Consensus Paper. Cerebellar Reserve: From Cerebellar Physiology to Cerebellar Disorders.

Cerebellar reserve refers to the capacity of the cerebellum to compensate for tissue damage or loss of function resulting from many different etiologies. When the inciting event produces acute focal damage (e.g., stroke, trauma), impaired cerebellar function may be compensated for by other cerebellar areas or by extracerebellar structures (i.e., structural cerebellar reserve). In contrast, when pathological changes compromise cerebellar neuronal integrity gradually leading to cell death (e.g., metabolic and immune-mediated cerebellar ataxias, neurodegenerative ataxias), it is possible that the affected area itself can compensate for the slowly evolving cerebellar lesion (i.e., functional cerebellar reserve). Here, we examine cerebellar reserve from the perspective of the three cornerstones of clinical ataxiology: control of ocular movements, coordination of voluntary axial and appendicular movements, and cognitive functions. Current evidence indicates that cerebellar reserve is potentiated by environmental enrichment through the mechanisms of autophagy and synaptogenesis, suggesting that cerebellar reserve is not rigid or fixed, but exhibits plasticity potentiated by experience. These conclusions have therapeutic implications. During the period when cerebellar reserve is preserved, treatments should be directed at stopping disease progression and/or limiting the pathological process. Simultaneously, cerebellar reserve may be potentiated using multiple approaches. Potentiation of cerebellar reserve may lead to compensation and restoration of function in the setting of cerebellar diseases, and also in disorders primarily of the cerebral hemispheres by enhancing cerebellar mechanisms of action. It therefore appears that cerebellar reserve, and the underlying plasticity of cerebellar microcircuitry that enables it, may be of critical neurobiological importance to a wide range of neurological/neuropsychiatric conditions.

Activity-dependent structural plasticity of Purkinje cell spines in cerebellar vermis and hemisphere.

The environmental enrichment (EE) paradigm is widely used to study experience-dependent brain plasticity. In spite of a long history of research, the EE influence on neuronal morphology has not yet been described in relation to the different regions of the cerebellum. Thus, aim of the present study was to characterize the EE effects on density and size of dendritic spines of Purkinje cell proximal and distal compartments in cerebellar vermian and hemispherical regions. Male Wistar rats were housed in an enriched or standard environment for 3.5 months from the 21st post-natal day onwards. The morphological features of Purkinje cell spines were visualized on calbindin immunofluorescence-stained cerebellar vermian and hemispherical sections. Density, area, length and head diameter of spines were manually (ImageJ) or automatically (Imaris) quantified. Results demonstrated that the Purkinje cell spine density was higher in enriched rats than in controls on both proximal and distal dendrite compartments in the hemisphere, while it increased only on distal compartment in the vermis. As for spine size, a significant increase of area, length and head diameter was found in the distal dendrites in both vermis and hemisphere. Thus, the exposure to a complex environment enhances synapse formation and plasticity either in the vermis involved in balance and locomotion and in the hemisphere involved in complex motor adaptations and acquisition of new motor strategies. These data highlight the importance of cerebellar activity-dependent structural plasticity underling the EE-related high-level performances.

Features of sequential learning in hemicerebellectomized rats.

Because the sequencing property is one of the functions in which cerebellar circuits are involved, it is important to analyze the features of sequential learning in the presence of cerebellar damage. Hemicerebellectomized and control rats were tested in a four-choice visuomotor learning task that required both the detection of a specific sequence of correct choices and the acquisition of procedural rules about how to perform the task. The findings indicate that the presence of the hemicerebellectomy did not affect the first phases of detection and acquisition of the sequential visuomotor task, delayed but did not prevent the learning of the sequential task, slowed down speed-up and proceduralization phases, and loosened the reward-response associative structure. The performances of hemicerebellectomized animals in the serial learning task as well as in the open field task demonstrated that the delayed sequential learning task could not be ascribed to impairment of motor functions or discriminative abilities or to low levels of motivation. The delay in sequential learning observed in the presence of a cerebellar lesion appeared to be related mainly to a delay of the automatization of the response. In conclusion, it may be advanced that, through cortical and subcortical connections, the cerebellum provides the acquisition of rapid and accurate sensory-guided sequence of responses.

Cerebellar involvement in cognitive flexibility.

The aim of the present study was to investigate whether the cerebellar structures are involved in functions requiring cognitive flexibility abilities. The flexibility of the hemicerebellectomized and control animals in learning a four-choice learning task, adapting to ever-changing response rules was investigated. While in the initial phase of the task both experimental groups exhibited similar performances, only the control animals significantly improved their performance as the sessions went by. The lack of improvement in lesioned animals' performance rendered their responses particularly defective in the final phases of the task, when conversely intact animals performed best, exploiting their "learning to learn" ability. The findings demonstrate the defective influence of the cerebellar lesion on the acquisition, not the execution, of new responses. The results underline the crucial role of the cerebellum in mediating cognitive flexibility behaviors.

Environmental enrichment mitigates the effects of basal forebrain lesions on cognitive flexibility.

The aim of the present study was to investigate whether basal forebrain lesions were able to impair a task requiring cognitive flexibility abilities and analyzing the effect of the rearing in an enriched environment on such form of flexibility in rats with or without basal forebrain cholinergic lesions. In adult rats reared in enriched or standard conditions of the cholinergic projection to the neocortex damage was inflicted by 192 IgG-saporin injection into Ch4 region of basal forebrain. Their performance was compared with those of intact animals reared in analogous conditions in a four-choice serial learning task which taps flexibility in adapting to changing response rules. The results underlined the crucial role of the basal forebrain in mediating cognitive flexibility behaviors and revealed that the increase in social interactions, cognitive stimulation and physical activity of the rearing in enriched environment attenuated impairments caused by the cholinergic lesion. These findings demonstrate that rearing in an enriched environment can improve the ability to cope with brain damage suffered in adulthood.