Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits

Elyza Kelly, Fantao Meng, Hirofumi Fujita, Felipe Morgado, Yasaman Kazemi, Laura C. Rice, Chongyu Ren, Christine Ochoa Escamilla, Jennifer M. Gibson, Sanaz Sajadi, Robert J. Pendry, Tommy Tan, Jacob Ellegood, M. Albert Basson, Randy D. Blakely, Scott V. Dindot, Christelle Golzio, Maureen K. Hahn, Nicholas Katsanis, Diane M. RobinsJill L. Silverman, Karun K. Singh, Rachel Wevrick, Margot J. Taylor, Christopher Hammill, Evdokia Anagnostou, Brad E. Pfeiffer, Catherine J. Stoodley, Jason P. Lerch, Sascha du Lac, Peter T. Tsai*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown. In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors; and showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD. We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC. Modulation of this circuit induced social deficits and repetitive behaviors, whereas activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice. These data raise the possibility that these circuits might provide neuromodulatory targets for the treatment of ASD.

Original languageEnglish (US)
Pages (from-to)1102-1110
Number of pages9
JournalNature neuroscience
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2020

ASJC Scopus subject areas

  • Neuroscience(all)

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    Kelly, E., Meng, F., Fujita, H., Morgado, F., Kazemi, Y., Rice, L. C., Ren, C., Escamilla, C. O., Gibson, J. M., Sajadi, S., Pendry, R. J., Tan, T., Ellegood, J., Albert Basson, M., Blakely, R. D., Dindot, S. V., Golzio, C., Hahn, M. K., Katsanis, N., ... Tsai, P. T. (2020). Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits. Nature neuroscience, 23(9), 1102-1110. https://doi.org/10.1038/s41593-020-0665-z