A decrementing form of plasticity apparent in cerebellar learning

Abstract

Long-term synaptic plasticity is believed to underlie the capacity for learning and memory. In the cerebellum, for example, long-term plasticity contributes to eyelid conditioning and to learning in eye movement systems. We report evidence for a decrementing form of cerebellar plasticity as revealed by the behavioral properties of eyelid conditioning in the rabbit. We find that conditioned eyelid responses exhibit within-session changes that recover by the next day. These changes, which increase with the interstimulus interval, involve decreases in conditioned response magnitude and likelihood as well as increases in latency to onset. Within-subject comparisons show that these changes differ in magnitude depending on the type of training, arguing against motor fatigue or changes in motor pathways downstream of the cerebellum. These phenomena are also observed when stimulation of mossy fibers substitutes for the conditioned stimulus, suggesting that changes take place within the cerebellum or in downstream efferent pathways. Together, these observations suggest a plasticity mechanism in the cerebellum that is induced during training sessions and fades within 23 h. To formalize this hypothesis more specifically, we show that incorporating a short-lasting potentiation at the granule cell to Purkinje cell synapses in a computer simulation of the cerebellum reproduces these behavioral effects. We propose the working hypothesis that the presynaptic form of long-term potentiation observed at these synapses is reversed by time rather than by a corresponding long-term depression. These results demonstrate the utility of eyelid conditioning as a means to identify and characterize the rules that govern input to output transformations in the cerebellum.

Figure 1.

Evidence from three groups of animals for within-session changes in conditioned eyelid responses that reverse between sessions. Two groups of rabbits were trained with delay conditioning using an ISI of 500 ms (D500, n = 33) and 1000 ms (D1000, n = 18), and a third group was trained with trace conditioning using a 500 ms CS and a 500 ms trace interval for a total ISI of 1000 ms (T1000, n = 33). A, B, Ten daily training sessions reveal that at asymptotic levels of performance (here, days 6–10) there are within-session decreases in response likelihood (A) and increases in latency to onset (B). C, more subtle within-session decreases are shown in response magnitude, which is the average amplitude of the responses that met the criterion for a conditioned response (i.e., excluding nonconditioned responses). For all three response measures, the within-session changes reverse between sessions.

Figure 2.

Analysis of within-session changes averaged over sessions 9 and 10 for five response measures for the same three groups shown in Figure 1. The abscissa shows the 12 nine-trial blocks that comprised each session. Each response measure involved an average of the nine trials for each block normalized to the average of the first block of that session, with data from sessions 9 and 10 then averaged to produce a single data point per animal per block. For the top four panels, the data were normalized as the percentage of the first block, whereas in the bottom panel the latency to onset was normalized as a difference score from the first block. A, There is a significant decrease within training sessions in response likelihood that is greater for the groups with an ISI of 1000 ms. B, There were small decreases in the magnitude of responses for the two delay conditioning groups. C, There were no significant changes in the amplitude of the URs. D, There were robust increases in the latencies to onset of the conditioned responses for all three groups. E, When the latency to onset data are normalized as a difference score the within-session increases are larger for the groups with an ISI of 1000 ms.

Figure 3.

The effect of ISI on within-session changes of conditioned responses. Separate groups of animals were trained using ISIs of 200 ms (n = 4), 250 ms (n = 8), 350 ms (n = 8), 500 ms (n = 34), 750 ms (n = 8), 1000 ms (n = 21), and 1150 ms (n = 7). For the panels at left, the data were normalized as in Figure 2 (as a difference score relative to block 1) and averaged over the last two sessions of training for each animal (the total number of sessions varied from animal to animal, but performance was at asymptote for both). The graphs at right plot the same data as a single difference score (average of the last three blocks relative to first block) for all seven groups. There were significant increases in latency to onset and decreases in conditioned response likelihood that generally increased with the ISI. In the right panels, the asterisks denote significant differences from no change (*p < 0.05, **p < 0.01, ***p < 0.001). The horizontal lines denote significant differences between groups (Tukey test), where dotted lines denote p < 0.05 and solid lines denote p < 0.01).

Figure 4.

A within-subject comparison (n = 49) of the within-session changes for animals trained using two CSs, one trained with delay conditioning (D500) and the other trained with trace conditioning (T1000). The delay and trace trials were intermixed during the sessions and then subjected to separate analyses. A–C, For response likelihood (A), latency to onset (B), and response magnitude (C), the within-session changes were significantly larger for the T1000 trials than for the D500 trials. The bar graphs at right show the corresponding response measures as difference scores (last three blocks relative to the first block) averaged over sessions 9 and 10. For all three response measures and for both trial types, the within-session changes were significant (p < 0.05 for comparison to 0). All three responses measures showed significant differences between the two trial types, as indicated by difference scores that were reliably different from 0 (p < 0.01 in each case).

Figure 5.

Using electrical stimulation of mossy fibers as a substitute for the tone CS also produced within-session changes in conditioned responses that were greater for an ISI of 1000 (MF1000, n = 8) than for an ISI of 500 ms (MF500, n = 27). For comparison purposes, data from animals using a tone CS (D500 and D1000, taken from Fig. 2) are also shown. These data, which are averages from sessions 9 and 10, are again normalized either as a percentage of block 1 (likelihood data) or as a difference score relative to block 1 (latency to onset data). Bar graphs at right show the same data expressed as a single normalized score (last three blocks relative to first block) averaged over sessions 9 and 10. Results from mossy fiber stimulation parallel those for a tone CS: there are larger differences in response likelihood and latency to onset for the longer ISI. In the bar graphs, all four groups show reliable differences from zero change (p < 0.01). All comparisons between the same ISI were not significant, and all comparisons between different ISIs were reliably different (p < 0.05).

Figure 6.

Results from a computer simulation of the cerebellum subjected to training using the same seven ISIs used with the rabbit experiments. When a decrementing form of potentiation (dP) is implemented at the granule to Purkinje synapses, within-session changes in magnitude and latency to onset were observed. A, For the data shown, the responses were normalized and analyzed using the same procedures shown in Figures 3 and 5. With the exception that the 750 group showed larger changes than the 1000 group, the data closely parallel the ISI-dependent increases in latency to onset and decreases in conditioned response magnitude. B, The magnitude of the within-session changes scales with the maximum obtainable value of dP. Without dP, both response measures are relatively stable within sessions. The red lines show results for the values used in A. C, A comparison of these effects for two different ways to implement dP. For “independent,” the induction of dP was completely independent of climbing fiber inputs. For “CF-dependent,” the induction of dP was cancelled for activity that occurred over time spans where LTD was induced (the 100 ms before any climbing fiber input). The changes in latency to onset were essentially identical (data not shown), and, aside from slightly smaller effects at longer ISIs, the results for magnitude were quite similar.