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The cerebellum, traditionally associated with motor coordination and balance, also plays a crucial role in various aspects of higher-order function and dysfunction. Emerging research has shed light on the cerebellum's broader contributions to cognitive, emotional, and reward processes. The cerebellum's influence on autonomic function further highlights its significance in regulating motivational and emotional states. Perturbations in cerebellar development and function have been implicated in various neurodevelopmental disorders, including autism spectrum disorder and attention deficit hyperactivity disorder. An increasing appreciation for neuropsychiatric symptoms that arise from cerebellar dysfunction underscores the importance of elucidating the circuit mechanisms that underlie complex interactions between the cerebellum and other brain regions for a comprehensive understanding of complex behavior. By briefly discussing new advances in mapping cerebellar function in affective, cognitive, autonomic, and social processing and reviewing the role of the cerebellum in neuropathology beyond the motor domain, this Mini-Symposium review aims to provide a broad perspective of cerebellar intersections with the limbic brain in health and disease.
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Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Transtornos do Neurodesenvolvimento , Humanos , Cognição/fisiologia , Cerebelo/fisiologia , Transtornos do Neurodesenvolvimento/patologiaRESUMO
Fascial therapy is an effective, yet painful, procedure. Information about pain level is essential for the physiotherapist to adjust the therapy course and avoid potential tissue damage. We have developed a method for automatic pain-related reaction assessment in physiotherapy due to the subjectivity of a self-report. Based on a multimodal data set, we determine the feature vector, including wavelet scattering transforms coefficients. The AdaBoost classification model distinguishes three levels of reaction (no-pain, moderate pain, and severe pain). Because patients vary in pain reactions and pain resistance, our survey assumes a subject-dependent protocol. The results reflect an individual perception of pain in patients. They also show that multiclass evaluation outperforms the binary recognition.
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Dor , Modalidades de Fisioterapia , Análise de Ondaletas , Humanos , Medição da DorRESUMO
Cerebellar cortical throughput involved in motor control comprises granule cells (GCs) and Purkinje cells (PCs), both of which receive inhibitory GABAergic input from interneurons. The GABAergic input to PCs is essential for learning and consolidation of the vestibulo-ocular reflex, but the role of GC excitability remains unclear. We now disrupted the Kcc2 K-Cl cotransporter specifically in either cell type to manipulate their excitability and inhibition by GABA(A)-receptor Cl(-) channels. Although Kcc2 may have a morphogenic role in synapse development, Kcc2 disruption neither changed synapse density nor spine morphology. In both GCs and PCs, disruption of Kcc2, but not Kcc3, increased [Cl(-)](i) roughly two-fold. The reduced Cl(-) gradient nearly abolished GABA-induced hyperpolarization in PCs, but in GCs it merely affected excitability by membrane depolarization. Ablation of Kcc2 from GCs impaired consolidation of long-term phase learning of the vestibulo-ocular reflex, whereas baseline performance, short-term gain-decrease learning and gain consolidation remained intact. These functions, however, were affected by disruption of Kcc2 in PCs. GC excitability plays a previously unknown, but specific role in consolidation of phase learning.
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Córtex Cerebelar/metabolismo , Cloretos/metabolismo , Citosol/química , Aprendizagem , Neurônios/metabolismo , Reflexo Vestíbulo-Ocular , Simportadores/metabolismo , Animais , Córtex Cerebelar/citologia , Camundongos , Camundongos Knockout , Simportadores/genética , Cotransportadores de K e Cl-RESUMO
Mechanisms of cerebellar motor learning are still poorly understood. The standard Marr-Albus-Ito theory posits that learning involves plasticity at the parallel fiber to Purkinje cell synapses under control of the climbing fiber input, which provides an error signal as in classical supervised learning paradigms. However, a growing body of evidence challenges this theory, in that additional sites of plasticity appear to contribute to motor adaptation. Here, we consider phase-reversal training of the vestibulo-ocular reflex (VOR), a simple form of motor learning for which a large body of experimental data is available in wild-type and mutant mice, in which the excitability of granule cells or inhibition of Purkinje cells was affected in a cell-specific fashion. We present novel electrophysiological recordings of Purkinje cell activity measured in naive wild-type mice subjected to this VOR adaptation task. We then introduce a minimal model that consists of learning at the parallel fibers to Purkinje cells with the help of the climbing fibers. Although the minimal model reproduces the behavior of the wild-type animals and is analytically tractable, it fails at reproducing the behavior of mutant mice and the electrophysiology data. Therefore, we build a detailed model involving plasticity at the parallel fibers to Purkinje cells' synapse guided by climbing fibers, feedforward inhibition of Purkinje cells, and plasticity at the mossy fiber to vestibular nuclei neuron synapse. The detailed model reproduces both the behavioral and electrophysiological data of both the wild-type and mutant mice and allows for experimentally testable predictions.
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Adaptação Fisiológica/genética , Cerebelo/fisiologia , Aprendizagem/fisiologia , Camundongos Mutantes/fisiologia , Modelos Biológicos , Reflexo Vestíbulo-Ocular/genética , Animais , Cerebelo/citologia , Simulação por Computador , Movimentos Oculares/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Dinâmica não Linear , Células de Purkinje/fisiologia , Receptores de GABA/genética , Receptores de GABA-A , Simportadores/genética , Sinapses/genética , Cotransportadores de K e Cl-RESUMO
The investigation of the dynamics of Purkinje cell (PC) activity is crucial to unravel the role of the cerebellum in motor control, learning and cognitive processes. Within the cerebellar cortex (CC), these neurons receive all the incoming sensory and motor information, transform it and generate the entire cerebellar output. The relatively homogenous and repetitive structure of the CC, common to all vertebrate species, suggests a single computation mechanism shared across all PCs. While PC models have been developed since the 70's, a comprehensive review of contemporary models is currently lacking. Here, we provide an overview of PC models, ranging from the ones focused on single cell intracellular PC dynamics, through complex models which include synaptic and extrasynaptic inputs. We review how PC models can reproduce physiological activity of the neuron, including firing patterns, current and multistable dynamics, plateau potentials, calcium signaling, intrinsic and synaptic plasticity and input/output computations. We consider models focusing both on somatic and on dendritic computations. Our review provides a critical performance analysis of PC models with respect to known physiological data. We expect our synthesis to be useful in guiding future development of computational models that capture real-life PC dynamics in the context of cerebellar computations.
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In Bilateria, many axons cross the midline of the central nervous system, forming well-defined commissures. Whereas in mammals the functions of commissures in the forebrain and in the visual system are well established, functions at other axial levels are less clearly understood. Here, we have dissected the function of several hindbrain commissures using genetic methods. By taking advantage of multiple Cre transgenic lines, we have induced site-specific deletions of the Robo3 receptor. These lines developed with the disruption of specific commissures in the sensory, motor, and sensorimotor systems, resulting in severe and permanent functional deficits. We show that mice with severely reduced commissures in rhombomeres 5 and 3 have abnormal lateral eye movements and auditory brainstem responses, respectively, whereas mice with a primarily uncrossed climbing fiber/Purkinje cell projection are strongly ataxic. Surprisingly, although rerouted axons remain ipsilateral, they still project to their appropriate neuronal targets. Moreover, some Cre;Robo3 lines represent potential models that can be used to study human syndromes, including horizontal gaze palsy with progressive scoliosis (HGPPS). To our knowledge, this study is one of the first to link defects in commissural axon guidance with specific cellular and behavioral phenotypes.
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Axônios , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Rombencéfalo , Animais , Axônios/fisiologia , Axônios/ultraestrutura , Comportamento Animal/fisiologia , Padronização Corporal/genética , Padronização Corporal/fisiologia , Embrião de Mamíferos/anatomia & histologia , Embrião de Mamíferos/fisiologia , Potenciais Evocados Auditivos/fisiologia , Movimentos Oculares/fisiologia , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/fisiologia , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Transtornos da Motilidade Ocular/genética , Receptores de Superfície Celular , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Rombencéfalo/anatomia & histologia , Rombencéfalo/fisiologia , Teste de Desempenho do Rota-RodRESUMO
Delay eyeblink conditioning has been extensively used to study associative learning and the cerebellar circuits underlying this task have been largely identified. However, there is a little knowledge on how factors such as strain, sex and innate behaviour influence performance during this type of learning. In this study, we used male and female mice of C57BL/6J (B6) and B6CBAF1 strains to investigate the effect of sex, strain and locomotion in delay eyeblink conditioning. We performed a short and a long delay eyeblink conditioning paradigm and used a c-Fos immunostaining approach to explore the involvement of different brain areas in this task. We found that both B6 and B6CBAF1 females reach higher learning scores compared to males in the initial stages of learning. This sex-dependent difference was no longer present as the learning progressed. Moreover, we found a strong positive correlation between learning scores and voluntary locomotion irrespective of the training duration. c-Fos immunostainings after the short paradigm showed positive correlations between c-Fos expression and learning scores in the cerebellar cortex and brainstem, as well as previously unreported areas. By contrast, after the long paradigm, c-Fos expression was only significantly elevated in the brainstem. Taken together, we show that differences in voluntary locomotion and activity across brain areas correlate with performance in delay eyeblink conditioning across strains and sexes.
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Encéfalo , Cerebelo , Feminino , Masculino , Animais , Camundongos , Camundongos Endogâmicos C57BL , LocomoçãoRESUMO
Tuberous sclerosis complex 1 (TSC1) is a tumor suppressor that promotes the inhibition of mechanistic target of rapamycin (mTOR) pathway, and mutations in TSC1 lead to a rare complex disorder of the same name. Despite phenotype heterogeneity, up to 50% of TSC patients present with autism spectrum disorder (ASD). Consequently, TSC models are often used to probe molecular and behavioral mechanisms of ASD development. Amongst the different brain areas proposed to play a role in the development of ASD, the cerebellum is commonly reported to be altered, and cerebellar-specific deletion of Tsc1 in mice is sufficient to induce ASD-like phenotypes. However, despite these functional changes, whether Tsc1 haploinsufficiency affects cerebellar development is still largely unknown. Given that the mTOR pathway is a master regulator of cell replication and migration, we hypothesized that dysregulation of this pathway would also disrupt the development of cell populations during critical periods of cerebellar development. Here, we used a mouse model of TSC to investigate gene and protein expression during embryonic and early postnatal periods of cerebellar development. We found that, at E18 and P7, mRNA levels of the cerebellar inhibitory interneuron marker paired box gene 2 (Pax2) were dysregulated. This dysregulation was accompanied by changes in the expression of mTOR pathway-related genes and downstream phosphorylation of S6. Differential gene correlation analysis revealed dynamic changes in correlated gene pairs across development, with an overall loss of correlation between mTOR- and cerebellar-related genes in Tsc1 mutants compared to controls. We corroborated the genetic findings by characterizing the mTOR pathway and cerebellar development on protein and cellular levels with Western blot and immunohistochemistry. We found that Pax2-expressing cells were largely unchanged at E18 and P1, while at P7, their number was increased and maturation into parvalbumin-expressing cells delayed. Our findings indicate that, in mice, Tsc1 haploinsufficiency leads to altered cerebellar development and that cerebellar interneuron precursors are particularly susceptible to mTOR pathway dysregulation.
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The marble burying test is a commonly used paradigm to describe phenotypes in mouse models of neurodevelopmental and psychiatric disorders. The current methodological approach relies predominantly on reporting the number of buried marbles at the end of the test. By measuring the proxy of the behavior (buried marbles), many important characteristics regarding the temporal aspect of this assay are lost. Here, we introduce a novel, automated method to quantify mouse behavior during the marble burying test with the focus on the burying bouts and movement dynamics. Using open-source software packages, we trained a supervised machine learning algorithm (the "classifier") to distinguish burying behavior in freely moving mice. In order to confirm the classifier's accuracy and characterize burying events in high detail, we performed the marble burying test in three mouse models: Ube3am-/p+ [Angelman syndrome (AS) model], Shank2-/- (autism model), and Sapap3-/- [obsessive-compulsive disorder (OCD) model] mice. The classifier scored burying behavior accurately and consistent with the previously reported phenotype of the Ube3am-/p+ mice, which showed decreased levels of burying compared with controls. Shank2-/- mice showed a similar pattern of decreased burying behavior, which was not found in Sapap3-/- mice. Tracking mouse behavior throughout the test revealed hypoactivity in Ube3am-/p+ and hyperactivity in the Shank2-/- mice, indicating that mouse activity is unrelated to burying behavior. Reducing activity with midazolam in Shank2-/- mice did not alter the burying behavior. Together, we demonstrate that our classifier is an accurate method for the analysis of the marble burying test, providing more information than currently used methods.
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Carbonato de Cálcio , Transtorno Obsessivo-Compulsivo , Animais , Comportamento Animal , Modelos Animais de Doenças , Humanos , Camundongos , Proteínas do Tecido Nervoso , Padrões de ReferênciaRESUMO
Volitional suppression of responses to distracting external stimuli enables us to achieve our goals. This volitional inhibition of a specific behavior is supposed to be mainly mediated by the cerebral cortex. However, recent evidence supports the involvement of the cerebellum in this process. It is currently not known whether different parts of the cerebellar cortex play differential or synergistic roles in the planning and execution of this behavior. Here, we measured Purkinje cell (PC) responses in the medial and lateral cerebellum in two rhesus macaques during pro- and anti-saccade tasks. During an antisaccade trial, non-human primates (NHPs) were instructed to make a saccadic eye movement away from a target, rather than toward it, as in prosaccade trials. Our data show that the cerebellum plays an important role not only during the execution of the saccades but also during the volitional inhibition of eye movements toward the target. Simple spike (SS) modulation during the instruction and execution periods of pro- and anti-saccades was prominent in PCs of both the medial and lateral cerebellum. However, only the SS activity in the lateral cerebellar cortex contained information about stimulus identity and showed a strong reciprocal interaction with complex spikes (CSs). Moreover, the SS activity of different PC groups modulated bidirectionally in both of regions, but the PCs that showed facilitating and suppressive activity were predominantly associated with instruction and execution, respectively. These findings show that different cerebellar regions and PC groups contribute to goal-directed behavior and volitional inhibition, but with different propensities, highlighting the rich repertoire of the cerebellar control in executive functions.
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The genetic causes of primary antibody deficiencies and autism spectrum disorder (ASD) are largely unknown. Here, we report a patient with hypogammaglobulinemia and ASD who carries biallelic mutations in the transcription factor PAX5. A patient-specific Pax5 mutant mouse revealed an early B cell developmental block and impaired immune responses as the cause of hypogammaglobulinemia. Pax5 mutant mice displayed behavioral deficits in all ASD domains. The patient and the mouse model showed aberrant cerebellar foliation and severely impaired sensorimotor learning. PAX5 deficiency also caused profound hypoplasia of the substantia nigra and ventral tegmental area due to loss of GABAergic neurons, thus affecting two midbrain hubs, controlling motor function and reward processing, respectively. Heterozygous Pax5 mutant mice exhibited similar anatomic and behavioral abnormalities. Lineage tracing identified Pax5 as a crucial regulator of cerebellar morphogenesis and midbrain GABAergic neurogenesis. These findings reveal new roles of Pax5 in brain development and unravel the underlying mechanism of a novel immunological and neurodevelopmental syndrome.
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Agamaglobulinemia , Transtorno do Espectro Autista , Animais , Transtorno do Espectro Autista/genética , Heterozigoto , Camundongos , Mutação/genética , Fator de Transcrição PAX5/genéticaRESUMO
The phosphoinositide-3-kinase (PI3K) family plays a major role in cell signaling and is predominant in leukocytes. Gain-of-function (GOF) mutations in the PIK3CD gene lead to the development of activated PI3Kδ syndrome (APDS), a rare primary immunodeficiency disorder. A subset of APDS patients also displays neurodevelopmental delay symptoms, suggesting a potential role of PIK3CD in cognitive and behavioural function. However, the extent and nature of the neurodevelopmental deficits has not been previously quantified. Here, we assessed the cognitive functions of two APDS patients, and investigated the causal role of the PIK3CD GOF mutation in neurological deficits using a murine model of this disease. We used p110δE1020K knock-in mice, harbouring the most common APDS mutation in patients. We found that APDS patients present with visuomotor deficits, exacerbated by autism spectrum disorder comorbidity, whereas p110δE1020K mice exhibited impairments in motor behaviour, learning and repetitive behaviour patterning. Our data indicate that PIK3CD GOF mutations increase the risk for neurodevelopmental deficits, supporting previous findings on the interplay between the nervous and the immune system. Further, our results validate the knock-in mouse model, and offer an objective assessment tool for patients that could be incorporated in diagnosis and in the evaluation of treatments.
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PURPOSE: Genetically epileptic WAG/Rij rats develop spontaneous absence-like seizures after 3 months of age. We used WAG/Rij rats to examine whether absence seizures are associated with changes in the expression of type-1 cannabinoid (CB1) receptors. METHODS: Receptor expression was examined by in situ hybridization and western blot analysis in various brain regions of "presymptomatic" 2-month old and "symptomatic" 8-month-old WAG/Rij rats relative to age-matched nonepileptic control rats. Furthermore, we examined whether pharmacologic activation of CB1 receptor affects absence seizures. We recorded spontaneous spike-wave discharges (SWDs) in 8-month old WAG/Rij rats systemically injected with the potent CB1 receptor agonist, R(+)WIN55,212-2 (3-12 mg/kg, s.c.), given alone or combined with the CB1 receptor antagonist/inverse agonist, AM251 (12 mg/kg, s.c.). RESULTS: Data showed a reduction of CB1 receptor mRNA and protein levels in the reticular thalamic nucleus, and a reduction in CB1 receptor protein levels in ventral basal thalamic nuclei of 8-month-old WAG/Rij rats, as compared with age-matched ACI control rats. In vivo, R(+)WIN55,212-2 caused a dose-dependent reduction in the frequency of SWDs in the first 3 h after the injection. This was followed by a late increase in the mean SWD duration, which suggests a biphasic modulation of SWDs by CB1 receptor agonists. Both effects were reversed or attenuated when R(+)WIN55,212-2 was combined with AM251. DISCUSSION: These data indicate that the development of absence seizures is associated with plastic modifications of CB1 receptors within the thalamic-cortical-thalamic network, and raise the interesting possibility that CB1 receptors are targeted by novel antiabsence drugs.
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Benzoxazinas/farmacologia , Epilepsia Tipo Ausência/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Morfolinas/farmacologia , Naftalenos/farmacologia , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Núcleos Talâmicos/efeitos dos fármacos , Análise de Variância , Animais , Benzoxazinas/uso terapêutico , Modelos Animais de Doenças , Eletroencefalografia/métodos , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia Tipo Ausência/genética , Masculino , Morfolinas/uso terapêutico , Movimento/efeitos dos fármacos , Naftalenos/uso terapêutico , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Endogâmicos ACI , Ratos Mutantes , Receptor CB1 de Canabinoide/genética , Núcleos Talâmicos/fisiopatologiaRESUMO
Saccadic eye movements enable fast and precise scanning of the visual field, which is partially controlled by the posterior cerebellar vermis. Textbook saccades have a straight trajectory and a unimodal velocity profile, and hence have well-defined epochs of start and end. However, in practice only a fraction of saccades matches this description. One way in which a saccade can deviate from its trajectory is the presence of an overshoot or undershoot at the end of a saccadic eye movement just before fixation. This additional movement, known as a glissade, is regarded as a motor command error and was characterized decades ago but was almost never studied. Using rhesus macaques, we investigated the properties of glissades and changes to glissade kinematics following cerebellar lesions. Additionally, in monkeys with an intact cerebellum, we investigated whether the glissade amplitude can be modulated using multiple adaptation paradigms. Our results show that saccade kinematics are altered by the presence of a glissade, and that glissades do not appear to have any adaptive function as they do not bring the eye closer to the target. Quantification of these results establishes a detailed description of glissades. Further, we show that lesions to the posterior cerebellum have a deleterious effect on both saccade and glissade properties, which recovers over time. Finally, the saccadic adaptation experiments reveal that glissades cannot be modulated by this training paradigm. Together our work offers a functional study of glissades and provides new insight into the cerebellar involvement in this type of motor error.
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Percutaneous ablation methods are used to treat primary and metastatic liver tumors. Image guided navigation support minimally invasive interventions of rigid anatomical structures. When working with the displacement and deformation of soft tissues during surgery, as in the abdomen, imaging navigation systems are in the preliminary implementation stage. In this study a multi-stage approach has been developed to support percutaneous liver tumors ablation. It includes CT image acquisition protocol with the amplitude of respiratory motion that yields images subjected to a semi-automatic method able to deliver personalized abdominal model. Then, US probe and ablation needle calibration, as well as patient position adjustment method during the procedure for the preoperative anatomy model, have been combined. Finally, an advanced module for fusion of the preoperative CT with intraoperative US images was designed. These modules have been tested on a phantom and in the clinical environment. The final average Spatial calibration error was 1,7â¯mm, the average error of matching the position of the markers was about 2â¯mm during the entire breathing cycle, and average markers fusion error 495â¯mm. The obtained results indicate the possibility of using the developed method of navigation in clinical practice.
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Neoplasias Abdominais/diagnóstico por imagem , Técnicas de Ablação , Neoplasias Hepáticas/diagnóstico por imagem , Procedimentos Cirúrgicos Minimamente Invasivos , Interpretação de Imagem Radiográfica Assistida por Computador , Cirurgia Assistida por Computador , Tomografia Computadorizada por Raios X , Neoplasias Abdominais/cirurgia , Pontos de Referência Anatômicos , Biópsia por Agulha , Humanos , Neoplasias Hepáticas/cirurgia , Planejamento de Assistência ao Paciente , Modelagem Computacional Específica para o Paciente , Imagens de Fantasmas , Radiografia AbdominalRESUMO
Cognitive and social capacities require postnatal experience, yet the pathways by which experience guides development are unknown. Here we show that the normal development of motor and nonmotor capacities requires cerebellar activity. Using chemogenetic perturbation of molecular layer interneurons to attenuate cerebellar output in mice, we found that activity of posterior regions in juvenile life modulates adult expression of eyeblink conditioning (paravermal lobule VI, crus I), reversal learning (lobule VI), persistive behavior and novelty-seeking (lobule VII), and social preference (crus I/II). Perturbation in adult life altered only a subset of phenotypes. Both adult and juvenile disruption left gait metrics largely unaffected. Contributions to phenotypes increased with the amount of lobule inactivated. Using an anterograde transsynaptic tracer, we found that posterior cerebellum made strong connections with prelimbic, orbitofrontal, and anterior cingulate cortex. These findings provide anatomical substrates for the clinical observation that cerebellar injury increases the risk of autism.
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Transtorno Autístico/fisiopatologia , Comportamento Animal/fisiologia , Cerebelo/fisiologia , Cognição/fisiologia , Animais , Mapeamento Encefálico , Cerebelo/diagnóstico por imagem , Modelos Animais de Doenças , Humanos , Processamento de Imagem Assistida por Computador , Interneurônios/fisiologia , Aprendizagem/fisiologia , Imageamento por Ressonância Magnética , Camundongos , Vias Neurais/fisiologia , Mudança SocialRESUMO
For half a century it was assumed that granule cells use ultra-sparse encoding, but now in vivo calcium-imaging studies have shown that large ensembles of granule cells provide dense signals, which themselves evolve and adapt during training.
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Cálcio/metabolismo , Cerebelo/fisiologia , Grânulos Citoplasmáticos/fisiologia , Modelos Neurológicos , Vias Neurais/fisiologia , Neurônios/fisiologia , Peixe-Zebra/fisiologia , Animais , Cerebelo/citologia , Neuroimagem/métodos , Neurônios/citologiaRESUMO
Cerebellar granule cells, which constitute half the brain's neurons, supply Purkinje cells with contextual information necessary for motor learning, but how they encode this information is unknown. Here we show, using two-photon microscopy to track neural activity over multiple days of cerebellum-dependent eyeblink conditioning in mice, that granule cell populations acquire a dense representation of the anticipatory eyelid movement. Initially, granule cells responded to neutral visual and somatosensory stimuli as well as periorbital airpuffs used for training. As learning progressed, two-thirds of monitored granule cells acquired a conditional response whose timing matched or preceded the learned eyelid movements. Granule cell activity covaried trial by trial to form a redundant code. Many granule cells were also active during movements of nearby body structures. Thus, a predictive signal about the upcoming movement is widely available at the input stage of the cerebellar cortex, as required by forward models of cerebellar control.
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Cerebelo/fisiologia , Retroalimentação , Aprendizagem/fisiologia , Neurônios/fisiologia , Animais , Antecipação Psicológica/fisiologia , Condicionamento Clássico/fisiologia , Masculino , Camundongos , Camundongos TransgênicosRESUMO
Translating neuronal activity to measurable behavioral changes has been a long-standing goal of systems neuroscience. Recently, we have developed a model of phase-reversal learning of the vestibulo-ocular reflex, a well-established, cerebellar-dependent task. The model, comprising both the cerebellar cortex and vestibular nuclei, reproduces behavioral data and accounts for the changes in neural activity during learning in wild type mice. Here, we used our model to predict Purkinje cell spiking as well as behavior before and after learning of five different lines of mutant mice with distinct cell-specific alterations of the cerebellar cortical circuitry. We tested these predictions by obtaining electrophysiological data depicting changes in neuronal spiking. We show that our data is largely consistent with the model predictions for simple spike modulation of Purkinje cells and concomitant behavioral learning in four of the mutants. In addition, our model accurately predicts a shift in simple spike activity in a mutant mouse with a brainstem specific mutation. This combination of electrophysiological and computational techniques opens a possibility of predicting behavioral impairments from neural activity.