The cerebellum from the fetus to the elderly: history, advances, and future challenges.

The cerebellum is now at the forefront of research in neuroscience. This is not just a coincidence, occurring about 250 years after the first description of the human cerebellum. The cerebellum contains the majority of neurons in the central nervous system and it is heavily connected with almost all cortical and subcortical areas of the supratentorial region as well as with the brainstem and the spinal cord. Cerebellar circuits are embedded in large-scale networks contributing to motor control and neurocognition. From a phenotypic standpoint, damage to cerebellar lobules interconnected with the sensorimotor cortices leads to a cerebellar motor syndrome, whereas lesions of the posterolateral cerebellum cause cognitive and neuropsychiatric impairments which may or may not be subtle. This topographic rule is valid in children and adults. Midline posterior vermal lesions cause behavioral/affective dysregulation, especially in kids. The extent of the spectrum of human cerebellar disorders is increasingly recognized from the fetus to the elderly, with recognition of consequences for the quality of life and socioeconomic costs due to lifelong morbidity of many cerebellar ataxias/pathologies. The prolonged duration of human cerebellar development makes the cerebellum especially susceptible to developmental disruption, both genetic and nongenetic. This explains the current emphasis on the clarification of the developmental course and impact of the cerebellum. The understanding of how germinal matrix zones and migration of neurons and glial cells end in a highly organized and foliated human cerebellum is essential. This is greatly accelerated by inputs from rodent developmental studies, in particular because cerebellar anatomy is conserved across species. Still, numerous questions on human fetal development remain unanswered. Although both advanced neuroimaging and genetic studies are currently leading to a better definition and understanding of the multitude of cerebellar symptoms, there is a gap, with a great need to develop therapies aiming at first, protection of the cerebellum during development, and second, restoration of cerebellar function in children and in adults. Dynamic profiles of the compensatory processes from newborns to elderly require specific studies.