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Acquisition of Eyeblink Conditioning Is Critically Dependent on Normal Function in Cerebellar Cortical Lobule HVI

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Acquisition of Eyeblink Conditioning Is Critically Dependent on Normal Function in Cerebellar Cortical Lobule HVI The Journal of Neuroscience, August 1, 2001, 21(15):5715–5722 Acquisition of Eyeblink Conditioning Is Critically Dependent on Normal Function in Cerebellar Cortical Lobule HVI Philip J. E. Attwell, Shbana Rahman, and Christopher H. Yeo Department of Anatomy and Developmental Biology, University College London, London WC1E 6BT, United Kingdom Classical conditioning of the nictitating membrane response lished responses. There was a strong correlation between the (NMR)/eyeblink response of rabbits is a simple form of inactivation effects on acquisition and subsequent inactivation cerebellar-dependent, associative motor learning. Reversible effects on performance, indicating that the same eyeblink- inactivations of the cerebellar nuclei and inferior olive have control cortical microzones are engaged in learning and ex- implicated the olivo-cortico-nuclear loop in the acquisition of pressing this behavior. The cortical component of the olivo- nictitating membrane conditioning, but the role of the cerebellar cortico-nuclear loop is essential for acquisition of classically cortex in acquisition has not been tested directly. Here we have conditioned nictitating membrane response learning, and eye- used local infusions of the water-soluble, disodium salt of blink control areas in HVI are critical. Our findings are consistent 6-cyano-7-nitroquinoxaline-2,3-dione reversibly to block cere- with models of cerebellar learning that assign essential plastic- bellar cortical AMPA/kainate receptors in lobule HVI during ity to the cortex or to a distribution between levels in olivo- acquisition training. After the drug effects dissipated, there was cortico-nuclear modules. no evidence that acquisition had taken place; the subjects behaved as if naive. Further training without inactivation then Key words: classical conditioning; acquisition; nictitating allowed normal acquisition, and further inactivations during membrane; cerebellar cortex; AMPA receptors; reversible performance of conditioned responses abolished these estab- inactivation The cerebellum is implicated in the acquisition and performance Gilbert, 1974, 1975; Ito, 1982, 1998), and we have shown that of motor skills, but whether motor memories are stored within its there is convergence of information essential for NMR condition- circuitry has not been resolved. Classical conditioning of the ing in cerebellar cortical lobule HVI (Yeo et al., 1985b), which eyeblink and nictitating membrane response (NMR) has been contains the major eyeblink control regions (Hesslow, 1994a,b). useful for investigating motor learning mechanisms. NMR con- However, if NMR conditioning is mainly mediated by cortical ditioning is known to be cerebellar dependent because lesions of plasticity, why should inactivation of the cerebellar nuclei com- discrete, eyeblink control regions of the cerebellar cortex, cere- pletely prevent it? We previously suggested one possibility (Ram- bellar nuclei, or inferior olive all impair performance of previ- nani and Yeo, 1996; Yeo et al., 1997). In addition to its effects on ously conditioned NMRs (for review, see Kim and Thompson, the excitatory output neurons of the cerebellar nuclei, muscimol 1997; Yeo and Hesslow, 1998). will also deeply inhibit the inhibitory neurons that provide regu- To analyze acquisition and storage processes for NMR condi- latory feedback to the inferior olive (Andersson et al., 1988). So, tioning, recent studies have used reversible inactivations of neural nuclear muscimol treatments would disturb the olivo-cortico- function during acquisition training. Localized infusions of the nuclear loop and could impair acquisition wholly, or partially, by GABAA agonist muscimol during NMR conditioning trials, with disturbance of cortical excitability mediated by changed climbing subsequent testing after the drug effects have dissipated, revealed fiber input (Fig. 1), consistent with the finding that direct inacti- that normal activity in the cerebellar nuclei is critical for acqui- vation of the inferior olive also prevents acquisition of NMR sition (Krupa et al., 1993; Hardiman et al., 1996; Yeo et al., 1997) conditioning (Welsh and Harvey, 1998). and extinction (Hardiman et al., 1996; Ramnani and Yeo, 1996). Reversible inactivation of critical cortical regions directly could Together with evidence that inactivations of cerebellar output in test whether acquisition is dependent on normal cortical activity. the superior cerebellar peduncle do not prevent acquisition If acquisition were to be normal, cerebellar cortex could be (Krupa and Thompson, 1995), these findings provide strong sup- critically involved in neither acquisition nor information storage port for the suggestion that essential plasticity for NMR condi- for NMR conditioning. In contrast, impairment of acquisition tioning is within the cerebellum. would implicate the cortex in the acquisition process and would Several theories suggest that a major component of motor also be consistent with information storage in the cortex, either as learning is within the cerebellar cortex (Marr, 1969; Albus, 1971; a principal component of the memory (Yeo et al., 1985a,b; Yeo and Hesslow, 1998) or as part of a distribution between the cortex Received March 6, 2001; revised May 9, 2001; accepted May 18, 2001. and nuclei (Raymond et al., 1996; Ohyama and Mauk, 2001). This study was supported by Biotechnology and Biological Sciences Research Council Grant 31/S10225. We thank Magnus Ivarsson for help with data and image Here, we test for these possibilities using localized infusions of analysis. the non-NMDA ionotropic glutamate receptor antagonist Correspondence should be addressed to Dr. Christopher H. Yeo, Department of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) reversibly to Anatomy and Developmental Biology, University College London, London WC1E 6BT, UK. E-mail: [email protected]. block cerebellar cortical AMPA/kainate receptor function dur- Copyright © 2001 Society for Neuroscience 0270-6474/01/215715-08$15.00/0 ing acquisition training. 5716 J. Neurosci., August 1, 2001, 21(15):5715–5722 Attwell et al. • Cerebellar Cortex and Eyeblink Conditioning MATERIALS AND METHODS after the completion of either CNQX or vehicle infusions in the right Surgery cerebellar cortex. Each session consisted of 50 trials and lasted 25 min. In 45 trials the CS and US were paired, and in 5 trials the CS was presented Nineteen male Dutch belted Rabbits (1.8–2.5 kg) were implanted with a alone with no US. The CS-alone was presented on every 10th trial. guide cannula directed toward the right cerebellar lobule HVI. Subjects Effective inactivation would produce low levels of conditioned responses were anesthetized using a fentanyl-fluanisone mixture (0.1–5.0 mg/kg, in the CNQX-treated groups during this phase. i.m.) with benzodiazepam (0.5 mg/kg, i.v.). Mannitol (20% w/v, 30 ml Experimental phase 2A: acquisition training with no infusions. Three over 30 min, i.v) was given to facilitate exposure of the cerebellum. Then, days after the end of Phase 1, subjects received four daily sessions of anesthesia was by fluothane (1–2%) in oxygen/nitrous oxide (2:1). A acquisition training. Each session consisted of 50 trials (45 paired trials cranial opening exposed cerebellar cortex and a 26 gauge (ga), 11 mm and 5 unpaired CS trials) and lasted 25 min. All protocols were as in stainless steel guide cannula was implanted into the right HVI and fixed phase 1 except that no CNQX or vehicle infusions were given. If CNQX with acrylic cement. A 33 ga dummy cannula fitted into the guide kept the treatment had impaired acquisition in phase 1, then the absence of CRs implant sealed. Postoperative analgesia (buprenorphine, 100 Ϫ Ϫ at the beginning of phase 2A would be evidence for the impaired ␮g ⅐ kg 1 ⅐ d 1, i.m.) and antibiotic cover (chloramphenicol, 30 ⅐ Ϫ1 ⅐ Ϫ1 acquisition in phase 1. The development of conditioning in phase 2 would mg kg d , i.m.) were given for 3 d. Subjects were kept on a 12 hr be evidence that the cannulation and drug infusions had produced no day/night cycle with ad libitum access to food and water. permanent damage to critical structures. Seven to 13 d after cannula guide implantation, a nylon monofilament Experimental phase 2B: acquisition training with no infusions (contin- suture loop was placed in the right nictitating membrane (NM) under ued). Three days after the end of phase 2A, all CNQX-treated subjects local anesthesia (proxymetacaine hydrochloride, 0.5% w/v). received a further four daily sessions of acquisition training with all Conditioning apparatus and stimuli protocols as in phase 2A. If drug infusions had completely prevented acquisition in phase 1, then CR frequencies for CNQX-treated sub- Rabbits were trained using techniques similar to those first developed by jects in phase 2B would be similar to those for vehicle-treated subjects Gormezano et al. (1962) and described in detail by Yeo and Hardiman in phase 2A. (1992). Subjects were placed in a restraining stock and movement of the Experimental phase 3: performance testing for efficacy of cortical infu- NM was recorded using an isotonic transducer (Gormezano and Gibbs, sions. To test whether the CNQX infusions in phase 1 had been in 1988) linked to the membrane by the monofilament loop. appropriate locations and sufficient to fully inactivate the critical control Each subject was placed in a ventilated, sound-attenuating chamber regions, in phase 3 we tested their efficacy in blocking the performance facing a centrally mounted loudspeaker. The conditioned stimulus (CS) of conditioned responses established previously in phases 2A and 2B. wasa1kHzsinewave tone of 410 msec duration and an intensity of 87 The phase 3 session began with 20 trials (18 paired CS–US trials and 2 dBA. Background noise produced by ventilation fans was 57 dBA. The unpaired CS trials). CNQX (same dose and concentration as in phase 1) unconditioned stimulus (US) was peri-orbital electrical stimulation. Each was then infused. After 2 min, the session continued with 50 trials (45 US was a 60 msec train of three biphasic current pulses (2 mA). The paired CS–US and 5 unpaired CS) as in the conditioning sessions of interstimulus interval between the CS and US onsets on paired trials was phase 1.
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