Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits
AbstractCerebellar 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.
Data availabilityThe authors confirm that all relevant non-MRI data are included in the paper and/or its supplementary information files. Raw MRI data that support the findings of this study are available from the corresponding author upon reasonable request.Code availability
All code is publicly available on GitHub (https://github.com/Mouse-Imaging-Centre/RMINC) or is available upon reasonable request.
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Download referencesAcknowledgementsP.T.T. acknowledges support from the National Institute of Neurologic Disorders and Stroke (NS083733), the National Institute of Mental Health (MH116882), the Tuberous Sclerosis Alliance and the Department of Defense. E.K. acknowledges support from National Institute of Neurologic Disorders and Stroke (NS107004) and Autism Speaks. H.F. and S.d.L. acknowledge support from the National Institute of Neurologic Disorders and Stroke (NS095232 and NS105039). F. Morgado, J.E. and J.P.L. acknowledge support from the Canadian Institute for Health Research and the Ontario Brain Institute. L.C.R and C.J.S. acknowledge support from the National Institute for Health (MH106957). M.A.B. acknowledges support from the Medical Research Council (MR/K022377/1). N.K. acknowledges support from the National Institute of Mental Health (MH094268) and declares that he is a paid consultant for Rescindo Therapeutics, although this does not provide a competing interest with this study. P.T.T. and E.K. acknowledge support from V. Jakkamsetti and J. Pascual for support with in vivo extracellular and acute slice recordings recordings and analysis; S. Birnbaum for assistance in behavioral studies; G. Konopka, C. Powell, L. Osburne, J. Foster, J. Lai, K. Rilett, E. Kim and A. Raznahan for generous provision of animal models; and J. Chadwick for graphics assistance.Author informationAffiliationsDepartment of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USAElyza Kelly, Fantao Meng, Yasaman Kazemi, Chongyu Ren, Christine Ochoa Escamilla, Jennifer M. Gibson, Sanaz Sajadi, Tommy Tan & Peter T. TsaiDepartment of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USAElyza Kelly, Jennifer M. Gibson, Robert J. Pendry, Brad E. Pfeiffer & Peter T. TsaiDepartments of Otolaryngology-Head and Neck Surgery, Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USAHirofumi Fujita & Sascha du LacDepartment of Medical Biophysics, University of Toronto, Toronto, ON, CanadaFelipe Morgado & Jason P. LerchMouse Imaging Centre, Toronto Hospital for Sick Children, Toronto, ON, CanadaFelipe Morgado, Jacob Ellegood, Christopher Hammill & Jason P. LerchDepartment of Neuroscience, Center for Behavioral Neuroscience, American University, Washington, DC, USALaura C. Rice & Catherine J. StoodleyCentre for Craniofacial and Regenerative Biology and MRC Centre for Neurodevelopmental Disorders, Kingʼs College London, London, UKM. Albert BassonDepartment of Biomedical Science, Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic University, Jupiter, Florida, USARandy D. Blakely & Maureen K. HahnDepartment of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, USAScott V. DindotInstitut de Génétique et de Biologie Moléculaire et Cellulaire; Centre National de la Recherche Scientifique; Institut National de la Santé et de la Recherche Médicale; Université de Strasbourg, Illkirch, FranceChristelle GolzioACT-GeM, Department of Human Genetics at Stanley Manne Children’s Research Institute; Department of Pediatrics and Cellular and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL, USANicholas KatsanisDepartment of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USADiane M. RobinsMIND Institute and Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USAJill L. SilvermanDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, CanadaKarun K. SinghDepartment of Medical Genetics, University of Alberta, Edmonton, AB, CanadaRachel WevrickDepartment of Medical Imaging and Psychology, University of Toronto; Diagnostic Imaging, Hospital for Sick Children, Toronto, ON, USAMargot J. TaylorDepartment of Pediatrics, University of Toronto, Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, USAEvdokia AnagnostouWellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UKJason P. LerchDepartments of Psychiatry and Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USAPeter T. TsaiContributionsE.K., F. Meng, H. F., J.P.L., S.d.L. and P.T.T. formulated experiments and analysis. E.K., F. Meng, H.F., Y.K., C.O.E., J.M.G., S.S., C.R., D.J., R.P., T.T. and B.E.P. performed experiments and analysis. F. Morgado, J.E. and J.P.L. carried out the mouse structural imaging experiments and analysis. F. Morgado, J.E., M.J.T, C.H., E.A. and J.P.L. carried out the human structural imaging experiments and analysis. L.C.R. and C.J.S. performed functional imaging in humans and analysis of these studies. M.A.B., R.D.B., S.D., C.G., M.K.H., N.K., D.M.R., J.L.S, K.K.S. and R.W. provided critical reagents. E.K., H.F., J.P.L., S.d.L. and P.T.T. prepared the manuscript.Corresponding authorCorrespondence to
Peter T. Tsai.Ethics declarations
Competing interests
The authors declare no competing interests.
Additional informationPeer review information Nature Neuroscience thanks Ted Abel, Sarah Ferri and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended dataExtended Data Fig. 1 mPFC Gi DREADDs in PC-Tsc1 mutant mice.a, Sample of injection site locations from PC-Tsc1 mutants injected with Gi (inhibitory) DREADDs/GFP into left prelimbic (PRL) medial prefrontal cortex (mPFC). b, Awake in vivo single unit recordings in the left PRL of control or PC- Tsc1 mutant mice. c, Three chambered social approach assay; time spent sniffing novel animal (NA), or novel object (NO). d, Three chambered social novelty testing; time spent sniffing NA or familiar animal (FA). e, Time in the open arm and distance traveled in the elevated plus maze assay. f, Time in the center of the open field and g, distance traveled in the open field. h, Latency to fall in accelerating rotarod test. Box line denoted median/whiskers denoted 5–95%. n ≥ 10 for all experiments. All behavioral tests were analyzed with two or three-way ANOVA and Sidak post test and single unit recordings were analyzed with Mann-Whitney test, shown as mean SEM. ****P
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