Developmental changes in eye-blink conditioning and neuronal activity in the inferior olive.
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Neuronal activity was recorded in the dorsal accessory inferior olive in infant rats during classical conditioning of the eye-blink response. The percentage and amplitude of eye-blink conditioned responses (CRs) increased as a function of age. The magnitude of the neuronal response to the unconditioned stimulus (US) decreased with age. There were also age-specific modifications of US-elicited inferior olive neuronal activity during paired trials in which a conditioned eye-blink response was performed. The results indicate that the development of the conditioned eye-blink response may depend on dynamic interactions between multiple developmental processes within the eye-blink circuitry. Differences in the functional maturity of olivo-cerebellar pathways may limit the induction of plasticity in the cerebellum and thereby limit the development of eye-blink conditioned responses. (+info)
Cerebellar posterior interpositus nucleus as an enhancer of classically conditioned eyelid responses in alert cats.
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Cerebellar posterior interpositus neurons were recorded in cats during delayed and trace conditioning of eyeblinks. Type A neurons increased their firing in the time interval between conditioned and unconditioned stimulus presentations for both paradigms, while type B neurons decreased it. The discharge of different type A neurons recorded across successive conditioning sessions increased, with slopes of 0.061-0.078 spikes/s/trial. Both types of neurons modified their firing several trials in advance of the appearance of eyelid conditioned responses, but for each conditioned stimulus presentation their response started after conditioned response onset. Interpositus microstimulation evoked eyelid responses similar in amplitude and profiles to conditioned responses, and microinjection of muscimol decreased conditioned response amplitude. It is proposed that the interpositus nucleus is an enhancer, but not the initiator, of eyelid conditioned responses. (+info)
Learning- and expectation-related changes in the human brain during motor learning.
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We have studied a simple form of motor learning in the human brain so as to isolate activity related to motor learning and the prediction of sensory events. Whole-brain, event-related functional magnetic resonance imaging (fMRI) was used to record activity during classical discriminative delay eyeblink conditioning. Auditory conditioned stimulus (CS+) trials were presented either with a corneal airpuff unconditioned stimulus (US, paired), or without a US (unpaired). Auditory CS- trials were never reinforced with a US. Trials were presented pseudorandomly, 66 times each. The subjects gradually produced conditioned responses to CS+ trials, while increasingly differentiating between CS+ and CS- trials. The increasing difference between hemodynamic responses for unpaired CS+ and for CS- trials evolved slowly during conditioning in the ipsilateral cerebellar cortex (Crus I/Lobule HVI), contralateral motor cortex and hippocampus. To localize changes that were related to sensory prediction, we compared trials on which the expected airpuff US failed to occur (Unpaired CS+) with trials on which it occurred as expected (Paired CS+). Error-related signals in the contralateral cerebellum and somatosensory cortex were seen to increase during learning as the sensory prediction became stronger. The changes seen in the ipsilateral cerebellar cortex may be due either to the violations of sensory predictions, or to learning-related increases in the excitability of cerebellar neurons to presentations of the CS+. (+info)
Latent acquisition of timed responses in cerebellar cortex.
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Evidence indicates that rabbit eyelid conditioning is mediated by plasticity in the interpositus cerebellar nucleus and in cerebellar cortex. Although the relative contributions of these sites are not fully characterized, evidence suggests that plasticity in the cerebellar cortex influences conditioned response amplitude and timing, whereas plasticity in the interpositus nucleus is necessary or permissive for conditioned response expression. Recent empirical and computational analyses suggest that, during training, plasticity is initially established in the cerebellar cortex, whereas conditioned response expression begins later as plasticity is induced in the interpositus nucleus. We used the dependence of response timing on the interstimulus interval (ISI) to test this latent learning hypothesis. Rabbits were initially trained using a tone conditioned stimulus (CS) with a relatively long ISI to a low-criterion threshold. The relative absence of plasticity in the interpositus nucleus was then examined via reversible disconnection of the cerebellar cortex. Later, to induce plasticity in the interpositus nucleus, subjects were trained to robust levels of conditioned response expression using a shorter ISI. Reversible disconnection of the cerebellar cortex at this time confirmed the presence of robust interpositus nucleus plasticity after the second phase. Subsequent probe trials with the long CS alone then revealed double-peaked responses whose peaks were appropriately timed to the two ISIs. The results are consistent with the hypothesis that temporally specific learning occurs first in the cerebellar cortex before the appearance of conditioned responses. This latent learning is expressed only after plasticity is induced in the interpositus nucleus. (+info)
A mechanism for savings in the cerebellum.
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The phenomenon of savings (the ability to relearn faster than the first time) is a familiar property of many learning systems. The utility of savings makes its underlying mechanisms of special interest. We used a combination of computer simulations and reversible lesions to investigate mechanisms of savings that operate in the cerebellum during eyelid conditioning, a well characterized form of motor learning. The results suggest that a site of plasticity outside the cerebellar cortex (possibly in the cerebellar nucleus) can be protected from the full consequences of extinction and that the residual plasticity that remains can later contribute to the savings seen during relearning. (+info)
The p38 mitogen-activated protein kinase is involved in associative learning in rabbits.
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This study examined the role of the mitogen-activated protein kinase (MAPK) family during acquisition of the rabbit's classically conditioned eye-blink response. Eye-blink conditioning produced a significant, bilateral activation of both extracellular signal-regulated protein kinases (ERKs) and p38 MAPK in the anterior cerebellar vermis. There was also a significant bilateral activation of ERKs in the dorsal hippocampus with no change in p38 MAPK. These changes were seen at 2 min after the last conditioning session, were maintained for at least 180 min, and occurred without any change in the protein expression of either ERKs or p38 MAPK. There were no changes in ERKs or p38 MAPK in frontal cortex, in cerebellar hemispheral lobule VI, or in a section of brainstem containing the inferior olive. Moreover, the stress-related protein kinase Jun N-terminal kinase (JNK), another subfamily of MAPKs, was not altered in any of the brain regions examined. Animals receiving explicitly unpaired presentations of a conditioned stimulus and an unconditioned stimulus did not acquire conditioned responses (CRs) and did not demonstrate any changes in ERKs, p38 MAPK, or JNK. The intraventricular injection of SB203580, a selective p38 MAPK inhibitor, significantly retarded CR acquisition and blocked the learning-related increases in p38 MAPK activity in the anterior vermis. PD98059, a selective MAPK kinase inhibitor, had a smaller and only marginally significant effect on CR acquisition, although it did block the learning-related increases in ERK activity in both the hippocampus and anterior vermis. These results indicate that p38 MAPK is activated during associative learning and may play a role in the transcriptional events that lead to memory consolidation. (+info)
Associative learning elicits the formation of multiple-synapse boutons.
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The formation of new synapses has been suggested to underlie learning and memory. However, previous work from this laboratory has demonstrated that hippocampus-dependent associative learning does not induce a net gain in the total number of hippocampal synapses and, hence, a net synaptogenesis. The aim of the present work was to determine whether associative learning involves a specific synaptogenesis confined to the formation of multiple-synapse boutons (MSBs) that synapse with more than one dendritic spine. We used the behavioral paradigm of trace eyeblink conditioning, which is a hippocampus-dependent form of associative learning. Conditioned rabbits were given daily 80-trial sessions to a criterion of 80% conditioned responses in a session. During each trial, the conditioned stimulus (tone) and the unconditioned stimulus (corneal airpuff) were presented with an intervening trace interval of 500 msec. Brain tissue was taken for morphological analyses 24 hr after the last session. Unbiased stereological methods were used for obtaining estimates of the total number of MSBs in the stratum radiatum of hippocampal subfield CA1. The results showed that the total number of MSBs was significantly increased in conditioned rabbits as compared with pseudoconditioned or unstimulated controls. This conditioning-induced change, which occurs without a net synaptogenesis, reflects a specific synaptogenesis resulting in MSB formation. Models of the latter process are proposed. The models postulate that it requires spine motility and may involve the relocation of existing spines from nonactivated boutons or the outgrowth of newly formed spines for specific synaptogenesis with single-synapse boutons activated by the conditioning stimulation. (+info)
Acquisition of eyeblink conditioning is critically dependent on normal function in cerebellar cortical lobule HVI.
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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 eyeblink-control cortical microzones are engaged in learning and expressing this behavior. The cortical component of the olivo-cortico-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 olivo-cortico-nuclear modules. (+info)