Memory Consolidation in the Cerebellar Cortex

Ten male albino rabbits were implanted with stimulating electrodes in the lateral reticular nucleus (LRN). These rabbits were given paired classical conditioning training of the nictitating membrane response with stimulation of the LRN as the conditioned stimulus (CS). Each rabbit was given daily training sessions until it consistently made conditioned responses (CRs). Each rabbit then received an aspiration lesion of cerebellar cortex: the ipsilateral anso-paramedian lobule (n = 6), the anterior or central vermis (n = 2), the central vermis and ansiform lobule (n = 1), or the central vermis and paramedian lobule (n = 1). After recovery, these rabbits were again given paired classical conditioning training with LRN stimulation as the CS. The rabbits with anso-paramedian lesions did not retain the CR after the lesion, but were able to relearn it. The rabbits with lesions of the vermis, the vermis and ansiform, or the vermis and paramedlan retained the CR after the lesion. These results are contrasted with previous results, which show that after aspiration of the anso-paramedian lobule, the conditioned response is not retained or relearned when stimulation of the dorsolateral pontine nucleus (DLPN) is used as a CS. The differences between the mossy fiber outputs of the LRN and DLPN may account for this discrepancy. Different regions of the cerebellum are apparently involved in retention of classically conditioned responses depending on the population of mossy fibers carrying the CS information.

The Journal of Neuroscience, 2001

Classical conditioning of the nictitating membrane response (NMR)/eyeblink response of rabbits is a simple form of cerebellar-dependent, associative motor learning. Reversible inactivations of the cerebellar nuclei and inferior olive have implicated the olivo-cortico-nuclear loop in the acquisition of nictitating membrane conditioning, but the role of the cerebellar cortex in acquisition has not been tested directly. Here we have used local infusions of the water-soluble, disodium salt of 6-cyano-7-nitroquinoxaline-2,3-dione reversibly to block cerebellar cortical AMPA/kainate receptors in lobule HVI during acquisition training. After the drug effects dissipated, there was no evidence that acquisition had taken place; the subjects behaved as if naive. Further training without inactivation then allowed normal acquisition, and further inactivations during performance of conditioned responses abolished these established responses. There was a strong correlation between the inactivation effects on acquisition and subsequent inactivation effects on performance, indicating that the same eyeblinkcontrol cortical microzones are engaged in learning and expressing this behavior. The cortical component of the olivocortico-nuclear loop is essential for acquisition of classically conditioned nictitating membrane response learning, and eyeblink control areas in HVI are critical. Our findings are consistent with models of cerebellar learning that assign essential plasticity to the cortex or to a distribution between levels in olivocortico-nuclear modules.

Trends in Neurosciences, 1997

Proceedings of The National Academy of Sciences, 2002

The cerebellum is considered a brain structure in which memories for learned motor responses (e.g., conditioned eyeblink responses) are stored. Within the cerebellum, however, the relative importance of the cortex and the deep nuclei in motor learning͞memory is not entirely clear. In this study, we show that the cerebellar cortex exerts both basal and stimulus-activated inhibition to the deep nuclei. Sequential application of a ␥-aminobutyric acid type A receptor (GABAAR) agonist and a noncompetitive GABAAR antagonist allows selective blockade of stimulus-activated inhibition. By using the same sequential agonist and antagonist methods in behaving animals, we demonstrate that the conditioned response (CR) expression and timing are completely dissociable and involve different inhibitory inputs; although the basal inhibition modulates CR expression, the conditioned stimulus-activated inhibition is required for the proper timing of the CR. In addition, complete blockade of cerebellar deep nuclear GABAARs prevents CR acquisition. Together, these results suggest that different aspects of the memories for eyeblink CRs are encoded in the cerebellar cortex and the cerebellar deep nuclei.

Journal of Neuroscience, 2007

Associative learning in the cerebellum underlies motor memories and probably also cognitive associations. Pavlovian eyeblink conditioning, a widely used experimental model of such learning, depends on the cerebellum, but the memory locus within the cerebellum as well as the underlying mechanisms have remained controversial. To date, crucial information on how cerebellar Purkinje cells change their activity during learning has been ambiguous and contradictory, and there is no information at all about how they behave during extinction and reacquisition. We have now tracked the activity of single Purkinje cells with microelectrodes for up to 16 h in decerebrate ferrets during learning, extinction, and relearning. We demonstrate that paired peripheral forelimb and periocular stimulation, as well as paired direct stimulation of cerebellar afferent pathways (mossy and climbing fibers) consistently causes a gradual acquisition of an inhibitory response in Purkinje cell simple spike firing. This conditioned cell response has several properties that matches known features of the behavioral conditioned response. The response latency varies with the interstimulus interval, and the response maximum is adaptively timed to precede the unconditioned stimulus. Across training trials, it matches behavioral extinction to unpaired stimulation and also the substantial savings that occur when paired stimulation is reinstated. These data suggest that many of the basic behavioral phenomena in eyeblink conditioning can be explained at the level of the single Purkinje cell.

Neural Plasticity, 2018

Associative learning of sensorimotor contingences, as it occurs in eyeblink classical conditioning (EBCC), is known to involve the cerebellum, but its mechanism remains controversial. EBCC involves a sequence of learning processes which are thought to occur in the cerebellar cortex and deep cerebellar nuclei. Recently, the extinction phase of EBCC has been shown to be modulated after one week by cerebellar continuous theta-burst stimulation (cTBS). Here, we asked whether cerebellar cTBS could affect retention and reacquisition of conditioned responses (CRs) tested immediately after conditioning. We also investigated a possible lateralized cerebellar control of EBCC by applying cTBS on both the right and left cerebellar hemispheres. Both right and left cerebellar cTBSs induced a statistically significant impairment in retention and new acquisition of conditioned responses (CRs), the disruption effect being marginally more effective when the left cerebellar hemisphere was stimulated. ...

Proceedings of the National Academy of Sciences, 2007

Classical conditioning of the eyeblink reflex is elicited by paired presentation of a conditioned stimulus and an unconditioned stimulus and represents a basic form of cerebellum-dependent motor learning. Purkinje cells and the deep nuclei receive convergent information of conditioned stimulus and unconditioned stimulus through the mossy fiber and climbing fiber projections, respectively. To explore the relative importance of these neural circuits and the underlying mechanism in associative eyeblink learning, we adopted a novel gene-manipulating technique, termed reversible neurotransmission blocking (RNB). In this technology, cerebellar granule cells specifically expressed neurotransmission-blocking tetanus toxin in a doxycycline (DOX)-dependent manner. Extracellular recording of Purkinje cells in awake RNB mice revealed that DOX treatment and withdrawal reversibly turned off and on simple spikes elicited by granule cell inputs, respectively, without interference with complex spike...

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

Many studies have confirmed the time-limited involvement of the hippocampus in mnemonic processes and suggested that there is reorganization of the responsible brain circuitry during memory consolidation. To clarify such reorganization, we chose trace classical eyeblink conditioning, in which hippocampal ablation produces temporally graded retrograde amnesia. Here, we extended the temporal characterization of retrograde amnesia to other regions that are involved in acquisition during this task: the medial prefrontal cortex (mPFC) and the cerebellum. At a various time interval after establishing the trace conditioned response (CR), rats received an aspiration of one of the three regions. After recovery, the animals were tested for their CR retention. When ablated 1 d after the learning, both the hippocampal lesion and the cerebellar lesion group of rats exhibited a severe impairment in retention of the CR, whereas the mPFC lesion group showed only a slight decline. With an increase i...

Science, 1998

There is increasing experimental support for the idea that the cerebellum has a special role in motor learning and, perhaps, the storage of motor memories (1, 2). A consistent feature of many models of such cerebellar learning is that memories might be encoded by changes in efficacy of parallel fiber synapses on Purkinje cells, changes that might be governed by a teaching or reinforcing input through a climbing fiber from the inferior olive to each Purkinje cell. Such input might behave in a manner predicted in a formal model of classical conditioning (3), in which reinforcement value declines as learning proceeds. One of us suggested previously that nucleo-olivary inhibition (4) could serve to inhibit olivary input to the cerebellar cortex as learning occurs and so provide a mechanism for Kamin blocking (5) in cerebellar-dependent classical conditioning (6). In their report "Inhibitory cerebello-olivary projections and blocking effect in classical conditioning" (23 Jan., p. 570), Jeansok J. Kim, David J. Krupa, and Richard F. Thompson state that their findings support both hypotheses. They analyzed olivary activity before and after classical conditioning of the rabbit eyeblink-nictitating membrane response (NMR), which is a cerebellar-dependent learning task. Cerebellar Purkinje-cell complex spikes (which are responses to climbing fiber input) were elicited by an air puff unconditional stimulus (US) before and after conditioning if the US was presented alone. Kim et al. found that, after conditioning, if a tone conditional stimulus (CS) preceded the US and a conditioned response (CR) was elicited, then complex spikes were absent at the onset of the US. In a second experiment, nucleoolivary inhibition was antagonized with picrotoxin and Kamin blocking was prevented. dEbates: Submit a response to this article Download to Citation Manager Alert me when: new articles cite this article Search for similar articles in:

Neuron, 2002

Department of Anatomy and Normal function in the cerebellar nuclei (Krupa et al., Developmental Biology 1993), inferior olive (Welsh and Harvey, 1998), and cere-University College London bellar cortex (Attwell et al., 2001) is essential for acquisi-Gower Street tion of NMR conditioning. Inactivating any of these London WC1E 6BT structures during conditioning training results in a failure United Kingdom to acquire conditioned responses (CRs), as measured by performance after recovery from the inactivation. In contrast, inactivation of cerebellar outputs within the Summary superior cerebellar peduncle does not prevent acquisition (Krupa and Thompson, 1995). Several forms of motor learning, including classical Although this set of findings confirms that information conditioning of the eyeblink and nictitating membrane storage essential for NMR conditioning is within the cerresponse (NMR), are dependent upon the cerebellum, ebellum, its localization at any particular level within the but it is not known how motor memories are stored cerebellar circuitry is not disclosed. With the discovery within the cerebellar circuitry. Localized infusions of of an inhibitory feedback projection from the cerebellar the GABA A agonist muscimol were used to target putanuclei to the inferior olive (Andersson et al., 1988; Antive consolidation processes by producing reversible dersson and Hesslow, 1987a, 1987b), it became clear inactivations after NMR conditioning sessions. Postthat the cerebellum has multiple compartments, each training inactivations of eyeblink control regions in containing an olivo-cortico-nucleo-olivary loop. Interfercerebellar cortical lobule HVI completely prevented ence by reversible inactivation at any level in this loop conditioning from developing over four sessions. In will have consequences for information processing at contrast, similar inactivations of eyeblink control rethe other levels (Attwell et al., 2001; Ramnani and Yeo, gions in the cerebellar nuclei allowed conditioning to 1996; Yeo et al., 1997) (see Figure 1). For example, inactidevelop normally. These findings provide evidence vation of olivary output produces marked elevations of that there are critical posttraining memory consolida-Purkinje cell simple spike discharge rates (Benedetti et tion processes for eyeblink conditioning mediated by al., 1983; Colin et al., 1980; Montarolo et al., 1982) that the cerebellar cortex. tonically inhibit the cerebellar nuclei and sharply affect the processing of mossy fiber information entering the