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

• Published in: Nature neuroscience Vol. 23; no. 9; pp. 1102 - 1110
• Main Authors: Kelly, Elyza, Meng, Fantao, Fujita, Hirofumi, Morgado, Felipe, Kazemi, Yasaman, Rice, Laura C., Ren, Chongyu, Escamilla, Christine Ochoa, Gibson, Jennifer M., Sajadi, Sanaz, Pendry, Robert J., Tan, Tommy, Ellegood, Jacob, Basson, M. Albert, Blakely, Randy D., Dindot, Scott V., Golzio, Christelle, Hahn, Maureen K., Katsanis, Nicholas, Robins, Diane M., Silverman, Jill L., Singh, Karun K., Wevrick, Rachel, Taylor, Margot J., Hammill, Christopher, Anagnostou, Evdokia, Pfeiffer, Brad E., Stoodley, Catherine J., Lerch, Jason P., du Lac, Sascha, Tsai, Peter T.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-09-2020; Nature Publishing Group
• Subjects: 14; 14/63; 59/36; 59/57; 631/378/1689/1373; 631/378/3920; 64/110; 64/60; 692/699/476/1373; 9/74; Animal Genetics and Genomics; Animal models; Animals; Autism; Autism Spectrum Disorder - physiopathology; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Cell activation; Cerebellum; Cerebellum - physiopathology; Circuits; Genetics; Health aspects; Life Sciences; Male; Mice; Mice, Mutant Strains; Mouse devices; Mutants; Neural networks; Neural Pathways - physiopathology; Neurobiology; Neurosciences; Pervasive developmental disorders; Prefrontal cortex; Prefrontal Cortex - physiopathology; Psychological aspects; Purkinje cells; Social behavior; Thalamus; United States
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-020-0665-z

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.
Kelly et al. describe two cerebellum–thalamus–mPFC pathways in mice that regulate social and repetitive behavior. PC activation in Rcrus1 and posterior vermis improved social and reduced repetitive behaviors, respectively, in PC-
Tsc1
mutant mice.