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Cerebellum-dependent associative learning is not impaired in a mouse model of neurofibromatosis type 1.

ABSTRACT: Individuals with Neurofibromatosis type 1 (NF1) experience a high degree of motor problems. The cerebellum plays a pivotal role in motor functioning and the NF1 gene is highly expressed in cerebellar Purkinje cells. However, it is not well understood to what extent NF1 affects cerebellar functioning and how this relates to NF1 motor functioning. Therefore, we subjected global Nf1^+/- mice to a cerebellum-dependent associative learning task, called Pavlovian eyeblink conditioning. Additionally, we assessed general motor function and muscle strength in Nf1^+/- mice. To our surprise, we found that Nf1^+/- mice showed a moderately increased learning rate of conditioned eyeblink responses, as well as improved accuracy in the adaptive timing of the eyeblink responses. Locomotion, balance, general motor function, and muscle strength were not affected in Nf1^+/- mice. Together, our results support the view that cerebellar function in Nf1^+/- mice is unimpaired.

SUBMITTER: Ottenhoff MJ

PROVIDER: S-EPMC9646701 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Cerebellum-dependent associative learning is not impaired in a mouse model of neurofibromatosis type 1.

Ottenhoff M J MJ Dijkhuizen S S Ypelaar A C H ACH de Oude N L NL Koekkoek S K E SKE Wang S S-H SS De Zeeuw C I CI Elgersma Y Y Boele H J HJ

Scientific reports 20221109 1

Individuals with Neurofibromatosis type 1 (NF1) experience a high degree of motor problems. The cerebellum plays a pivotal role in motor functioning and the NF1 gene is highly expressed in cerebellar Purkinje cells. However, it is not well understood to what extent NF1 affects cerebellar functioning and how this relates to NF1 motor functioning. Therefore, we subjected global Nf1<sup>+/-</sup> mice to a cerebellum-dependent associative learning task, called Pavlovian eyeblink conditioning. Addit ...[more]

PMID: 36351971

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Project description:Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures, or both. Although dystonia is traditionally associated with basal ganglia dysfunction, recent evidence has been pointing to a role of the cerebellum, a brain area involved in motor control and learning. Cerebellar abnormalities have been correlated with dystonia but their potential causative role remains elusive. Here, we simulated the cerebellar input-output relationship with high-resolution computational modeling. We used a data-driven cerebellar Spiking Neural Network and simulated a cerebellum-driven associative learning task, Eye-Blink Classical Conditioning (EBCC), which is characteristically altered in relation to cerebellar lesions in several pathologies. In control simulations, input stimuli entrained characteristic network dynamics and induced synaptic plasticity along task repetitions, causing a progressive spike suppression in Purkinje cells with consequent facilitation of deep cerebellar nuclei cells. These neuronal processes caused a progressive acquisition of eyelid Conditioned Responses (CRs). Then, we modified structural or functional local neural features in the network reproducing alterations reported in dystonic mice. Either reduced olivocerebellar input or aberrant Purkinje cell burst-firing resulted in abnormal learning curves imitating the dysfunctional EBCC motor responses (in terms of CR amount and timing) of dystonic mice. These behavioral deficits might be due to altered temporal processing of sensorimotor information and uncoordinated control of muscle contractions. Conversely, an imbalance of excitatory and inhibitory synaptic densities on Purkinje cells did not reflect into significant EBCC deficit. The present work suggests that only certain types of alterations, including reduced olivocerebellar input and aberrant PC burst-firing, are compatible with the EBCC changes observed in dystonia, indicating that some cerebellar lesions can have a causative role in the pathogenesis of symptoms.

Dataset Information

Cerebellum-dependent associative learning is not impaired in a mouse model of neurofibromatosis type 1.

Publications

Cerebellum-dependent associative learning is not impaired in a mouse model of neurofibromatosis type 1.

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