Abstract: 

Associative learning in the cerebellum underlies motor memories and probably also cognitive associations. Pavlovian eyeblink conditioning, a widely used experimental model of such learning, depends upon the cerebellum, but the memory locus within the cerebellum as well as the underlying mechanisms have remained controversial. We have recently been able to follow the activity of single Purkinje cells with microelectrodes for more than 15 hours in decerebrate ferrets during acquisition, extinction and relearning. We have shown that paired peripheral forelimb and periocular stimulation, as well as paired direct stimulation of cerebellar afferent pathways (mossy and climbing fibers) consistently causes a gradual acquisition of an inhibitory response in Purkinje cell simple spike firing. These conditioned cell response have several properties which match known features of the behavioral conditioned response. For instance, unpaired mossy and climbing fibre stimulation causes extinction and reinstating paired stimulation after extinction causes very rapid reacquisition. The response latency varies with the interstimulus interval and the response maximum is adaptively timed to precede the unconditioned stimulus. Manipulations of the conditioned stimulus that causes changes in behavioral responses have parallel effects on Purkinje cell responses.  These data suggest that many of the basic behavioral phenomena in eyeblink conditioning can be explained at the level of the single Purkinje cell. Although the recordings do not in themselves point to specific cellular mechanisms underlying the learning but they do indicate constraints on which mechanisms are possible. Complex spike recordings during conditioning support the idea that the nucleo-olivary pathway functions as a negative feedback system for controlling the learning and that this may explain some classical puzzles of learning such as blocking and overexpectation.