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1.
Cerebellum ; 18(6): 1036-1063, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31124049

RESUMO

Tremor is the most common movement disorder; however, we are just beginning to understand the brain circuitry that generates tremor. Various neuroimaging, neuropathological, and physiological studies in human tremor disorders have been performed to further our knowledge of tremor. But, the causal relationship between these observations and tremor is usually difficult to establish and detailed mechanisms are not sufficiently studied. To overcome these obstacles, animal models can provide an important means to look into human tremor disorders. In this manuscript, we will discuss the use of different species of animals (mice, rats, fruit flies, pigs, and monkeys) to model human tremor disorders. Several ways to manipulate the brain circuitry and physiology in these animal models (pharmacology, genetics, and lesioning) will also be discussed. Finally, we will discuss how these animal models can help us to gain knowledge of the pathophysiology of human tremor disorders, which could serve as a platform towards developing novel therapies for tremor.


Assuntos
Encéfalo/diagnóstico por imagem , Consenso , Prova Pericial , Modelos Animais , Rede Nervosa/diagnóstico por imagem , Tremor/diagnóstico por imagem , Animais , Encéfalo/fisiopatologia , Drosophila , Prova Pericial/normas , Haplorrinos , Camundongos , Rede Nervosa/fisiopatologia , Ratos , Suínos , Tremor/fisiopatologia
2.
Cerebellum ; 18(6): 1064-1097, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31165428

RESUMO

The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson's disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward.


Assuntos
Cerebelo/fisiologia , Consenso , Estimulação Encefálica Profunda/métodos , Modelos Animais , Animais , Cerebelo/citologia , Estimulação Encefálica Profunda/tendências , Humanos
3.
Cerebellum ; 17(1): 56-61, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28940157

RESUMO

The cerebellum is critical for an array of motor functions. During postnatal development, the Purkinje cells (PCs) guide afferent topography to establish the final circuit. Perturbing PC morphogenesis or activity during development can result in climbing fiber (CF) multi-innervation or mis-patterning. Structural defects during circuit formation typically have long-term effects on behavior as they contribute to the phenotype of movement disorders such as cerebellar ataxia. The Car8 wdl mouse is one model in which early circuit destruction influences movement. However, although the loss of Car8 leads to the mis-wiring of afferent maps and abnormal PC firing, adult PC morphology is largely intact and there is no neurodegeneration. Here, we sought to uncover how defects in afferent connectivity arise in Car8 wdl mutants to resolve how functional deficits persist in motor diseases with subtle neuropathology. To address this problem, we analyzed CF development during the first 3 weeks of life. By immunolabeling CF terminals with VGLUT2, we found evidence of premature CF synapse elimination and delayed translocation from PC somata at postnatal day (P) 10 in Car8 wdl mice. Surprisingly, by P15, the wiring normalized, suggesting that CAR8 regulates the early but not the late stages of CF development. The data support the hypothesis of a defined sequence of events for cerebellar circuits to establish function.


Assuntos
Biomarcadores Tumorais/metabolismo , Cerebelo/citologia , Cerebelo/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/genética , Fibras Nervosas/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Células de Purkinje/metabolismo , Potenciais de Ação/genética , Fatores Etários , Animais , Animais Recém-Nascidos , Biomarcadores Tumorais/genética , Calbindinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
4.
Neurobiol Dis ; 86: 86-98, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26586559

RESUMO

Neurological diseases are especially devastating when they involve neurodegeneration. Neuronal destruction is widespread in cognitive disorders such as Alzheimer's and regionally localized in motor disorders such as Parkinson's, Huntington's, and ataxia. But, surprisingly, the onset and progression of these diseases can occur without neurodegeneration. To understand the origins of diseases that do not have an obvious neuropathology, we tested how loss of CAR8, a regulator of IP3R1-mediated Ca(2+)-signaling, influences cerebellar circuit formation and neural function as movement deteriorates. We found that faulty molecular patterning, which shapes functional circuits called zones, leads to alterations in cerebellar wiring and Purkinje cell activity, but not to degeneration. Rescuing Purkinje cell function improved movement and reducing their Ca(2+) influx eliminated ectopic zones. Our findings in Car8(wdl) mutant mice unveil a pathophysiological mechanism that may operate broadly to impact motor and non-motor conditions that do not involve degeneration.


Assuntos
Ataxia/patologia , Ataxia/fisiopatologia , Biomarcadores Tumorais/genética , Proteínas do Tecido Nervoso/genética , Tremor/patologia , Tremor/fisiopatologia , Animais , Ataxia/genética , Ataxia/psicologia , Biomarcadores Tumorais/metabolismo , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cerebelo/patologia , Cerebelo/fisiologia , Clorzoxazona/administração & dosagem , Aprendizagem/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Vias Neurais/metabolismo , Vias Neurais/patologia , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Células de Purkinje/fisiologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Tremor/genética , Tremor/psicologia , Tirosina 3-Mono-Oxigenase/metabolismo
5.
Adv Neurobiol ; 31: 93-117, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37338698

RESUMO

Dystonia is a neurological disease that is currently ranked as the third most common motor disorder. Patients exhibit repetitive and sometimes sustained muscle contractions that cause limb and body twisting and abnormal postures that impair movement. Deep brain stimulation (DBS) of the basal ganglia and thalamus can be used to improve motor function when other treatment options fail. Recently, the cerebellum has garnered interest as a DBS target for treating dystonia and other motor disorders. Here, we describe a procedure for targeting DBS electrodes to the interposed cerebellar nuclei to correct motor dysfunction in a mouse model with dystonia. Targeting cerebellar outflow pathways with neuromodulation opens new possibilities for using the expansive connectivity of the cerebellum to treat motor and non-motor diseases.


Assuntos
Estimulação Encefálica Profunda , Distonia , Camundongos , Animais , Distonia/terapia , Núcleos Cerebelares , Estimulação Encefálica Profunda/métodos , Cerebelo , Gânglios da Base , Modelos Animais de Doenças
7.
Cells ; 11(23)2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36497147

RESUMO

Tremor is the most common movement disorder. Several drugs reduce tremor severity, but no cures are available. Propranolol, a ß-adrenergic receptor blocker, is the leading treatment for tremor. However, the in vivo circuit mechanisms by which propranolol decreases tremor remain unclear. Here, we test whether propranolol modulates activity in the cerebellum, a key node in the tremor network. We investigated the effects of propranolol in healthy control mice and Car8wdl/wdl mice, which exhibit pathophysiological tremor and ataxia due to cerebellar dysfunction. Propranolol reduced physiological tremor in control mice and reduced pathophysiological tremor in Car8wdl/wdl mice to control levels. Open field and footprinting assays showed that propranolol did not correct ataxia in Car8wdl/wdl mice. In vivo recordings in awake mice revealed that propranolol modulates the spiking activity of control and Car8wdl/wdl Purkinje cells. Recordings in cerebellar nuclei neurons, the targets of Purkinje cells, also revealed altered activity in propranolol-treated control and Car8wdl/wdl mice. Next, we tested whether propranolol reduces tremor through ß1 and ß2 adrenergic receptors. Propranolol did not change tremor amplitude or cerebellar nuclei activity in ß1 and ß2 null mice or Car8wdl/wdl mice lacking ß1 and ß2 receptor function. These data show that propranolol can modulate cerebellar circuit activity through ß-adrenergic receptors and may contribute to tremor therapeutics.


Assuntos
Cerebelo , Propranolol , Camundongos , Animais , Propranolol/farmacologia , Cerebelo/metabolismo , Células de Purkinje , Ataxia , Neurônios/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Biomarcadores Tumorais
8.
Nat Commun ; 12(1): 1295, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637754

RESUMO

Deep brain stimulation (DBS) relieves motor dysfunction in Parkinson's disease, and other movement disorders. Here, we demonstrate the potential benefits of DBS in a model of ataxia by targeting the cerebellum, a major motor center in the brain. We use the Car8 mouse model of hereditary ataxia to test the potential of using cerebellar nuclei DBS plus physical activity to restore movement. While low-frequency cerebellar DBS alone improves Car8 mobility and muscle function, adding skilled exercise to the treatment regimen additionally rescues limb coordination and stepping. Importantly, the gains persist in the absence of further stimulation. Because DBS promotes the most dramatic improvements in mice with early-stage ataxia, we postulated that cerebellar circuit function affects stimulation efficacy. Indeed, genetically eliminating Purkinje cell neurotransmission blocked the ability of DBS to reduce ataxia. These findings may be valuable in devising future DBS strategies.


Assuntos
Ataxia Cerebelar/metabolismo , Cerebelo/fisiologia , Movimento/fisiologia , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ataxia Cerebelar/genética , Núcleos Cerebelares/fisiologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Doença de Parkinson , Células de Purkinje/fisiologia , Transmissão Sináptica
9.
Dis Model Mech ; 13(2)2019 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-31704708

RESUMO

Duchenne muscular dystrophy (DMD) is a debilitating and ultimately lethal disease involving progressive muscle degeneration and neurological dysfunction. DMD is caused by mutations in the dystrophin gene, which result in extremely low or total loss of dystrophin protein expression. In the brain, dystrophin is heavily localized to cerebellar Purkinje cells, which control motor and non-motor functions. In vitro experiments in mouse Purkinje cells revealed that loss of dystrophin leads to low firing rates and high spiking variability. However, it is still unclear how the loss of dystrophin affects cerebellar function in the intact brain. Here, we used in vivo electrophysiology to record Purkinje cells and cerebellar nuclear neurons in awake and anesthetized female mdx (also known as Dmd) mice. Purkinje cell simple spike firing rate is significantly lower in mdx mice compared to controls. Although simple spike firing regularity is not affected, complex spike regularity is increased in mdx mutants. Mean firing rate in cerebellar nuclear neurons is not altered in mdx mice, but their local firing pattern is irregular. Based on the relatively well-preserved cytoarchitecture in the mdx cerebellum, our data suggest that faulty signals across the circuit between Purkinje cells and cerebellar nuclei drive the abnormal firing activity. The in vivo requirements of dystrophin during cerebellar circuit communication could help explain the motor and cognitive anomalies seen in individuals with DMD.This article has an associated First Person interview with the first author of the paper.


Assuntos
Cerebelo/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia , Rede Nervosa/fisiopatologia , Potenciais de Ação , Animais , Comportamento Animal , Cerebelo/patologia , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/patologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Rede Nervosa/patologia , Neurônios/metabolismo , Neurônios/patologia , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Vigília
10.
Neural Dev ; 14(1): 6, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30867000

RESUMO

BACKGROUND: Purkinje cells play a central role in establishing the cerebellar circuit. Accordingly, disrupting Purkinje cell development impairs cerebellar morphogenesis and motor function. In the Car8wdl mouse model of hereditary ataxia, severe motor deficits arise despite the cerebellum overcoming initial defects in size and morphology. METHODS: To resolve how this compensation occurs, we asked how the loss of carbonic anhydrase 8 (CAR8), a regulator of IP3R1 Ca2+ signaling in Purkinje cells, alters cerebellar development in Car8wdl mice. Using a combination of histological, physiological, and behavioral analyses, we determined the extent to which the loss of CAR8 affects cerebellar anatomy, neuronal firing, and motor coordination during development. RESULTS: Our results reveal that granule cell proliferation is reduced in early postnatal mutants, although by the third postnatal week there is enhanced and prolonged proliferation, plus an upregulation of Sox2 expression in the inner EGL. Modified circuit patterning of Purkinje cells and Bergmann glia accompany these granule cell adjustments. We also find that although anatomy eventually normalizes, the abnormal activity of neurons and muscles persists. CONCLUSIONS: Our data show that losing CAR8 only transiently restricts cerebellar growth, but permanently damages its function. These data support two current hypotheses about cerebellar development and disease: (1) Sox2 expression may be upregulated at sites of injury and contribute to the rescue of cerebellar structure and (2) transient delays to developmental processes may precede permanent motor dysfunction. Furthermore, we characterize waddles mutant mouse morphology and behavior during development and propose a Sox2-positive, cell-mediated role for rescue in a mouse model of human motor diseases.


Assuntos
Ataxia/fisiopatologia , Biomarcadores Tumorais/fisiologia , Proliferação de Células/fisiologia , Cerebelo/citologia , Cerebelo/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Homeostase/fisiologia , Transtornos dos Movimentos/fisiopatologia , Proteínas do Tecido Nervoso/fisiologia , Células de Purkinje/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Animais , Animais Recém-Nascidos , Comportamento Animal/fisiologia , Biomarcadores Tumorais/deficiência , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/deficiência
11.
Front Neural Circuits ; 12: 83, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30364100

RESUMO

The brain contains a large diversity of unique cell types that use specific genetic programs to control development and instruct the intricate wiring of sensory, motor, and cognitive brain regions. In addition to their cellular diversity and specialized connectivity maps, each region's dedicated function is also expressed in their characteristic gross external morphologies. The folds on the surface of the cerebral cortex and cerebellum are classic examples. But, to what extent does structure relate to function and at what spatial scale? We discuss the mechanisms that sculpt functional brain maps and external morphologies. We also contrast the cryptic structural defects in conditions such as autism spectrum disorders to the overt microcephaly after Zika infections, taking into consideration that both diseases disrupt proper cognitive development. The data indicate that dynamic processes shape all brain areas to fit into jigsaw-like patterns. The patterns in each region reflect circuit connectivity, which ultimately supports local signal processing and accomplishes multi-areal integration of information processing to optimize brain functions.


Assuntos
Mapeamento Encefálico , Encéfalo/citologia , Encéfalo/fisiologia , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Potenciais de Ação/fisiologia , Animais , Mapeamento Encefálico/métodos , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos
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