Proc. Natl. Acad. Sci. USA Vol. 94, pp. 14200–14205, December 1997 Psychology A model of long-term memory storage in the cerebellar cortex: A possible role for plasticity at parallel fiber synapses onto stellateybasket interneurons GARRETT T. KENYON† Department of Neurobiology and Anatomy, University of Texas Medical School at Houston, 6431 Fannin, Houston, TX 77030 Edited by Richard F. Thompson, University of Southern California, Los Angeles, CA, and approved October 3, 1997 (received for review April 14, 1997) ABSTRACT By evoking changes in climbing fiber activity, Despite evidence supporting their postulated role in motor movement errors are thought to modify synapses from parallel learning, theoretical arguments suggest that memories stored fibers onto Purkinje cells (pf*Pkj) so as to improve subse- at pf*Pkj synapses would be susceptible to long-term degra- quent motor performance. Theoretical arguments suggest dation as a result of ongoing motor adaptation. First, motor there is an intrinsic tradeoff, however, between motor adap- memories are likely to be distributed across overlapping sets of tation and long-term storage. Assuming a baseline rate of pf*Pkj synapses. If motor memories did not overlap, the motor errors is always present, then repeated performance of storage capacity of pf*Pkj synapses would be greatly reduced any learned movement will generate a series of climbing (12, 17). Second, it is reasonable to assume that the pattern of fiber-mediated corrections. By reshuffling the synaptic synaptic weights necessary to effect any given movement is weights responsible for any given movement, such corrections non-unique. If the activity of a Purkinje cell depends only on will degrade the memories for other learned movements stored the total sum of the synaptic input at any given moment, then in overlapping sets of synapses. The present paper shows that there will be a virtual infinity of synaptic weight combinations long-term storage can be accomplished by a second site of capable of producing the same Purkinje cell output. Third, it plasticity at synapses from parallel fibers onto stellateybasket can be further assumed that repeated execution of any learned interneurons (pf*StyBk). Plasticity at pf*StyBk synapses can movement in the face of constantly fluctuating internal and be insulated from ongoing fluctuations in climbing fiber external environmental conditions will generate a constant activity by assuming that changes in pf*StyBk synapses occur stream of error signals. Given these three assumptions, it only after changes in pf*Pkj synapses have built up to a follows that motor adaptation is an inherently noisy process, threshold level. Although climbing fiber-dependent plasticity and that random corrections to any given movement inevitably at pf*Pkj synapses allows for the exploration of novel motor will damage other existing motor memories. In particular, strategies in response to changing environmental conditions, ongoing corrections to any given movement will tend to plasticity at pf*StyBk synapses transfers successful strategies reshuffle the pattern of synaptic weights responsible for that to stable long-term storage. To quantify this hypothesis, both movement, and thus destroy any information relating to other learned motor behaviors stored at the same synapses. sites of plasticity are incorporated into a dynamical model of Anatomical arguments suggest that a second site of plasticity the cerebellar cortex and its interactions with the inferior at parallel fiber to stellateybasket (pf*StyBk) synapses could olive. When used to simulate idealized motor conditioning provide an alternative locus of stable long-term storage in a trials, the model predicts that plasticity develops first at manner consistent with climbing fiber-dependent plasticity at pf*Pkj synapses, but with additional training is transferred to pf*Pkj synapses. First, learned pauses in Purkinje cell activity, pf*StyBk synapses for long-term storage. which in the above models results from the induction of long-term depression (LTD) at pf*Pkj synapses, also could be Animal studies indicate that the cerebellum contributes to a produced by appropriately timed increases in the inhibitory variety of learned motor behaviors (1–7), a conclusion sup- synaptic input from stellateybasket cells. Second, stellate and ported in humans by both behavioral experiments (8, 9) and basket cells greatly outnumber Purkinje cells (30) and receive imaging studies (10, 11). Starting with the original models of similar patterns of parallel fiber input from granule cells, thus Marr (12) and Albus (13), a number of theoretical analyses pf*StyBk synapses provide a potentially large reservoir of have postulated that climbing fiber-dependent plasticity at additional storage capacity. Third, the projection patterns of synapses from parallel fibers onto Purkinje cells (pf*Pkj) in the stellateybasket cells respect the parasagital motor organization cerebellar cortex contributes to motor adaptation (14–23). of the cerebellar cortex (30, 31), suggesting that such projec- The anatomical assumptions underlying MarryAlbus-based tions may play a direct role in the execution of movements. models of cerebellar involvement in motor learning are sup- Fourth, recent studies report that rats raised in environments ported by evidence of a strong topographical organization in requiring increased motor learning exhibit a significant expan- the reciprocal interactions between the cerebellum and the sion in the number of stellate dendrites (32). Finally, plasticity inferior olive (24, 25). In addition, electrophysiological studies has been reported at synapses onto analogous interneurons in report changes in cerebellar activity after climbing fiber stim- other brain areas (33). ulation (26–28) and during motor adaptation (2, 4, 7, 29) that In this paper, we use a mathematical model of the cerebellar are consistent with the postulated role of climbing fiber- cortex and its reciprocal interactions with the inferior olive to dependent plasticity at pf*Pkj synapses. This paper was submitted directly (Track II) to the Proceedings office. The publication costs of this article were defrayed in part by page charge Abbreviations: pf*Pkj, parallel fiber onto Purkinje cell (i.e., pf*Pkj synapses); pf*StyBk, parallel fiber onto stellateybasket cell; LTD, payment. This article must therefore be hereby marked ‘‘advertisement’’ in long-term depression; CS, conditioned stimulus; US, unconditioned accordance with 18 U.S.C. §1734 solely to indicate this fact. stimulus. © 1997 by The National Academy of Sciences 0027-8424y97y9414200-6$2.00y0 †To whom reprint requests should be addressed. e-mail: gkenyon@ PNAS is available online at http:yywww.pnas.org. nba19.med.uth.tmc.edu. 14200 Downloaded by guest on September 26, 2021 Psychology: Kenyon Proc. Natl. Acad. Sci. USA 94 (1997) 14201 investigate how the two proposed sites of plasticity could The sole output of the cerebellar cortex is via Purkinje cells. interact in complementary manner. Although plasticity at The influence of Purkinje cells on climbing fibers is via a synapses onto interneurons in the cerebellar cortex has been disynaptic pathway consisting of two inhibitory synapses in studied in previous models (13, 16), these analyses did not series; Purkinje cells make inhibitory synapses in the cerebellar address the issue of how plasticity at pf*StyBk synapses might nuclei, and the cerebellar nuclei send a prominent inhibitory be specialized for stable long-term storage. As a tractable projection to the inferior olive (35, 36), which is the sole source example of motor learning, the present model is applied to the of climbing fibers. Because both climbing fibers and cerebellar analysis of idealized Pavlovian conditioning trials. Our prin- nucleus neurons are tonically active (4, 37), it should be cipal finding is that when plasticity at pf*StyBk synapses is possible to model the two inhibitory synapses between Pur- sensitive to changes in Purkinje cell activity, motor memories kinje cells and climbing fibers as a single excitatory connection, automatically are transferred from pf*Pkj to pf*StyBk syn- as shown in Fig. 1. apses during continued reinforcement training. These results At the highest level of organization, the present model suggest that pf*StyBk synapses could provide a site of stable assumes that the cerebellar cortex is divided into functionally long-term memory storage, whereas climbing fiber-dependent distinct microzones, each of which controls a specific muscle plasticity pf*Pkj synapses provides a means of exploring novel group (24, 25). As illustrated in Fig. 1, each microzone consists motor strategies in an intrinsically noisy environment without of a parasagital strip that runs transversely to the long axis of the folia. The dendritic planes of the individual Purkinje cells damaging previously learned behaviors. are oriented along the axis of their corresponding microzones, whereas parallel fibers run in a perpendicular direction, THEORY transecting multiple microzones as they course along the long axis of the folia. The axons of stellate and basket cells run The Anatomy of the Cerebellar-Olivary System. The anat- transversely to the folia so as to potentially link different omy of the cerebellar-olivary system relevant to the present Purkinje cells within the same microzone. model is illustrated in Fig. 1 (34). Input to the cerebellar cortex Because of regular patterns of connectivity within a single is via both mossy fibers