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Reversible Inactivation of the Cerebellar Interpositus Nucleus Completely Prevents Acquisition of the Classically Conditioned Eye-Blink Response David J

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Reversible Inactivation of the Cerebellar Interpositus Nucleus Completely Prevents Acquisition of the Classically Conditioned Eye-Blink Response David J Downloaded from learnmem.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Reversible Inactivation of the Cerebellar Interpositus Nucleus Completely Prevents Acquisition of the Classically Conditioned Eye-Blink Response David J. Krupa 1 and Richard F. Thompson Neur0sciences Program University of S0uthem Calif0mia Los Angeles, California 90089-2520 Abstract These results confirm and extend the original findings that appropriate lesions Numerous studies from several (either temporary or permanent) of the laboratories report that temporary interpositus nucleus completely prevent inactivation of the cerebellar interpositus acquisition of the conditioned eye-blink nucleus and regions of overlying cortex response. Other issues regarding reversible during eye-blink conditioning completely inactivation studies are also discussed. prevents acquisition of the conditioned eye-blink response (CR) without affecting Introduction the ability to learn the CR in subsequent training without inactivation. Recently, Numerous lines of evidence, ranging in diver- these results have been challenged by the sity from purely theoretical considerations (Marr suggestion that learning was not completely 1969; Albus 1971) to human functional imaging blocked in these studies. Instead, it has been studies (Molchan et al. 1994; Logan and Grafton suggested that low levels of responses on 1995; Blaxton et al. 1996), have consistently impli- test sessions might represent a retarded cated the cerebellum as being critically involved in form of learning caused by drug effects on a number of learning related tasks (for instance, see cerebellar cortex. The present study was Lisberger 1988; Thatch et al. 1992; Thompson and designed to address this issue directly. Very Krupa 1994). Among the many tasks in which the low doses of muscimol were used to cerebellum is critically involved, a number of stud- selectively inactivate the interpositus ies from several laboratories have demonstrated nucleus of rabbits during five conditioning that the cerebellum is essentially involved in acqui- sessions. Animals performed no significant sition and expression of classically conditioned dis- levels of CRs during those sessions. Training crete skeletal movements, in particular, the classi- was continued four more sessions without cally conditioned eye-blink response. any inactivations to test whether any Briefly, the evidence supporting cerebellar in- learning had occurred during the previous volvement in eye-blink conditioning includes the five sessions. Detailed analysis of responses following: (1) Appropriate lesions of a restricted during session six revealed that learning region of lateral cerebellar hemisphere, including was completely blocked by the low doses of lesions limited to the anterior interpositus nucleus, muscimol infused into the interpositus completely and permanently abolish both acquisi- during the first five sessions. Animals tion and expression of conditioned eye-blink re- subsequently acquired the CR normally. sponses (CRs) without affecting performance of the reflexive, unconditioned response (UR) (Lin- coln et al. 1982; McCormick and Thompson 1984a; Lavond et al. 1985; Yeo et al. 1985; Steinmetz et al. 1Corresponding author. Present address: Department of Neurobiology, Duke University Medical Center, Durham, 1992). (2) Electrophysiological recordings of neu- North Carolina 27710. ronal activity from within this region of cerebellum LEARNING & MEMORY 3:545-556 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 545 Downloaded from learnmem.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Krupa and Thompson reveal populations of neurons that respond not Subsequent studies have largely ruled out this only to conditioned and unconditioned stimuli but second possibility. Reversibly inactivating the also during performance of CRs in a manner that brain-stem motor nuclei and surrounding reticular precedes and predicts their occurrence, suggesting formation responsible for performance of the CR a causal role (McCormick and Thompson 1984b; has no effect at all on the ability to acquire the CR Berthier and Moore 1986, 1990; Foy et al. 1992). but does block CR expression, thus ruling out (3) Electrical microstimulation of brain stem pre- these structures as possible loci for the memory cerebellar nuclei or fibers immediately afferent to trace (Zhang and Lavond 1991; Krupa et al. 1996). the cerebellum serves as an effective conditioned Similarly, inactivation of the magnocellular red stimulus (CS) or unconditioned stimulus (US), de- nucleus, a structure that receives direct input from pending on stimulus location. CRs elicited by these the interpositus and is essentially involved in eye- stimuli are completely abolished by appropriate, blink conditioning, also prevents CR expression focal lesions of lateral cerebellum (Mauk et al. with no effect on CR acquisition (Clark and Lavond 1986; Steinmetz et al. 1986; Lavond et al. 1987). 1993; Krupa et al. 1993). Finally, inactivation of all Collectively, these results demonstrate that the cer- of the output fibers of the interpositus nucleus dur- ebellum is necessary for both acquisition and ex- ing conditioning by either injection of tetrodotoxin pression of the eye-blink CR. in the superior cerebellar peduncle or lidocaine Recently, several studies, each using reversible into the white matter ventral to the interpositus inactivation techniques, have provided very com- has the same effect: complete blockade of CR ex- pelling evidence that the essential locus of memory pression with no effect on CR acquisition (Nord- formation and storage (i.e., the memory trace) for holm et al. 1993; Krupa and Thompson 1995). Col- this type of learning is located within the restricted lectively, these results, along with the cerebellar region of lateral cerebellum encompassing the in- reversible inactivation results (above), provide terpositus nucleus and localized regions of overly- compelling data in support of a cerebellar memory ing cerebellar cortex that project to the interposi- trace: Inactivating this localized region of cerebel- tus nucleus. Clark et al. (1992) initially reported lum (including the interpositus nucleus and over- that temporary, reversible inactivation (by local lying cortex) during conditioning completely pre- cooling) of this localized region of cerebellum dur- vents learning from occurring, whereas inactivat- ing eye-blink conditioning in rabbits completely ing essential structures in the eyeblink circuit that prevented acquisition of the eye-blink CR without are downstream from the cerebellum (including all affecting the ability to acquire the CR following of the output from this region of cerebellum) has removal of the cooling and without affecting the no effect on the ability to learn the CR but does ability to perform the UR. This initial result was prevent CR expression. subsequently confirmed and extended by several Recently, Bloedel and Bracha (1995) have sug- studies, each using different techniques such as gested that our previous reversible inactivation local microinjection into the anterior interpositus studies (in which the interpositus nucleus and lo- nucleus of muscimol, baclofen, or lidocaine to fo- calized regions of overlying cortex were reversibly cally and reversibly inactivate this region of cer- inactivated with either muscimol or lidocaine; ebellum (Krupa et al. 1993; Nordholm et al. 1993; Krupa et al. 1993; Nordholm et al. 1993) did not Hardiman et al. 1996; Ramirez et al. 1997). The completely prevent learning from occurring but, results of each of these studies were the same: instead, resulted in "...a low level of conditioned Appropriate inactivation of the critical region of responses during the retention testing [which] re- cerebellum completely prevented acquisition of flects not an absence of learning but rather a 're- the eye-blink CR with no effect on subsequent tarded' process of learning caused by the drug ef- learning following removal of inactivation and with fect on the cerebellar cortex"(p. 12). Although the no effect on the ability to perform the UR. These data from those previous studies directly and com- results indicate that the memory trace for this type pletely contradict this suggestion (see Discussion), of learning must be localized either (1) within the the present study was designed to test this possi- region of cerebellum that was inactivated in these bility in even more detail. Here, we used a very low studies or (2) in some other structure(s) down- dose of muscimol to selectively inactivate the in- stream from this region of cerebellum that receives terpositus nucleus during five sessions of eye-blink cerebellar input that is essential for both acquisi- conditioning. Retention tests (which would reveal tion and expression of the CR. any signs of learning even on the first trial of test- L E A R N / N G & M E M 0 R Y 546 Downloaded from learnmem.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press INTERPOSITUS INACTIVATION BLOCKS CR ACQUISITION ing) following removal of this inactivation revealed restraint in a Plexiglas restrainer and the sound no evidence at all of learning with no effect at all attenuating behavioral recording chamber for 1 on the rate of subsequent learning in the absence hour. Rabbits were randomly assigned to one of of inactivation. The present results, therefore, con- two groups. One group (n
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