Learning Stimulus Intervals—Adaptive Timing of Conditioned Purkinje Cell Responses

Abstract

Classical conditioning of motor responses, such as the eyeblink response, is an experimental model of associative learning and of adaptive timing of movements. A conditioned blink will have its maximum amplitude near the expected onset of the unconditioned blink-eliciting stimulus and it adapts to changes in the interval between the conditioned and unconditioned stimuli. Previous studies have shown that an eyeblink conditioning protocol can make cerebellar Purkinje cells learn to pause in response to the conditioned stimulus. According to the cerebellar cortical conditioning model, this conditioned Purkinje cell response drives the overt blink. If so, the model predicts that the temporal properties of the Purkinje cell response reflect the overt behaviour. To test this prediction, in vivo recordings of Purkinje cell activity were performed in decerebrate ferrets during conditioning, using direct stimulation of cerebellar mossy and climbing fibre afferents as conditioned and unconditioned stimuli. The results show that Purkinje cells not only develop a change in responsiveness to the conditioned stimulus. They also learn a particular temporal response profile where the timing, not only of onset and maximum but also of offset, is determined by the temporal interval between the conditioned and unconditioned stimuli.

Learned response sequences in cerebellar Purkinje cells

“…This is illustrated by a case in a previous study (13), in which a cell had first been conditioned with a mossy fiber CS to an interval of 200 ms that was later shifted to 600 ms, after which it learned a response sequence that was adaptively timed to both intervals (compare Fig. 4c in ref.…”

“…This meant the second ISI had to be relatively long compared with the first. However, conditioning with long ISIs requires more time (3,13,24), and the acute setup in these experiments provides only a limited window for studying learning effects. In this trade-off, we settled on a paradigm with a 300-ms difference between the two ISIs (150 and 450 ms).…”

“…Using very different ISIs, in contrast, means the second has to be quite long. Because learning to long ISIs is considerably slower than learning to shorter ones (3,13,24), it is difficult to obtain learning in the limited time available in the acute decerebrate preparation.…”

“…These cells receive the CS signal via the mossy fiber/parallel fiber system, and the US signal via the climbing fibers from the inferior olive (10,11). The conditional Purkinje cell response (Purkinje cell CR, or PcCR) is elicited by input from the parallel fibers (12), triggering a delayed and adaptively timed pause in the Purkinje cell's simple spike firing (13), illustrated in Fig. 1A.…”

“…First, it may be asked whether a Purkinje cell can learn more than one interval; that is, can the cell learn to respond to a uniform repetitive CS containing no temporal code, with sequences corresponding to the long-duration or double-peaked eyeblink CRs, after training with alternating ISIs? There are data that suggest this is the case, but they consist only of unsystematic observations in a very small number of subjects: three decerebrate ferrets (12,13) and two intact rabbits (18). Second, if a cell can learn a response sequence, the question may be asked of how the components of such a sequence are related to each other.…”