering is explained by prefrontal deficits

  • Combinatorial targeting of both deficits rescued noise hypersensitivity

Summary

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.

Keywords

autism spectrum disorder
noise hypersensitivity
prefrontal cortex
thalamic reticular nucleus
modafinil
sensory filtering

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