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1.
Neuroscience ; 462: 274-287, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33253824

RESUMO

Autism spectrum disorders (ASD) are highly prevalent neurodevelopmental disorders; however, the neurobiological mechanisms underlying disordered behavior in ASD remain poorly understood. Notably, individuals with ASD have demonstrated difficulties generating implicitly derived behavioral predictions and adaptations. Although many brain regions are involved in these processes, the cerebellum contributes an outsized role to these behavioral functions. Consistent with this prominent role, cerebellar dysfunction has been increasingly implicated in ASD. In this review, we will utilize the foundational, theoretical contributions of the late neuroscientist Masao Ito to establish an internal model framework for the cerebellar contribution to ASD-relevant behavioral predictions and adaptations. Additionally, we will also explore and then apply his key experimental contributions towards an improved, mechanistic understanding of the contribution of cerebellar dysfunction to ASD.


Assuntos
Transtorno do Espectro Autista , Doenças Cerebelares , Encéfalo , Cerebelo , Humanos , Resolução de Problemas
2.
Nat Neurosci ; 23(9): 1102-1110, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32661395

RESUMO

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.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Cerebelo/fisiopatologia , Vias Neurais/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Animais , Masculino , Camundongos , Camundongos Mutantes
3.
J Biomech Eng ; 141(3)2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30347048

RESUMO

Causes of autism spectrum disorders (ASD) are understood poorly, making diagnosis and treatment challenging. While many studies have investigated the biochemical and genetic aspects of ASD, whether and how mechanical characteristics of the autistic brain can modulate neuronal connectivity and cognition in ASD are unknown. Previously, it has been shown that ASD brains are characterized by abnormal white matter and disorganized neuronal connectivity; we hypothesized that these significant cellular-level structural changes may translate to changes in the mechanical properties of the autistic brain or regions therein. Here, we focused on tuberous sclerosis complex (TSC), a genetic disorder with a high penetrance of ASD. We investigated mechanical differences between murine brains obtained from control and TSC cohorts at various deformation length- and time-scales. At the microscale, we conducted creep-compliance and stress relaxation experiments using atomic force microscope(AFM)-enabled indentation. At the mesoscale, we conducted impact indentation using a pendulum-based instrumented indenter to extract mechanical energy dissipation metrics. At the macroscale, we used oscillatory shear rheology to quantify the frequency-dependent shear moduli. Despite significant changes in the cellular organization of TSC brain tissue, we found no corresponding changes in the quantified mechanical properties at every length- and time-scale explored. This investigation of the mechanical characteristics of the brain has broadened our understanding of causes and markers of TSC/ASD, while raising questions about whether any mechanical differences can be detected in other animal models of ASD or other disease models that also feature abnormal brain structure.

4.
Nat Neurosci ; 21(7): 1016, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29549317

RESUMO

In the version of this article initially published, the Simons Foundation was missing from the list of sources of support to P.T.T. in the Acknowledgments. The error has been corrected in the HTML and PDF versions of the article.

5.
Neuropsychopharmacology ; 43(6): 1457-1465, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29206810

RESUMO

Drugs targeting metabotropic glutamate receptor 5 (mGluR5) have therapeutic potential in autism spectrum disorders (ASD), including tuberous sclerosis complex (TSC). The question whether inhibition or potentiation of mGluR5 could be beneficial depends, among other factors, on the specific indication. To facilitate the development of mGluR5 treatment strategies, we tested the therapeutic utility of mGluR5 negative and positive allosteric modulators (an mGluR5 NAM and PAM) for TSC, using a mutant mouse model with neuronal loss of Tsc2 that demonstrates disease-related phenotypes, including behavioral symptoms of ASD and epilepsy. This model uniquely enables the in vivo characterization and rescue of the electrographic seizures associated with TSC. We demonstrate that inhibition of mGluR5 corrects hyperactivity, seizures, and elevated de novo synaptic protein synthesis. Conversely, positive allosteric modulation of mGluR5 results in the exacerbation of hyperactivity and epileptic phenotypes. The data suggest a meaningful therapeutic potential for mGluR5 NAMs in TSC, which warrants clinical exploration and the continued development of mGluR5 therapies.


Assuntos
Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Esclerose Tuberosa/tratamento farmacológico , Regulação Alostérica , Animais , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Feminino , Imidazóis/farmacologia , Masculino , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fenótipo , Piridinas/farmacologia , Ratos Long-Evans , Receptor de Glutamato Metabotrópico 5/agonistas , Receptor de Glutamato Metabotrópico 5/metabolismo , Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/deficiência , Proteína 2 do Complexo Esclerose Tuberosa/genética
6.
Nat Neurosci ; 20(12): 1744-1751, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29184200

RESUMO

Cerebellar abnormalities, particularly in Right Crus I (RCrusI), are consistently reported in autism spectrum disorders (ASD). Although RCrusI is functionally connected with ASD-implicated circuits, the contribution of RCrusI dysfunction to ASD remains unclear. Here neuromodulation of RCrusI in neurotypical humans resulted in altered functional connectivity with the inferior parietal lobule, and children with ASD showed atypical functional connectivity in this circuit. Atypical RCrusI-inferior parietal lobule structural connectivity was also evident in the Purkinje neuron (PN) TscI ASD mouse model. Additionally, chemogenetically mediated inhibition of RCrusI PN activity in mice was sufficient to generate ASD-related social, repetitive, and restricted behaviors, while stimulation of RCrusI PNs rescued social impairment in the PN TscI ASD mouse model. Together, these studies reveal important roles for RCrusI in ASD-related behaviors. Further, the rescue of social behaviors in an ASD mouse model suggests that investigation of the therapeutic potential of cerebellar neuromodulation in ASD may be warranted.


Assuntos
Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/psicologia , Cerebelo/patologia , Animais , Comportamento Animal , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Vias Neurais/fisiopatologia , Células de Purkinje , Descanso , Olfato , Comportamento Social , Adulto Jovem
7.
J Vis Exp ; (115)2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27684097

RESUMO

To design and engineer materials inspired by the properties of the brain, whether for mechanical simulants or for tissue regeneration studies, the brain tissue itself must be well characterized at various length and time scales. Like many biological tissues, brain tissue exhibits a complex, hierarchical structure. However, in contrast to most other tissues, brain is of very low mechanical stiffness, with Young's elastic moduli E on the order of 100s of Pa. This low stiffness can present challenges to experimental characterization of key mechanical properties. Here, we demonstrate several mechanical characterization techniques that have been adapted to measure the elastic and viscoelastic properties of hydrated, compliant biological materials such as brain tissue, at different length scales and loading rates. At the microscale, we conduct creep-compliance and force relaxation experiments using atomic force microscope-enabled indentation. At the mesoscale, we perform impact indentation experiments using a pendulum-based instrumented indenter. At the macroscale, we conduct parallel plate rheometry to quantify the frequency dependent shear elastic moduli. We also discuss the challenges and limitations associated with each method. Together these techniques enable an in-depth mechanical characterization of brain tissue that can be used to better understand the structure of brain and to engineer bio-inspired materials.


Assuntos
Encéfalo , Microscopia de Força Atômica , Engenharia Tecidual , Fenômenos Biomecânicos , Módulo de Elasticidade , Humanos
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