Ontogenetic and comparative aspects of cerebellar and motor development

Sammanfattning: During the course of development the motor repertoire of animals and humans alike go through dramatic changes. New motor patterns arise; movements become coordinated, improve in precision and are at the same time continuously calibrated to the changing body dimensions. The cerebellum is critical for movement coordination and adaptation in adults. Also, interfering with cerebellar development during early life causes behavioural deficits suggesting an important role of the cerebellum in the formation of motor synergies. Hence, to understand the dramatic change in motor competence that characterizes postnatal development it may be of particular interest to study processes underlying the formation and shaping of the cerebellar neuronal networks. Unfortunately, little is known about how the cerebellum actually contributes to motor development. In order to elucidate the relationships between cerebellar ontogenetic changes and postnatal motor development a suitable animal model for multiple levels of analysis is a prerequisite. In this thesis, we therefore sought to develop and evaluate an experimental model that is suitable for combined behavioural, structural and systems level electrophysiological investigations of cerebellar development. For a number of reasons, the postnatal ferret seemed to be a suitable candidate. Although the ferret is commonly used as an experimental model in developmental studies on sensory systems, the development of its motor systems and motor behaviour had not been previously investigated. As a first step, we characterized the postnatal motor development in ferret kits in daily sessions from postnatal day (P)2 to P63. A battery of motor tests spanning the entire developmental period was used to assess locomotor activity and ability and the maturation of postural dynamic reflexes. Secondly, we characterized the morphological development of the ferret cerebellum. Overall cerebellar size, foliation and thickness of cortical layers were quantified and Purkinje cell morphology was characterized from P1 to P63. Thirdly, we investigated the zonal organization of climbing fibre input to the cerebella of ferret kits; a fundamental and general physiological feature of cerebellar function in the adult animal. These studies provide the first investigations of motor behavioural and cerebellar morphological development in the ferret. The electrophysiological data obtained represent a first important step towards the understanding of cerebellar physiological processes in the course of motor development. We conclude that the ferret in many aspects is a particularly suitable animal model for the study of cerebellar mechanisms underlying motor development. In a parallel approach, we assessed how timescales of motor and cerebellar morphological development can be translated between species with differently long developmental time periods, such as the ferret and rat. Linear regression analyses were performed on time points defining the corresponding levels of motor development and cerebellar maturation in ferrets and rats (rat data from Altman and Bayer, 1997). The derived time-conversion equations describing cerebellar morphological development and motor development in ferret and rat were highly congruent. To extend the comparative analysis to also include humans a model was formulated that takes into consideration comparative time courses of neurogenesis and cerebellar morphogenesis and relative timing of birth. Using behavioural data from rats and ferrets as input, the model predicts corresponding motor developmental dates that fall within 10% of actual mean values for the human population. Such astonishing predictive accuracy indicates that motor development in animals and man is governed by very similar principles and that these principles are successfully captured by our model.