17916690
Learning-Induced Plasticity in Deep Cerebellar Nucleus
Evidence that cerebellar learning involves more than one site of plasticity comes from, in part, pavlovian eyelid conditioning, where disconnecting the cerebellar cortex abolishes one component of learning, response timing, but spares the expression of abnormally timed short-latency responses (SLRs). Here, we provide evidence that SLRs unmasked by cerebellar cortex lesions are mediated by an associative form of learning-induced plasticity in the anterior interpositus nucleus (AIN) of the cerebellum. We used pharmacological inactivation and/or electrical microstimulation of various sites afferent and efferent to the AIN to systematically eliminate alternative candidate sites of plasticity upstream or downstream from this structure. Collectively, the results suggest that cerebellar learning is mediated in part by plasticity in target nuclei downstream of the cerebellar cortex. These data demonstrate an instance in which an aspect of associative learning, SLRs, can be used as an index of plasticity at a specific site in the brain.
12178572
A primary acoustic startle circuit: lesion and stimulation studies
The latency of the acoustic startle reflex in the rat is 8 msec, measured from tone onset to the beginning of the electromyographic response in the hindleg. This extremely short latency indicates that only a few synapses could be involved in some primary acoustic startle circuit. Acoustic startle is being used as a model system for studying habituation, sensitization, prepulse inhibition, classical conditioning, fear or anxiety, and drug effects on behavior. The present study attempted to delineate a short latency acoustic startle circuit, since this would provide critical information for further study in all of these areas. Bilateral lesions of the ventral cochlear nucleus, which receives the primary auditory input, abolish acoustic startle. Electrical, single pulse stimulation of the ventral cochlear nucleus elicits startle-like responses with a latency of about 7 msec. Bilateral lesions of the dorsal and ventral nuclei of the lateral lemniscus, which receive direct input from the ventral cochlear nuclei, abolish acoustic startle. Electrical stimulation of these nuclei elicits startle-like responses with a latency of about 6 msec. Bilateral lesions of ventral regions of the nucleus reticularis pontis caudalis, which contain cell bodies that give rise to the reticulospinal tract, abolish acoustic startle. Electrical stimulation of these points elicits startle-like responses with a latency of about 5 msec. Reaction product from horseradish peroxidase iontophoresed into this area is found in the nuclei of the lateral lemniscus. In contrast, lesions of the dorsal cochlear nuclei, vestibular nuclei, nucleus reticularis pontis oralis, nucleus reticularis gigantocellularis, and dorsal regions of the nucleus reticularis pontis caudalis fail to abolish acoustic startle. Also, “startle” cannot be elicited electrically from these areas. The data suggest that a primary acoustic startle circuit in the rat consists of auditory nerve, ventral cochlear nucleus, nuclei of the lateral lemniscus, nucleus reticularis pontis caudalis, spinal interneuron, lower motor neuron, and muscles. Hence, five synapses, plus the neuromuscular junction, are probably involved.
37698260
Classical conditioning using stimulation of the inferior olive as the unconditioned stimulus.
We show that conditioned eyelid responses develop when the unconditioned stimulus is electrical stimulation of the dorsal accessory nucleus of the inferior olive. When compared to conditioning using a standard unconditioned stimulus (air puff), the conditioning produced in this manner appears quite normal: the responses develop at a similar rate, are of comparable magnitude and topography, and demonstrate a steep interstimulus interval function; and response topography varies according to the interstimulus interval. These data indicate that activation of neurons in the dorsal accessory olive is a sufficient condition for a stimulus to be an effective unconditioned stimulus. Previous experiments indicate the dorsal accessory olive is necessary in that lesions have effects functionally equivalent to removal of the unconditioned stimulus. These data indicate that the dorsal accessory olive forms a portion of the pathway conveying information about the occurrence of an unconditioned stimulus to sites of synaptic plasticity responsible for conditioning.
8153356
Classical conditioning in rabbits using pontine nucleus stimulation as a conditioned stimulus and inferior olive stimulation as an unconditioned stimulus
Classical conditioning of skeletal muscle responses was accomplished by pairing microstimulation of the pontine nuclei as a conditioned stimulus (CS) with microstimulation of the dorsal accessory olive as an unconditioned stimulus (US). A conditioned response identical in form to the behavioral response elicited by the olivary stimulation was established when the CS was forward paired with the US, and behavioral extinction occurred with CS‐alone presentations or unpaired CS‐US presentations. Conditioned responding could not be established or maintained when the CS and US were simultaneously presented or when the US preceded the CS (i.e., backward paired). Complete lesions of the interpositus nucleus abolished both conditioned and unconditioned responses. These findings support the idea that plasticity associated with classical conditioning of skeletal muscle responses occurs in regions of the cerebellum that receive convergent CS and US input.
10773278
Learned Movements Elicited by Direct Stimulation of Cerebellar Mossy Fiber Afferents
Definitive evidence is presented that the conditioned stimulus (CS) in classical conditioning reaches the cerebellum via the mossy fiber system. Decerebrate ferrets received paired forelimb and periocular stimulation until they responded with blinks to the forelimb stimulus. When direct mossy fiber stimulation was then given, the animals responded with conditioned blinks immediately, that is, without ever having been trained to the mossy fiber stimulation. Antidromic activation was prevented by blocking mossy fibers with lignocaine ventral to the stimulation site. It could be excluded that cerebellar output functioned as the CS. Analysis of latencies suggests that conditioned responses (CRs) are not generated by mossy fiber collaterals to the deep nuclei. Hence, the memory trace is probably located in the cerebellar cortex.
10147240
Cerebellum: essential involvement in the classically conditioned eyelid response.
Classical conditioning of the eyelid response in the rabbit was used to investigate the neuronal structures mediating basic associative learning of discrete, adaptive responses. Lesions of the ipsilateral dentate-interpositus nuclei, but not of the cerebellar cortex, abolished the learned eyeblink response. Recordings from these nuclei have revealed neuronal responses related to the learning of the response. Stimulating these recording sites produced the eyelid response. The dentate-interpositus nuclei were concluded to be critically involved in the learning and production of classically conditioned responses.
19050990
Cerebellar neuronal activity expresses the complex topography of conditioned eyeblink responses.
Pavlovian eyeblink conditioning is a useful model system for studying how the temporal relationship between a conditioned stimulus and an unconditioned stimulus is represented in the brain. As an example, the response topography formed under a complex conditioning paradigm, involving 2 randomly alternating interstimulus intervals (ISIs), manifests a conditioned response (CR) with 2 distinctive peaks that correspond to the 2 ISIs. The authors present the first full report of neuronal activities in the cerebellar interpositus nucleus of rabbits performing bimodal responses. All CR-related activities exhibited firing patterns that highly correlated with and preceded eyeblink responses. The striking similarity between the time course of bimodal CRs and neuronal responses indicates that neuronal activities in the cerebellum are causally related to the production of behavioral CRs.
16944655
Cerebellar cortex lesions disrupt learning-dependent timing of conditioned eyelid responses
Among the many issues surrounding the involvement of the cerebellum in motor learning, the relative roles of the cerebellar cortex and cerebellar nuclei in Pavlovian conditioning have been particularly difficult to assess. While previous studies have investigated the effects of cerebellar cortex lesions on the acquisition and retention of conditioned movements, we have examined the effects of these lesions on the timing of Pavlovian eyelid responses. The rationale for this approach arises from previous studies indicating that this timing is a component of Pavlovian eyelid responses that is learned and that involves temporal discrimination. To permit within-animal comparisons, rabbits were trained to produce differently timed responses to high- and low-frequency auditory conditioned stimuli (CSs). Before the lesion the conditioned responses to both CSs were appropriately timed--each peaked near the time at which the unconditioned stimulus was presented for that CS. However, after the lesion both CSs could elicit similarly timed conditioned responses that peaked inappropriately at very short latencies. The changes in responses timing were sensitive to the size of the lesion, particularly its rostral-caudal extent. Similar results were obtained in animals trained with one CS, indicating that the disruption of response timing is not related to impaired auditory discrimination. Because response timing is learned and therefore requires synaptic plasticity, these data suggest that there are at least two sites of plasticity involved in the motor expression of Pavlovian eyelid responses. Plasticity at one site is necessary for the learned timing of conditioned responses, while plasticity at another site is revealed by the inappropriately timed responses observed following removal of the cerebellar cortex. This lesion-induced dissociation of the expression of motor responses and their learned timing supports a synthesis of competing views by suggesting that motor learning involves both the cerebellar cortex and cerebellar nuclei. We hypothesize that motor learning involves a decrease in strength of the granule cell-Purkinje cell synapses (e.g., Ito and Kano, 1982) in the cerebellar cortex and an increase in strength of the mossy fiber- cerebellar nuclei synapses (e.g., Racine et al., 1986). Finally, these data suggest that the cerebellar cortex may mediate the temporal discriminations that are necessary for the learned timing of conditioned responses.
7454340
Extinction of conditioned eyelid responses requires the anterior lobe of cerebellar cortex
We test the hypothesis that the cerebellar cortex is required for the extinction of conditioned eyelid responses in rabbits trained using standard Pavlovian delay procedures. Following 10 daily training sessions during which rabbits achieved asymptotic performance, lesions of the ipsilateral hemisphere of the cerebellar cortex were made by aspiration. The target of these lesions was the anterior lobe, as suggested by previous observations that this region is necessary for the learning-dependent timing of conditioned eyelid responses (Perrett et al., 1993). We report that anterior lobe damage, as indicated by disrupted response timing and confirmed by tissue analysis, produces severe deficits in conditioned response extinction. Postlesion responses show no significant decline over ten training sessions, whereas response timing and extinction are unaffected by lesions that do not include the anterior lobe. These conditioned responses that do not extinguish display stimulus specificity, excluding the possibility that they are unlearned responses unmasked by cerebellar cortex lesions. These observations suggest that Pavlovian eyelid conditioning is mediated by synaptic plasticity in at least two sites and the anterior lobe of the cerebellar cortex influences one of these sites during extinction. Based on these and previous data, we propose the hypothesis that eyelid conditioning can involve plasticity in both the cerebellar cortex and interpositus nucleus and that plasticity in the nucleus is controlled by input from Purkinje cell activity in the cortex. This hypothesis is consistent with observations that the cerebellar cortex may not always be required for the expression of conditioned responses, but it is necessary for response timing and for extinction.
12899157
Cerebellar Cortex Lesions Prevent Acquisition of Conditioned Eyelid Responses
We have used aspiration and electrolytic lesions to investigate the contributions of cerebellar cortex to the acquisition and expression of conditioned eyelid responses. We show that lesions of the anterior lobe of rabbit cerebellar cortex disrupt the timing of previously learned conditioned eyelid responses. These short-latency responses were used as an indication that the cerebellar cortex was sufficiently damaged and that the underlying pathways necessary for the expression of responses were sufficiently intact to support responses. Rabbits were subsequently trained for 15 daily sessions using a new conditioned stimulus. Whereas rabbits in which lesions had no significant effect on response timing showed rapid acquisition of appropriately timed eyelid responses to the new conditioned stimulus, animals with lesions that disrupt timing showed no significant increases in either amplitude or probability of responses. Histological analysis suggests that damage to the anterior lobe of the cerebellar cortex is necessary and sufficient to abolish timing and prevent acquisition. These data indicate that the cerebellar cortex is necessary for the acquisition of conditioned eyelid responses and are consistent with the hypotheses that (1) eyelid conditioning results in plasticity in both the anterior lobe of the cerebellar cortex and in the anterior interpositus nucleus and (2) induction of plasticity in the interpositus requires intact input from the cerebellar cortex.
1723021
Timing Mechanisms in the Cerebellum: Testing Predictions of a Large-Scale Computer Simulation
We used large-scale computer simulations of eyelid conditioning to investigate how the cerebellum generates and makes use of temporal information. In the simulations the adaptive timing displayed by conditioned responses is mediated by two factors: (1) different sets of granule cells are active at different times during the conditioned stimulus (CS), and (2) responding is not only amplified at reinforced times but also suppressed at unreinforced times during the CS. These factors predict an unusual pattern of responding after partial removal of the cerebellar cortex that was confirmed using small, electrolytic lesions of cerebellar cortex. These results are consistent with timing mechanisms in the cerebellum that are similar to Pavlov's “inhibition of delay” hypothesis.
14274092
Pharmacological analysis of cerebellar contributions to the timing and expression of conditioned eyelid responses
Contradictory results have been reported regarding the effects of cerebellar cortex lesions on the expression of conditioned eyelid responses--either no effect, partial to complete abolition of responses, or disruption of response timing. This uncertainty is increased by debates regarding the region(s) of cerebellar cortex that are involved, by the likelihood that cortex lesions can inadvertently include damage to the interpositus nucleus or other pathways necessary for response expression, and by potential confounds from the degeneration of climbing fibers produced by cerebellar cortex lesions. We have addressed these issues by reversibly blocking cerebellar cortex output via infusion of the GABA antagonist picrotoxin into the interpositus nucleus. After picrotoxin infusion, conditioned responses are spared but their timing is disrupted and their amplitude diminished. In the same animals, conditioned responses were abolished by infusion of the GABA agonist muscimol and were unaffected by infusion of saline vehicle. These results are consistent with the hypothesis that (i) plasticity in the interpositus nucleus contributes to the expression of conditioned responses, as suggested by the responses seen with the cortex disconnected, and (ii) plasticity in the cerebellar cortex also contributes to conditioned response expression, as suggested by disruption of response timing.
14616263
A Mechanism for Savings in the Cerebellum
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.
9608418
Latent Acquisition of Timed Responses in Cerebellar Cortex
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.
10857224
Cerebellar cortical inhibition and classical eyeblink conditioning
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 learning/memory 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 γ-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.
14597440
Stimulus generalization of conditioned eyelid responses produced without cerebellar cortex: implications for plasticity in the cerebellar nuclei.
In Pavlovian eyelid conditioning and adaptation of the vestibulo-ocular reflex, cerebellar cortex lesions fail to completely abolish previously acquired learning, indicating an additional site of plasticity in the deep cerebellar or vestibular nucleus. Three forms of plasticity are known to occur in the deep cerebellar nuclei: formation of new synapses, plasticity at existing synapses, and changes in intrinsic excitability. Only a cell-wide increase in excitability predicts that learning should generalize broadly from a training stimulus to other stimuli capable of supporting learning, whereas the alternatives predict that learning should be relatively specific to the training stimulus. Here we show that deep nucleus plasticity, as assessed by conditioned eyelid responses produced without input from the cerebellar cortex, is relatively specific to the training conditioned stimulus (CS). We trained rabbits to a tone or light CS with periorbital stimulation as the unconditioned stimulus (US), and pharmacologically disconnected the cerebellar cortex during a posttraining generalization test. The short-latency conditioned responses unmasked by this treatment showed strong decrement along the dimension of auditory frequency and did not generalize across stimulus modalities. These results cannot be explained solely by a cell-wide increase in the excitability of deep nucleus neurons, and imply that an input-specific mechanism in the deep cerebellar nucleus operates as well.
20919394
GABA neurotransmission in the cerebellar interposed nuclei: involvement in classically conditioned eyeblinks and neuronal activity.
The cerebellar interposed nuclei (IN) are an essential part of circuits that control classically conditioned eyeblinks in the rabbit. The function of the IN is under the control of GABAergic projections from Purkinje cells of the cerebellar cortex. The exact involvement of cerebellar cortical input into the IN during eyeblink expression is not clear. While it is known that the application of gamma-aminobutyric acid-A (GABA(A)) agonists and antagonists affects the performance of classically conditioned eyeblinks, the effects of these drugs on IN neurons in vivo are not known. The purpose of the present study was to measure the effects of muscimol and picrotoxin on the expression of conditioned eyeblinks and the activity of IN cells simultaneously. Injections of muscimol abolished conditioned responses and either silenced or diminished the activity of IN cells. Two injections were administered in each picrotoxin experiment. The first injection of picrotoxin slightly modified the timing and amplitude of the eyeblink, produced mild tonic eyelid closure, increased tonic activity of IN cells, and reduced the amplitude of the neural responses. The second injection of picrotoxin abolished conditioned responses, further increased tonic eyelid closure, dramatically elevated the tonic activity of IN cells, and in most cases, abolished neuronal responses. These results demonstrate that both GABA(A)-mediated inactivation and tonic up-regulation of IN cells can interrupt the expression of conditioned eyeblinks and that this behavioral effect is accompanied by the suppression of the neuronal activity correlates of the conditioned stimulus and response.
41155462
The Cerebellum: A Neuronal Learning Machine?
Comparison of two seemingly quite different behaviors yields a surprisingly consistent picture of the role of the cerebellum in motor learning. Behavioral and physiological data about classical conditioning of the eyelid response and motor learning in the vestibulo-ocular reflex suggest that (i) plasticity is distributed between the cerebellar cortex and the deep cerebellar nuclei; (ii) the cerebellar cortex plays a special role in learning the timing of movement; and (iii) the cerebellar cortex guides learning in the deep nuclei, which may allow learning to be transferred from the cortex to the deep nuclei. Because many of the similarities in the data from the two systems typify general features of cerebellar organization, the cerebellar mechanisms of learning in these two systems may represent principles that apply to many motor systems.
14010419
A model of Pavlovian eyelid conditioning based on the synaptic organization of the cerebellum.
We present a model based on the synaptic and cellular organization of the cerebellum to derive a diverse range of phenomena observed in Pavlovian eyelid conditioning. These phenomena are addressed in terms of critical pathways and network properties, as well as the sites and rules for synaptic plasticity. The theory is based on four primary hypotheses: (1) Two cerebellar sites of plasticity are involved in conditioning: (a) bidirectional long-term depression/potentiation at granule cell synapses onto Purkinje cells (gr-->Pkj) in the cerebellar cortex and (b) bidirectional plasticity in the interpositus nucleus that is controlled by inhibitory inputs from Purkinje cells; (2) climbing fiber activity is regulated to an equilibrium level at which the net strength of gr-->Pkj synapses remains constant unless an unexpected unconditioned stimulus (US) is presented or an expected US is omitted; (3) a time-varying representation of the conditioned stimulus (CS) in the cerebellar cortex permits the temporal discrimination required for conditioned response timing; and (4) the ability of a particular segment of the CS to be represented consistently across trials varies as a function of time since CS onset. This variation in across-trials consistency is thought to contribute to the ISI function. The model suggests several empirically testable predictions, some of which have been tested recently.
27963067
Long-term potentiation in the interpositus and vestibular nuclei in the rat
SummaryPrevious unpublished experiments from this laboratory had revealed only post-activation depression effects in the cerebellar cortex when its inputs were activated by high frequency trains. In the experiments reported in this paper, we found reliable long-term potentiation (LTP) effects in the deep nuclei (interpositus and vestibular) when stimulation trains were applied to the white matter at the point where inferior peduncle fibers enter the cerebellum. LTP effects were found in both acute and chronic preparations. In the chronic preparations, LTP lasted for at least 8 days in all but one animal.
7679970
Synapse formation is associated with memory storage in the cerebellum
The idea that memory is encoded by means of synaptic growth is not new. However, this idea has been difficult to demonstrate in the mammalian brain because of both the complexity of mammalian behavior and the neural circuitry by which it is supported. Here we examine how eyeblink classical conditioning affects synapse number within the cerebellum; the brain region essential for long-term retention of the conditioned response. Results showed eyeblink-conditioned rats to have significantly more synapses per neuron within the cerebellar interpositus nucleus than both explicitly unpaired and untrained controls. Further analysis showed that the increase was caused by the addition of excitatory rather than inhibitory synapses. Thus, development of the conditioned eyeblink response is associated with a strengthening of inputs from precerebellar nuclei rather than from cerebellar cortex. These results demonstrate that the modifications of specific neural pathways by means of synaptogenesis contributes to formation of a specific memory within the mammalian brain.
1732215
Potentiation of Mossy Fiber EPSCs in the Cerebellar Nuclei by NMDA Receptor Activation followed by Postinhibitory Rebound Current
Behavioral and computational studies predict that synaptic plasticity of excitatory mossy fiber inputs to cerebellar nuclear neurons is required for associative learning, but standard tetanization protocols fail to potentiate nuclear cell EPSCs in mouse cerebellar slices. Nuclear neurons fire action potentials spontaneously unless strongly inhibited by Purkinje neurons, raising the possibility that plasticity-triggering signals in these cells differ from those at classical Hebbian synapses. Based on predictions of neuronal activity during delay eyelid conditioning, we developed quasi-physiological induction protocols consisting of high-frequency mossy fiber stimulation and postsynaptic hyperpolarization. Robust, NMDA receptor-dependent potentiation of nuclear cell EPSCs occurred with protocols including a 150-250 ms hyperpolarization in which mossy fiber stimulation preceded a postinhibitory rebound depolarization. Mossy fiber stimulation potentiated EPSCs even when postsynaptic spiking was prevented by voltage-clamp, as long as rebound current was evoked. These data suggest that Purkinje cell inhibition guides the strengthening of excitatory synapses in the cerebellar nuclei.
42444466
Long-Term Depression at the Mossy Fiber–Deep Cerebellar Nucleus Synapse
Several lines of evidence have indicated that the deep cerebellar nuclei (DCN) are a site of memory storage for certain forms of motor learning, most notably associative eyelid conditioning. In particular, these experiments, together with network models, have implicated the excitatory glutamatergic synapse between mossy fibers and DCN neurons in this memory trace. However, to date, evidence for persistent use-dependent change in the strength of this synapse has been almost entirely absent. Here, we report that high-frequency burst stimulation of mossy fibers, either alone or paired with postsynaptic depolarization, gives rise to long-term depression (LTD) of the mossy fiber–DCN synapse. This form of LTD is not associated with changes in the paired-pulse ratio and is blocked by loading with a postsynaptic Ca2+ chelator but not by bath application of an NMDA receptor antagonist. Mossy fiber–DCN LTD requires activation of a group I metabotropic glutamate receptor (mGluR) and protein translation. Unlike mGluR/translation-dependent LTD in other brain regions, this form of LTD requires mGluR1 and is mGluR5 independent.
206631305
Localization of a memory trace in the mammalian brain.
The localization of sites of memory formation within the brain has proven to be a formidable task even for simple forms of learning and memory. In order to localize a particular site of memory formation within the brain, the rabbit eyeblink response was classically conditioned while regions of the cerebellum or red nucleus were temporarily inactivated by microinfusions of the gamma-aminobutyric acid agonist muscimol. Cerebellar inactivation completely blocked learning but had no effect on subsequent learning after inactivation, whereas red nucleus inactivation did not prevent learning but did block the expression of conditioned responses. The site of memory formation for this learned response thus appears to be localized within the cerebellum.
13386685
Effects of lidocaine injection in the interpositus nucleus and red nucleus on conditioned behavioral and neuronal responses
The role of the cerebellum and the red nucleus in the conditioned eyeblink response was assessed, using a combination of reversible lesions and multiple-unit extracellular recording in the awake, behaving rabbit. Lesion, recording, and stimulation experiments have indicated that both of these structures are involved in the performance of learned skeletal muscle responses. The present study sought to distinguish the relative contributions of the interpositus nucleus and the red nucleus to the expression of the learned response by recording behavior-related multiple unit activity in one structure while reversibly inactivating the other via injections of local anesthetic. Results indicate that inactivating either the interpositus or the red nucleus temporarily abolishes the learned eyeblink response. Injection of lidocaine into the interpositus also abolishes the neuronal unit model of the conditioned response in the red nucleus, while injection into the red nucleus does not affect the model in the interpositus. These results are consistent with the hypothesis that the red nucleus acts as a relay for motor commands from the cerebellum, and that the plasticity that generates conditioned responses occurs in the cerebellum or an afferent structure.
17715456
Rapid, synaptically driven increases in the intrinsic excitability of cerebellar deep nuclear neurons
The neurons of the cerebellar deep nuclei are implicated in certain forms of motor learning such as associative eyeblink conditioning, partly because increases in their firing rates parallel acquisition of the conditioned response. Here we demonstrate that these neurons can show persistent increases in their intrinsic excitability following a Ca2+ load imposed by synaptic activation of NMDA receptors or direct current injection. This phenomenon, together with use-dependent alterations in synaptic strength, may provide a flexible and informationally rich engram for cerebellar motor learning.
22706587
Persistent changes in the intrinsic excitability of rat deep cerebellar nuclear neurones induced by EPSP or IPSP bursts
The deep cerebellar nuclei (DCN) are the major output of the cerebellum, and have been proposed as a site of memory storage for certain forms of motor learning. Microelectrode and whole‐cell patch recordings were performed on DCN neurones in acute slices of juvenile rat cerebellum. DCN neurones display tonic and bursting basal firing patterns. In tonically firing neurones, a stimulus consisting of EPSP bursts produced a brief increase in dendritic Ca2+ concentration and a persistent increase in the number of spikes elicited by a depolarizing test pulse, along with a decrease in spike threshold. In intrinsically bursting DCN neurones, EPSP bursts induced an increase in the number of depolarization‐evoked spikes in some neurones, but in others produced a change to a more tonic firing pattern. Application of IPSP bursts evoked a large number of rebound spikes and an associated dendritic Ca2+ transient, which also produced a persistent increase in the number of spikes elicited by a test pulse. Intracellular perfusion of the Ca2+ chelator BAPTA prevented the increase in intrinsic excitability. Thus, rapid changes in intrinsic excitability in the DCN may be driven by bursts of both EPSPs and IPSPs, and may result in persistent changes to both firing frequency and pattern.
34686603
Cerebellar Mechanisms in Eyeblink Conditioning
Abstract: A recent model of cerebellar learning in eyeblink conditioning predicts two sites of plasticity, the cerebellar cortex and cerebellar nuclei, which store information relating to timing and driving the movement, respectively. Consistent with this idea, lesions of the cortex or reversible “disconnections” of Purkinje cell output to the nuclei have been shown to disrupt response timing to produce short‐latency conditioned eyeblinks. To better characterize potential cortical and nuclear plasticities, we analyzed the effects upon nictitating membrane (NM) and eyeblink conditioned responses (CRs) of different drugs administered to the cortex and to the nuclei. When either excitatory or inhibitory inputs to the cerebellar cortical lobule HVI were blocked by infusions of the AMPA receptor antagonist CNQX or the GABA‐A receptor antagonists picrotoxin or SR95531, CRs were abolished. Similarly GABA‐A receptor antagonists in the cerebellar nuclei abolished CRs. CR latencies were never shortened. However, blockade of AMPA/kainate receptor‐mediated excitatory transmission to the nuclei had no effect upon CR frequencies or latencies. These results suggest that normal cortical and nuclear function is required for performance of NM and eyeblink CRs. We saw no evidence that CRs can be driven by AMPA/kainate receptor‐mediated transmission from mossy fiber afferents to the cerebellar nuclei. So, although plasticity in the cerebellar nuclei is not ruled out, it is unlikely that a long‐term change in AMPA receptor‐mediated transmission from mossy fiber inputs to the nuclei is an essential mechanism in eyeblink conditioning. Our findings indicate that a fully functional olivo‐cortico‐nuclear loop is required to express all characteristics of associatively conditioned responses.
10479443
Evidence of plasticity in the pontocerebellar conditioned stimulus pathway during classical conditioning of the eyeblink response in the rabbit.
Electrical stimulation thresholds required to elicit eyeblinks with either pontine or cerebellar interpositus stimulation were measured before and after classical eyeblink conditioning with paired pontine stimulation (conditioned stimulus, CS) and corneal airpuff (unconditioned stimulus, US). Pontine stimulation thresholds dropped dramatically after training and returned to baseline levels following extinction, whereas interpositus thresholds and input-output functions remained stable across training sessions. Learning rate, magnitude of threshold change, and electrode placements were correlated. Pontine projection patterns to the cerebellum were confirmed with retrograde labeling techniques. These results add to the body of literature suggesting that the pons relays CS information to the cerebellum and provide further evidence of synaptic plasticity in the cerebellar network.
5798044
Glutamate neurotransmission in the cerebellar interposed nuclei: involvement in classically conditioned eyeblinks and neuronal activity.
The cerebellar interposed nuclei (IN) are critical components of a neural network that controls the expression of classically conditioned eyeblinks. The IN receive 2 major inputs: the massive, gamma-aminobutyric acid (GABA)-mediated input from the Purkinje cells of the cerebellar cortex and the relatively weaker, glutamate-mediated input from collaterals of mossy and climbing fiber cerebellar afferent systems. To elucidate the role of IN glutamate neurotransmission in conditioned response (CR) expression, effects of blocking fast glutamatergic neurotransmission in the IN with gamma-d-glutamylglycine (DGG) on the expression of conditioned eyeblinks and on cerebellar nuclear neuronal activity were examined. Surprisingly, blocking fast glutamate receptors in the IN did not abolish CRs. DGG decreased CR incidence and slightly increased CR latency. In contrast, identical amounts of DGG applied to the cerebellar cortex abolished CRs. Similar to the behavioral effects, DGG had unexpectedly mild effects on IN neurons. At the population level, the baseline firing frequency of IN cells was not affected. After DGG injections, the incidence of excitatory modulation of cell activity in the interstimulus interval decreased but was not abolished. A combined block of fast glutamate and GABA(A) neurotransmission using a mixture of DGG and picrotoxin dramatically reduced CR incidence, increased the firing frequency of all cell types, and virtually abolished all modulation of neuronal activity. These results indicate that fast glutamate neurotransmission in the IN plays only an accessory role both in the expression of behavioral CRs and in the generation of associated neuronal activity in the IN.
7157466
A Theory of Cerebellar Function
Abstract A comprehensive theory of cerebellar function is presented, which ties together the known anatomy and physiology of the cerebellum into a pattern-recognition data processing system. The cerebellum is postulated to be functionally and structurally equivalent to a modification of the classical Perceptron pattern-classification device. It is suggested that the mossy fiber → granule cell → Golgi cell input network performs an expansion recoding that enhances the pattern-discrimination capacity and learning speed of the cerebellar Purkinje response cells. Parallel fiber synapses of the dendritic spines of Purkinje cells, basket cells, and stellate cells are all postulated to be specifically variable in response to climbing fiber activity. It is argued that this variability is the mechanism of pattern storage. It is demonstrated that, in order for the learning process to be stable, pattern storage must be accomplished principally by weakening synaptic weights rather than by strengthening them.
24159883
Plasticity in the vestibulo-ocular reflex: a new hypothesis.
The vestibulo-ocular reflex functions to prevent head movements from disturbing retinal images by generating compensatory eye movements to offset the head movements. In the monkey--the species mainly under consideration here--this reflex is machine-like and very effective. In the short-term, the VOR operates as an open-loop control system without the benefit of feedback and its performance is fixed and immutable: No matter what pattern of eye-head coordination the animal uses to view external objects, there is a continuing need for the VOR and it continues to operate; however, should the VOR consistently fail to stabilize the retinal images during head turns, it will gradually undergo long-term adaptive gain changes that restore, that stability. This adaptive capability is ultimately dependent upon vision, and a variety of optical devices that disturb the visual input normally associated with lead turns have been used to induce large changes in the reflex. Insofar as the monkey is concerned, all of the available evidence suggests to us that the modifiable elements underlying these long-term adjustments are located in the brainstem vestibular pathways and not, as previously suggested by others, in the floccular lobes of the cerebellum. However, the flocculus does appear to have an important, inductive role in the adaptive process providing at least part of the error signal guiding the long-term adjustments in the brainstem. In our view, the VOR is a particularly well-defined example of a plastic system and promises to be a most useful model for studying the cellular mechanisms underlying memory and learning the central nervous system.
24139184
Neural basis for motor learning in the vestibuloocular reflex of primates. III. Computational and behavioral analysis of the sites of learning.
1. We have used a combination of eye movement recordings and computer modeling to study long-term adaptive modification (motor learning) in the vestibuloocular reflex (VOR). The eye movement recordings place constraints on possible sites for motor learning. The computer model abides by these constraints, as well as constraints provided by data in previous papers, to formalize a new hypothesis about the sites of motor learning. The model was designed to reproduce as much of the existing neural and behavioral data as possible. 2. Motor learning was induced in monkeys by fitting them with spectacles that caused the gain of the VOR (eye speed divided by head speed) to increase to values > 1.6 or to decrease to values < 0.4. We elicited pursuit by providing ramp motion of a small target at 30 degrees/s along the horizontal axis. Changes in the gain of the VOR caused only small and inconsistent changes in the eye acceleration in the first 100 ms after the onset of pursuit and had no effect on the eye velocity during tracking of steady target motion. Electrical stimulation in the flocculus and ventral paraflocculus with single pulses or trains of pulses caused smooth eye movement toward the side of stimulation after latencies of 9-11 ms. Neither the latency, the peak eye velocity, nor the initial eye acceleration varied as a consistent function of the gain of the VOR. 3. The computer model contained nodes that represented position-vestibular-pause cells (PVP-cells) and flocculus target neurons (FTNs) in the vestibular nucleus, and horizontal gaze-velocity Purkinje cells (HGVP-cells) in the cerebellar flocculus and ventral paraflocculus. Node FTN represented only the "E-c FTNs," which show increased firing for eye motion away from the side of recording. The transfer functions in the model included dynamic elements (filters) as well as static elements (summing junctions, gain elements, and time delays). Except for the transfer functions that converted visual motion inputs into commands for smooth eye movement, the model was linear. 4. The performance of the model was determined both by computer simulation and, for the VOR in the dark, by analytic solution of linear equations. For simulation, we adjusted the parameters by hand to match the output of the model to the eye velocity of monkeys and to match the activity of the relevant nodes in the model to the firing of HGVP-cells, FTNs, and PVP-cells when the gain of the VOR was 0.4, 1.0, and 1.6.(ABSTRACT TRUNCATED AT 400 WORDS)
3169647
Learning and memory in the vestibulo-ocular reflex.
Studies of the neural basis of learning and memory in intact animals must, by their nature, start "from the top" by choosing a behavior that can be modified through learning, revealing how iaeuronal activity gives rise to that behavior, and then investigating, in the awake, behaving animal, changes in neural signaling that are associated with learning. Such studies also must recognize that the learning and memory expressed in the behavior of an animal will reflect both the properties of the neural network that mediates the behavior and the nature of the underlying changes in the operation of cells or synapses. In the past 10 years, there has been an explosion of information about learning and memory in the vestibulo-ocular reflex (VOR) of the awake, behaving monkey. At the same time, there have been unprecedented advances in understanding mechanisms of cellular plasticity such as long-term potentiation (LTP) in the hippocampus and long-term depression (LTD) in the cerebellum. A prerequisite for understanding learning and memory is to elevate specific mechanisms of cellular plasticity into cellular mechanisms of learning by establishing their function in the context of a neural system that mediates learning and memory in a particular behavior. Our review synthesizes the
13288680
Roles of Cerebellar Cortex and Nuclei in Motor Learning: Contradictions or Clues?
population of granule cells, whose activity is also influThe cerebellum, with its relatively simple and regular enced by the inhibitory Golgi cells. One numeric fact synaptic organization, has yielded much about its contriillustrates these dramatic differences in computing bution to brain function and its internal information propower; each nucleus cell receives around 10 mossy cessing. A central theme that has emerged is the cerefiber synapses (mf→nuc) and is influenced by 10 granbellum’s role in the adaptation or learning of movements. ule cell synapses onto Purkinje cells (gr→Pkj). Ideas about cerebellar-mediated motor learning began Early ideas about cerebellar-mediated motor learning in the 1960s, most notably with the seminal theory prowere based on thesenotable anatomicalcharacteristics. posed by Marr (1969). The basic tenets of this theory In 1969, Marr proposed a theory suggesting how plasticare supported by numerous studies. In particular, analyity in the cerebellar cortex at the gr→Pkj synapses could sis of two forms of motor learning, adaptation of the mediate motor learning. Three basic components of this vestibulo-ocular reflex (VOR) and Pavlovian eyelid contheory were: (i) the mossy fiber/granule cell system enditioning (EC), has revealed much about cerebellar concodes the contexts in which movements occur, with the tributions to motor learning and the cerebellar informaabundance of granule cells providing a rich representation processing involved. tion; (ii) climbing fibers signal that the movement conThe cerebellum is comprised of two anatomical comtrolled by its Purkinje cell should change, and (iii) these ponents, the cerebellar cortex and nuclei. Despite much climbing fiber inputs induce plasticity at coactive gr→Pkj progress, their relative contributions to motor learning synapses, improving subsequent movement perforremain a fundamentally important issue that is largely mance in the context encoded by that pattern of granule
10658357
Long-Lasting Increases in Intrinsic Excitability Triggered by Inhibition
Although experience-dependent changes in neural circuits are commonly assumed to be mediated by synaptic plasticity, modifications of intrinsic excitability may serve as a complementary mechanism. In whole-cell recordings from spontaneously firing vestibular nucleus neurons, brief periods of inhibitory synaptic stimulation or direct membrane hyperpolarization triggered long-lasting increases in spontaneous firing rates and firing responses to intracellular depolarization. These increases in excitability, termed firing rate potentiation, were induced by decreases in intracellular calcium and expressed as reductions in the sensitivity to the BK-type calcium-activated potassium channel blocker iberiotoxin. Firing rate potentiation is a novel form of cellular plasticity that could contribute to motor learning in the vestibulo-ocular reflex.
16659326
Decreases in CaMKII Activity Trigger Persistent Potentiation of Intrinsic Excitability in Spontaneously Firing Vestibular Nucleus Neurons
Calcium/calmodulin-dependent protein kinase II (CaMKII) has been described as a biochemical switch that is turned on by increases in intracellular calcium to mediate synaptic plasticity. Here, we show that reductions in CaMKII activity trigger persistent increases in intrinsic excitability. In spontaneously firing vestibular nucleus neurons, CaMKII activity is near maximal, and blockade of CaMKII activity increases excitability by reducing BK-type calcium-activated potassium currents. Firing rate potentiation, a form of plasticity in which synaptic inhibition induces long-lasting increases in excitability, is occluded by prior blockade of CaMKII and blocked by addition of constitutively active CaMKII. Reductions in CaMKII activity are necessary and sufficient to induce firing rate potentiation and may contribute to motor learning in the vestibulo-ocular reflex.
17397545
The other side of the engram: experience-driven changes in neuronal intrinsic excitability
Modern theories of memory storage have largely focused on persistent, experience-dependent changes in synaptic function such as long-term potentiation and depression. But in addition to these synaptic changes, certain learning tasks produce enduring changes in the intrinsic excitability of neurons by changing the function of voltage-gated ion channels, a change that can produce broader, even neuron-wide changes in synaptic throughput. We will consider the evidence for persistent changes in intrinsic neuronal excitability — what we will call intrinsic plasticity — that is produced by training in behaving animals and by artificial patterns of activation in brain slices and neuronal cultures. These intrinsic changes might function as part of the engram itself, or as a related phenomenon such as a trigger for the consolidation or adaptive generalization of memories.
17345075
Simulations of Cerebellar Motor Learning: Computational Analysis of Plasticity at the Mossy Fiber to Deep Nucleus Synapse
We question the widely accepted assumption that a molecular mechanism for long-term expression of synaptic plasticity is sufficient to explain the persistence of memories. Instead, we show that learning and memory require that these cellular mechanisms be correctly integrated within the architecture of the neural circuit. To illustrate this general conclusion, our studies are based on the well characterized synaptic organization of the cerebellum and its relationship to a simple form of motor learning. Using computer simulations of cerebellar-mediated eyelid conditioning, we examine the ability of three forms of plasticity at mossy fiber synapses in the cerebellar nucleus to contribute to learning and memory storage. Results suggest that when the simulation is exposed to reasonable patterns of “background” cerebellar activity, only one of these three rules allows for the retention of memories. When plasticity at the mossy fiber synapse is controlled by nucleus or climbing fiber activity, the circuit is unable to retain memories because of interactions within the network that produce spontaneous drift of synaptic strength. In contrast, a plasticity rule controlled by the activity of the Purkinje cell allows for a memory trace that is resistant to ongoing activity in the circuit. These results suggest specific constraints for theories of cerebellar motor learning and have general implications regarding the mechanisms that may contribute to the persistence of memories.
21952075
Suppression of cerebellar Purkinje cells during conditioned responses in ferrets.
Decerebrate ferrets were conditioned, using electrical stimulation of the forelimb as conditioned stimulus and periorbital stimulation as unconditioned stimulus, until they produced conditioned eyeblink responses. The latency of these was 125-250 ms. Microelectrode recordings were made from single Purkinje cells in an eyeblink controlling area in the c3 zone of the cerebellar cortex. Whereas Purkinje cells in animals, which had only received unpaired stimulus presentations, responded weakly or not at all to the conditioned stimulus, some cells in conditioned animals responded with a powerful suppression of simple spike firing. The latency of this suppression was 50-200 ms. The results support the hypothesis that classical conditioning involves plastic changes in cerebellar Purkinje cells.
12040645
The Site of a Motor Memory Shifts with Consolidation
The basis for the consolidation of memory is a controversial topic, particularly in the case of motor memory. One view is that motor memory is transferred, partially or completely, to a new location during the consolidation process (“systems consolidation”). We investigated this possibility in a primitive motor system, the vestibulo-ocular reflex (VOR). In the simple circuitry of the VOR, there are relatively few possible storage sites for memory. We partially blocked excitatory neurotransmission in the cerebellar cortex of cats with the glutamate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). If CNQX was injected immediately after 60 min of rotation under conditions that induced a learned decrease in the gain of the VOR, gain was returned to its baseline value. Expression of the new memory could also be disrupted by rotation in darkness, suggesting that consolidation had not taken place; however, after learning had continued for 3 d, expression of the learned change was diminished only slightly by blockade and was unaffected by rotation in darkness. Our interpretation of these results is that learning may take place initially in the cerebellar cortex and that during consolidation, motor memories are converted to a more distributed representation that includes the cerebellar cortex and another site.
15363087
Memory trace of motor learning shifts transsynaptically from cerebellar cortex to nuclei for consolidation
Adaptation of ocular reflexes is a prototype of motor learning. While the cerebellum is acknowledged as the critical site for motor learning, the functional differences between the cerebellar cortex and nuclei in motor memory formation are not precisely known. Two different views are proposed: one that the memory is formed within the cerebellar flocculus, and the other that the memory is formed within vestibular nuclei. Here we developed a new paradigm of long-term adaptation of mouse horizontal optokinetic response eye movements and examined the location of its memory trace. We also tested the role of flocculus and inferior olive in long-term adaptation by chronic lesion experiments. Reversible bilateral flocculus shutdown with local application of 0.5 microl-5% lidocaine extinguished the memory trace of day-long adaptation, while it very little affected the memory trace of week-long adaptation. The responsiveness of vestibular nuclei after week-long adaptation was examined by measuring the extracellular field responses to the electrical stimulation of vestibular nerve under trichloroacetaldehyde anesthesia. The amplitudes and slopes of evoked monosynaptic field response (N1) of week-long adapted mice were enhanced around the medial vestibular nucleus compared with those of control mice. Chronic flocculus or inferior olive lesions abolished both day and week-long adaptations. These results suggest that the functional memory trace of short-term adaptation is formed initially within the cerebellar cortex, and later transferred to vestibular nuclei to be consolidated to a long-term memory. Both day and week-long adaptations were markedly depressed when neural nitric oxide was pharmacologically blocked locally and when neuronal nitric oxide synthase was ablated by gene knockout, suggesting that cerebellar long-term depression underlies both acquisition and consolidation of motor memory.
27679504
Cholinergic innervation and receptors in the cerebellum.
We have studied the source and ultrastructural characteristics of ChAT-immunoreactive fibers in the cerebellum of the rat, and the distribution of muscarinic and nicotinic receptors in the cerebellum of the rat, rabbit, cat and monkey, in order to define which of the cerebellar afferents may use ACh as a neurotransmitter, what target structures are they, and which cholinergic receptor mediate the actions of these pathways. Our data confirm and extend previous observations that cholinergic markers occur at relatively low density in the cerebellum and show not only interspecies variability, but also heterogeneity between cerebellar lobules in the same species. As previously demonstrated by Barmack et al. (1992a,b), the predominant fiber system in the cerebellum that might use ACh as a transmitter or a co-transmitter is formed by mossy fibers originating in the vestibular nuclei and innervating the nodulus and ventral uvula. Our results show that these fibers innervate both granule cells and unipolar brush cells, and that the presumed cholinergic action of these fibers most likely is mediated by nicotinic receptors. In addition to cholinergic mossy fibers, the rat cerebellum is innervated by beaded ChAT-immunoreactive fibers. We have demonstrated that these fibers originate in the pedunculopontine tegmental nucleus (PPTg), the lateral paragigantocellular nucleus (LPGi), and to a lesser extent in various raphe nuclei. In both the cerebellar cortex and the cerebellar nuclei these fibers make asymmetric synaptic junctions with small and medium-sized dendritic profiles. Both muscarinic and nicotinic receptor could mediate the action of these diffuse beaded fibers. In the cerebellar nuclei the beaded cholinergic fibers form a moderately dense network, and could in principle have a significant effect on neuronal activity. For instance, the cholinergic fibers arising in the PPTg may modulate the excitability of the cerebellonuclear neurons in relation to sleep and arousal (e.g. McCormick, 1989). Studies on the distribution of cholinergic markers in the cerebellum have proven valuable besides the issue whether cholinergic mechanism play a role in the cerebellar circuitry, because they illustrate a complexity of the cerebellar anatomy that extends beyond its regular trilaminar and foliar arrangement. For instance, AChE histochemistry has been shown to preferentially stain the borders of white matter compartments (the 'raphes', Voogd, 1967), and therefore is useful in topographical analysis of the cortico-nuclear and olivocerebellar projections (Hess and Voogd, 1986; Tan et al., 1995; Voogd et al., 1996; see Voogd and Ruigrok, 1997, this Volume). ChAT-immunoreactivity, at least in rat, appears to be a good marker to outline the morphological heterogeneity of mossy fibers, and m2-immunocytochemistry could be used to label (subpopulations of) Golgi cells, subsets of mossy fibers and, in the rabbit, a specific subset of Purkinje cells (Jaarsma et al., 1995).
24492883
Firing activities of identified posterior interpositus nucleus neurons during associative learning in behaving cats
On the basis of stimulation and permanent or transient lesions of putatively involved structures, and using transgenic mice with defective functional circuits, it has been proposed that cerebellar cortex and/or nuclei could be the sites where classically conditioned nictitating membrane/eyelid responses are acquired and stored. Here, we review recent information regarding the electrical activities of deep cerebellar nuclei neurons recorded during the performance of reflex and acquired eyeblinks. In particular, the rostral pole of the dorsolateral region of the posterior interpositus nucleus contains neurons significantly related to reflexively evoked and classically conditioned eyelid responses. Thus, type A interpositus neurons increase their discharge rate during eyelid movements, modulating it depending upon eyelid motorics. In contrast, type B neurons decrease their firing, even to a stop, during the same eyelid responses. However, as these changes in firing start after the onset of eyelid conditioned responses (CRs), and because they do not seem to encode eyelid position and velocity during the CR, the interpositus nucleus cannot be conclusively considered the site where eyelid learned responses are generated and stored. Additional microstimulation and pharmacological blockage of the recorded sites support the suggestion that posterior interpositus neurons contribute to the enhancement of CRs. Moreover, interpositus neurons probably contribute to the proper damping of newly acquired eyelid responses. The contributing role of other neuronal centers and circuits related to the eyelid motor system are also discussed.
42477355
Cerebellar LTD and Learning-Dependent Timing of Conditioned Eyelid Responses
Mammals can be trained to make a conditioned movement at a precise time, which is correlated to the interval between the conditioned stimulus and unconditioned stimulus during the learning. This learning-dependent timing has been shown to depend on an intact cerebellar cortex, but which cellular process is responsible for this form of learning remains to be demonstrated. Here, we show that protein kinase C–dependent long-term depression in Purkinje cells is necessary for learning-dependent timing of Pavlovian-conditioned eyeblink responses.
15284834
Deletion of FMR1 in Purkinje Cells Enhances Parallel Fiber LTD, Enlarges Spines, and Attenuates Cerebellar Eyelid Conditioning in Fragile X Syndrome
Absence of functional FMRP causes Fragile X syndrome. Abnormalities in synaptic processes in the cerebral cortex and hippocampus contribute to cognitive deficits in Fragile X patients. So far, the potential roles of cerebellar deficits have not been investigated. Here, we demonstrate that both global and Purkinje cell-specific knockouts of Fmr1 show deficits in classical delay eye-blink conditioning in that the percentage of conditioned responses as well as their peak amplitude and peak velocity are reduced. Purkinje cells of these mice show elongated spines and enhanced LTD induction at the parallel fiber synapses that innervate these spines. Moreover, Fragile X patients display the same cerebellar deficits in eye-blink conditioning as the mutant mice. These data indicate that a lack of FMRP leads to cerebellar deficits at both the cellular and behavioral levels and raise the possibility that cerebellar dysfunctions can contribute to motor learning deficits in Fragile X patients.
20094165
Building new motor responses: eyelid conditioning revisited
Neural processes underlying memory and learning should be studied under the best possible physiological conditions - namely, in alert behaving animals. The classical conditioning of the nictitating membrane and eyelid response is a widely used experimental model for studying the neural bases of motor learning in mammals. Nevertheless, information is still needed on the functional aspects, taking place simultaneously in different cerebral structures, that underlie acquisition, extinction and recall of new motor and cognitive abilities. Here, we review recent data on the neural activity generated in selected brain sites (facial motor nuclei, deep cerebellar nuclei and the hippocampus) in simultaneity with the process of learning. The use of modern technologies for the proper recording of eyelid movements, for the identification of the recorded units, and for the activation of selective synaptic processes during the learning situation enables a precise redefinition of the role played by these neural structures in such associative learning. This review is part of the TINS special issue on The Neural Substrates of Cognition.
8093388
In vitro classical conditioning of the turtle eyeblink reflex: approaching cellular mechanisms of acquisition
The classically conditioned eyeblink reflex is the best studied model for understanding the neural mechanisms that underlie learning and memory. Here, data from an in vitro model of the conditioned eyeblink reflex are summarized with the aim of shedding some light on potential cellular mechanisms that may underlie eyeblink classical conditioning. An isolated brainstem-cerebellum preparation from turtles was developed in which to study the synaptic circuitry of pathways involving the cerebellum, red nucleus and brainstem nuclei. A neural correlate of an eyeblink response recorded in the abducens nerve can be conditioned entirely in vitro by pairing trigeminal and auditory nerve stimulation. Conditioned abducens nerve responses (CRs) are not generated or sustained by unpaired stimuli and their long latencies, on the order of hundreds of milliseconds, support the Interpretation that the CRs are not unconditioned responses. Ablation experiments show that CRs can be generated in brainstem preparations lacking a cerebellum or the medulla. However, the timing of the CRs are disrupted by removal of the cerebellar circuitry. Thus, a highly reduced in vitro brainstem preparation demonstrates acquisition of CRs but poor timing features. Recent experiments have focused on elucidating cellular mechanisms for CR acquisition in the brainstem blink circuitry. These studies show that NMDA-mediated synaptic mechanisms are required to generate CRs and that the level of conditioning is associated with the upregulation of GluR4-containing AMPA receptors in the abducens motor nuclei. Data from immunocytochemistry and physiological experiments using the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 suggest that CaMKII does not have a key role in mediating the induction or expression of abducens nerve CRs. It is hypothesized that GluR4-containing AMPA receptors In the abducens motor nuclei are targeted to auditory nerve synapses by an NMDA receptor-dependent process to strengthen the CS input during conditioning which results in the generation of CRs. Future studies will examine the synaptic localization of GluR4 and potential signal transduction pathways involved in in vitro conditioning. Moreover, the role feedback loops through the cerebellum and their role in CR timing will be a key issue to address using this preparation.