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The Learning-Related Activity That Develops in the Pontine Nuclei During Classical Eye- Blink Conditioning Is Dependent on the Interpositus Nucleus Robert E

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The Learning-Related Activity That Develops in the Pontine Nuclei During Classical Eye- Blink Conditioning Is Dependent on the Interpositus Nucleus Robert E Downloaded from learnmem.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press The Learning-Related Activity That Develops in the Pontine Nuclei During Classical Eye- Blink Conditioning Is Dependent on the Interpositus Nucleus Robert E. Clark, 1 Elizabeth B. Gohl, and David G. Lavond Departments of Psychologyand Biological Sciences University of Southern California Los Angeles, California 90089-2520 Abstract were still present. These results indicate that the learning-related activity exhibited by A growing body of research now some populations of pontine nuclei cells is implicates the cerebellum in the formation dependent on the interpositus nucleus and and storage of the critical neural plasticity may represent feedback from the that subserves the classically conditioned cerebellum. eye-blink response. Previous anatomical, physiological, and behavioral research Introduction suggests that auditory-conditioned stimulus information is routed to the cerebellum by Classical conditioning of the rabbit eye-blink the pontine nuclei. However, it has also or nictitating membrane (NM) response has been been observed from multiple unit used extensively to study the neurobiology of recordings that some populations of pontine simple associative memory in mammals. Compel- cells, in addition to showing ling evidence now exists that implicates the cer- auditory-evoked responses, also show ebellum as essential for the formation and storage changes in activity that is learning-related. It of this eye-blink engram. This research deals pri- is unknown whether this learning-related marily with simple delay conditioning. For more activity is generated by the pontine cells or complex conditioning tasks, like trace condition- whether it is generated by some other ing, the hippocampus is also critical (Kim et al. structure and projected to the pontine 1995). For simple delay conditioning, converging nuclei. Because the cerebellum has been evidence from permanent lesion, stimulation, and implicated in the formation of the essential recording studies have made possible the construc- plasticity that subserves this learned tion of a relatively complete theoretical circuit that behavior, we examined how multiple unit includes neural pathways for the conditioned recordings of learning-related activity within stimulus (CS), the unconditioned stimulus (US), the pontine nuclei are affected by reversible the conditioned response (CR), and the uncondi- inactivation of the interpositus nucleus of tioned response (UR). Auditory CS information is the cerebellum. The results indicated clearly relayed from the pontine nuclei, through mossy that when the interpositus nucleus was fibers, to the cerebeUar cortex and interpositus inactivated, the learning-related activity in nucleus, whereas somatosensory US information the pontine nuclei was abolished completely (typically an air puff) is relayed from the trigeminal and the auditory stimulus-evoked activity complex to the inferior olive and then, by climbing was unaffected. In contract, when the facial fibers, to the cerebellar cortex and interpositus. nucleus was inactivated, both the auditory The convergence of CS and US information in the stimulus and the learning-related activity cerebellum makes possible the neural plasticity that underlies the CR, which is then routed out of the cerebellum through the red nucleus to motor 1Corresponding author. nuclei responsible for driving the NM response (for LEARNING & MEMORY 3:532-544 91997 by Cold Spring Harbor Laboratory Press ISSN1072-0502/97 $5.00 L E A R N / N G & M E M O R Y 532 Downloaded from learnmem.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press EYE-BLINK CONDITIONING AND THE PONTINE NUCLEI an extensive review of this circuit, see Lavond et al. sidered. For example, although the auditory- 1993). evoked response in the pontine nuclei is well- The pontine nuclei are of interest because they known, there is evidence suggesting that this re- have been implicated in participating in the CS gion may also receive somatosensory information pathway for the conditioned eye-blink response. from the air puff (Lavond et al. 1981). This means Anatomical and electrophysiological studies have that the pontine nuclei could receive convergent indicated that the pontine nuclei send mossy fibers CS and US information and could be the essential through the middle cerebellar peduncle to the cer- site of plasticity. Couple this with the observation ebellar cortex (Brodal and Jansen 1946) and to the that this region also shows learning-related neural interpositus nucleus (Steinmetz and Sengelaub unit activity in well-trained animals (McCormick et 1992; Mihailoff 1993; J. Tracy, D.J. Krupa, N.L. al. 1983), a case can be made for this region being Bernasconi, J.S. Grethe, and R.F. Thompson, un- the possible site of essential plasticity that then publ.). projects the model to the cerebellum. However, an Stimulation of the pontine nuclei or of the alternative interpretation is that this unit model middle cerebellar peduncle can be used as an ef- could be formed in the cerebellum and projected fective conditioning stimulus (Steinmetz et al. to the pontine nuclei as feedback. 1985, 1989). In fact, pontine stimulation as a CS The strategy we adopted here to examine this yields more rapid acquisition than exteroceptive possibility has been used successfully previously to CSs. As with exteroceptive CSs, when CS stimula- study the relationship of the trigeminal and inter- tion alone trials are presented, the learned behav- positus nuclei (Clark and Lavond 1996) and the ior extinguishes (Steinmetz et al. 1986). Further- interpositus and bilateral regions of the cerebellar more, animals trained with pontine stimulation as cortex (Clark et al. 1997). Briefly, animals were the CS develop a neural model in the interpositus well-trained for the classically conditioned eye nucleus that is indistinguishable from the model blink response and then multiple unit activity was that develops with a tone CS (i.e., activity that is sampled from the pontine nuclei. The interpositus associated with and predictive of the learned be- nucleus was then temporarily inactivated by cool- havioral response). When these animals are ing while the multiple unit activity was monitored switched to a tone CS, considerable transfer is evi- continually for changes. As a control, we also dent-perfect in some cases (Steinmetz 1990). cooled the facial nucleus during recording from This argues that pontine stimulation activates a sig- the pontine nuclei. The facial nucleus is critically nificant portion of the neural elements normally involved in the expression of both the eye-blink CR activated with a tone CS. There is no transfer when and UR (Cegavske et al. 1976), although it is not a light CS is substituted. Lesion of the interpositus critical for the formation of the conditioned re- also abolish the CRs established with pontine CS sponse (Krupa et al. 1996; Clark et al. 1997; A.A. stimulation (Steinmetz et al. 1986). Zhang and D.G. Lavond, unpubl.). Middle cerebellar peduncular lesions abolish We chose to use a cooling probe, which re- CRs to auditory, visual, and tactile CSs (Solomon et versibly inactivates cell bodies without affecting al. 1986), whereas discrete lesions of the lateral fibers (Brooks 1983), because this study required pontine nuclei abolish CRs to a tone, but not to a greater control for numerous inactivations and re- light CS (Steinmetz et al. 1987). Recording studies versal of inactivations during a single training ses- have indicated that short latency auditory-evoked sion. The cooling probe possesses the ideal char- responses are present in the lateral pontine nuclei acteristics for this particular type of study because (Steinmetz et al. 1986) and this region receives pri- of its ability to produce a rapidly induced (<30 sec) mary auditory projections (Aitkin and Boyd 1978). lesion and a rapidly reversed (<30 sec) lesion These studies indicate that all CS modalities tested (Clark et al. 1992; Clark and Lavond 1993). Previ- are relayed to the cerebellum by the middle cer- ously, we have demonstrated that the interpositus ebellar peduncle, whereas the lateral pontine nu- can be reversibly lesioned repeatedly without de- clei seem to be specifically involved in the routing stroying the conditioned memory trace (Clark et al. of auditory CS information to the cerebellum 1992; Clark and Lavond 1996). In conjunction with through the middle cerebellar peduncle. multiple cooling periods, we used a movable re- Although the data presented above provide cording microelectrode that enabled us to collect a strong support for the pontine nuclei participating significant amount of data from each subject dur- in the CS pathway, other factors need to be con- ing a single training session. L E A R N I N G I M E M 0 R Y Downloaded from learnmem.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Clark et al. Materials and Methods rabbit was held in a standard Plexiglas rabbit re- strainer. An airhose for delivering the air puff and a SUBJECTS minitorque potentiometer for measuring the nicti- tating membrane response were attached to a The subjects for this experiment (N-22) socket cemented to the rabbit's cranium. were adult male New Zealand white rabbits (Oryc- Training for classical conditioning began the weighing 2.0 _+ 0.2 kg at the tolagus cuniculus) next day. The CS was a 352-msec, 1-kHz, 85-dB start of the experiment. M1 rabbits were housed SPL, free-field tone. The US was a lO0-msec, 2.1- individually and maintained on a 12-hr light/12-hr N/cm 2 (source pressure) air puff delivered to the dark cycle and given unlimited access to water and cornea. On paired trials the CS and US coterminate, food. The rabbits were cared for by the experi- creating a 252-msec interstimulus interval. Each menters and by the staff and veterinarians of the daily training session consisted of 108 total trials University of Southern California. Care and treat- composed of 12 blocks of nine trims per block.
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