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

Purkinje Cell Activity Determines the Timing of Sensory-Evoked Motor Initiation

“…Primate and human studies have suggested that the cognitive functions of the cerebellum ( Stoodley and Schmahmann, 2010 ) involve a combination of sensory processing ( Gao et al., 1996 ) and central timing generation ( Ivry and Keele, 1989 ; Jueptner et al., 1995 ). These functions can be reconciled by our proposed framework of cerebellar processing during rapid and precisely timed sensory-driven motor initiation, which may have implications for elucidating the cerebellar contributions to cognitive function and disease ( Carta et al., 2019 ; Chen et al., 2014 ; Kelly et al., 2020 ; Kostadinov et al., 2019 ; Parker et al., 2017 ; Stoodley et al., 2017 ; Tsai et al., 2012 , 2018 ).…”

Modular output circuits of the fastigial nucleus for diverse motor and nonmotor functions of the cerebellar vermis

“…In contrast to the widely accepted linkages of the cerebellar hemispheres and dentate nucleus with prefrontal cortex and cognitive functions, whether the vermis and fastigial nucleus participate in nonmotor functions has been controversial ( Glickstein, 2007 ; Gao et al, 2018 ; De Schutter, 2019 ; Gao et al, 2019 ). By using a sensitive AAV-mediated anterograde transsynaptic tracing methods, we identified robust disynaptic fastigial nucleus connections with several regions of prefrontal cortex ( Steriade, 1995 ; Watson et al, 2009 ; Watson et al, 2014 ; Badura et al, 2018 ; Kelly et al, 2020 ) mediated predominantly by small, ventrally located F4 neurons. Consistent with long standing physiological findings that stimulation of the FN evokes prominent changes in electroencephalographic activity throughout much of the cerebral cortex ( Dow and Moruzzi, 1958 ; Manzoni et al, 1967 ; Steriade, 1995 ), we demonstrated strikingly dense disynaptic input from the FN to widespread regions of the forebrain, including the cortex, striatum, and basal forebrain.…”

“…Consistent with long standing physiological findings that stimulation of the FN evokes prominent changes in electroencephalographic activity throughout much of the cerebral cortex ( Dow and Moruzzi, 1958 ; Manzoni et al, 1967 ; Steriade, 1995 ), we demonstrated strikingly dense disynaptic input from the FN to widespread regions of the forebrain, including the cortex, striatum, and basal forebrain. Modular connections of fastigial neurons with brainstem arousal, autonomic, and medial thalamic nuclei provide candidate circuit substrates for the cerebellar cognitive affective syndrome ( Schmahmann and Sherman, 1998 ; Albazron et al, 2019 ) and could account for the therapeutic effect of vermis intervention on neuropsychiatric disorders ( Demirtas-Tatlidede et al, 2010 ; Parker et al, 2014 ; Stoodley et al, 2017 ; Brady et al, 2019 ; Kelly et al, 2020 ).…”

“…The cerebellum has been implicated in several cognitive functions and neuropsychiatric disorders, which are more typically associated with the cerebral cortex and basal ganglia ( Tsai et al, 2012 ; Hariri, 2019 ; Schmahmann et al, 2019 ). Although it is widely assumed that such nonmotor functions are mediated by the cerebellar hemispheres and their connections with the thalamus ( Strick et al, 2009 ; Buckner, 2013 ; Wang et al, 2014 ; De Schutter, 2019 ), increasing functional and anatomical evidence points to roles for the vermis ( Schmahmann and Sherman, 1998 ; Watson et al, 2009 ; Halko et al, 2014 ; Watson et al, 2014 ; Zhang et al, 2016 ; Wagner et al, 2017 ; Badura et al, 2018 ; Xiao et al, 2018 ; Albazron et al, 2019 ; Brady et al, 2019 ; Watson et al, 2019 ; Kelly et al, 2020 ) an evolutionarily old portion of the cerebellum best known for its influence on brainstem circuits for posture and eye movements ( Chambers and Sprague, 1955 ; Ohtsuka and Noda, 1991 ). Structural and functional abnormalities of the vermis have been associated with various psychiatric disorders and conditions, including autism, schizophrenia, mood disorders, chronic pain, and addiction ( Weinberger et al, 1980 ; Courchesne et al, 1988 ; Sweeney et al, 1998 ; Strakowski et al, 2005 ; Andreasen and Pierson, 2008 ; Moulton et al, 2010 ; Fatemi et al, 2012 ; Moulton et al, 2014 ).…”

Neurobiologia do autismo infantil

“…A despeito de terem sido realizadas em modelos animais, pesquisas sugerem que o Transtorno do Espectro Autista está relacionado a uma disfunção cerebelar e, mais especificamente, que a deleção da Proteína 1 do Complexo Esclerose Tuberosa (TSC1)gene que codifica a proteína hamartinanas células de Purkinje reflete nos déficits sociais e no comportamento repetitivo observado em indivíduos com TEA. Além disso, é sugerido que o fenótipo do transtorno esteja associado a uma perturbação nos circuitos que conectam o cerebelo ao córtex pré-frontal medial e, também, a uma maior ativação desta última região (Kelly et al, 2020). Outrossim, D'Mello e Stoodley (2015) relatam que lesões no cerebelodevido a hemorragias, por exemplosão consideradas fator de risco para o desenvolvimento de TEA; e sabe-se que em crianças prematuras, nas quais há uma interrupção do desenvolvimento cerebelare uma intervenção na maturação das estruturas ou dos circuitoshá um aumento neste risco.…”