Eyelid Conditioning Research Articles

Extinction as new learning versus unlearning: considerations from a computer simulation of the cerebellum.

Like many forms of Pavlovian conditioning, eyelid conditioning displays robust extinction. We used a computer simulation of the cerebellum as a tool to consider the widely accepted view that extinction involves new, inhibitory learning rather than unlearning of acquisition. Previously, this simulation suggested basic mechanistic features of extinction and savings in eyelid conditioning, with predictions born out by experiments. We review previous work showing that the simulation reproduces behavioral phenomena and lesion effects generally taken as evidence that extinction does not reverse acquisition, even though its plasticity is bidirectional with no site dedicated to inhibitory learning per se. In contrast, we show that even though the sites of plasticity are, in general, affected in opposite directions by acquisition and extinction training, most synapses do not return to their naive state after acquisition followed by extinction. These results suggest caution in interpreting a range of observations as necessarily supporting extinction as unlearning or extinction as new inhibitory learning. We argue that the question "is extinction reversal of acquisition or new inhibitory learning?" is therefore not well posed because the answer may depend on factors such as the brain system in question or the level of analysis considered.

The neural basis of temporal processing.

A complete understanding of sensory and motor processing requires characterization of how the nervous system processes time in the range of tens to hundreds of milliseconds (ms). Temporal processing on this scale is required for simple sensory problems, such as interval, duration, and motion discrimination, as well as complex forms of sensory processing, such as speech recognition. Timing is also required for a wide range of motor tasks from eyelid conditioning to playing the piano. Here we review the behavioral, electrophysiological, and theoretical literature on the neural basis of temporal processing. These data suggest that temporal processing is likely to be distributed among different structures, rather than relying on a centralized timing area, as has been suggested in internal clock models. We also discuss whether temporal processing relies on specialized neural mechanisms, which perform temporal computations independent of spatial ones. We suggest that, given the intricate link between temporal and spatial information in most sensory and motor tasks, timing and spatial processing are intrinsic properties of neural function, and specialized timing mechanisms such as delay lines, oscillators, or a spectrum of different time constants are not required. Rather temporal processing may rely on state-dependent changes in network dynamics.

Neuroscience of Pavlovian conditioning: a brief review.

Current knowledge on the neuronal substrates of Pavlovian conditioning in animals and man is briefly reviewed. First, work on conditioning in aplysia, that has showed amplified pre-synaptic facilitation as the basic mechanism of associative learning, is summarized. Then, two exemplars of associative learning in vertebrates, fear conditioning in rodents and eyelid conditioning in rabbits, are described and research into its neuronal substrates discussed. Research showing the role of the amygdala in fear conditioning and of the cerebellum in eyelid conditioning is reviewed, both at the circuit and cellular plasticity levels. Special attention is given to the parallelism suggested by this research between the neuronal mechanisms of conditioning and the principles of formal learning theory. Finally, recent evidence showing a similar role of the amygdala and of the cerebellum in human Pavlovian conditioning is discussed.

Neuroscience. From molecules to memory in the cerebellum.

Neuroscientists have long sought to elucidate the molecular underpinnings of the memories needed to learn, for example, a motor task. In his Perspective, Linden discusses new work (Koekkoek et al.) suggesting that long-term depression in Purkinje cells mediated by protein kinase C signaling is responsible for motor memory in a task called associative eyelid conditioning.

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.

Trying to understand the cerebellum well enough to build one.

The development of an increasingly detailed computer simulation of the cerebellum is briefly described. Specific and relatively direct evaluation of the performance of this simulation is made possible by the straightforward way in which pavlovian eyelid conditioning engages the cerebellum. Inputs to the simulation are based on recordings of mossy fiber and climbing fiber responses to the stimuli used in eyelid conditioning, and the output of the simulation can be evaluated with respect to the extensively characterized behavioral properties of eyelid conditioning. Because construction of the simulation has been guided by a strong aversion to errors of commission, both failures and successes of the simulation have proven informative. The behavior of the simulation related to the inhibitory nucleo-olivary feedback connection and spontaneous activity of climbing fibers is described. A prediction of the simulation concerning extinction is confirmed by experiment.

Inhibition of climbing fibres is a signal for the extinction of conditioned eyelid responses.

A fundamental tenet of cerebellar learning theories asserts that climbing fibre afferents from the inferior olive provide a teaching signal that promotes the gradual adaptation of movements. Data from several forms of motor learning provide support for this tenet. In pavlovian eyelid conditioning, for example, where a tone is repeatedly paired with a reinforcing unconditioned stimulus like periorbital stimulation, the unconditioned stimulus promotes acquisition of conditioned eyelid responses by activating climbing fibres. Climbing fibre activity elicited by an unconditioned stimulus is inhibited during the expression of conditioned responses-consistent with the inhibitory projection from the cerebellum to inferior olive. Here, we show that inhibition of climbing fibres serves as a teaching signal for extinction, where learning not to respond is signalled by presenting a tone without the unconditioned stimulus. We used reversible infusion of synaptic receptor antagonists to show that blocking inhibitory input to the climbing fibres prevents extinction of the conditioned response, whereas blocking excitatory input induces extinction. These results, combined with analysis of climbing fibre activity in a computer simulation of the cerebellar-olivary system, suggest that transient inhibition of climbing fibres below their background level is the signal that drives extinction.

Responding under time pressure: testing two animal learning models and a model of visual categorization.

Two experiments are reported, which employed a Pavlovian eyelid conditioning procedure with human participants. The experiments tested the predictions of three models of the time-course of processing under time pressure. These were the extended generalized context model (Lamberts, 1998), and two variants of the Rescorla-Wagner model (Rescorla & Wagner, 1972), which were activated in cascade mode. Reinforcement schedules in the experiments were equivalent either to an AND rule or to an XOR rule. The time available for processing the conditioned stimulus and initiating a conditioned response was manipulated by varying the interval from the onset of the conditioned stimulus to the onset of the unconditioned stimulus. The results were in accord with the predictions of one of the two variants of the Rescorla-Wagner model.

Application of infrared detection in the recording of eylid movements in rabbits

Classical conditioning of the eyelid reflex has been used for a long time to study associative learning in animals and humans. A new experimental procedure for rabbit’s eyelid conditioning was constructed and described. A phonopneumatic stimulator generated conditioned and unconditioned stimuli 
 and a photoelectric transducer acting in close infrared converted movements of rabbits’ eyelid to electric signals. An example of acquisition and extinction 
 training is illustrated. This method of eyelid movement monitoring is noninvasive. It may be useful for chronic studies of learning processes in rabbits when used with headpieces for microdialysis probes, electrodes or cannulas which could be implanted into brain structures. 

Sex difference in rabbit eyelid conditioning

The rabbit eyelid conditioned reflex has been used to compare associative learning in males and ovariectomized females. A new method for monitoring eyelid movements is described. Rabbits were trained on simple delay classical conditioning. Conditioned responses were recorded during 8 acquisition days and 6 days of extinction training. Analysis of variance (ANOVA) and the least significant difference (LSD) post hoc test was used to analyze the data. The results showed that males achieved significantly better learning than females during the first day of acquisition but later they slowly attained the best result, contrary to females. Moreover, extinction of the conditioned reflex was significantly faster in females than in males. It is postulated that females earn and extinguish faster than males because of a higher level of brain plasticity.

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.

Beyond parallel fiber LTD: the diversity of synaptic and non-synaptic plasticity in the cerebellum.

In recent years, it has become clear that motor learning, as revealed by associative eyelid conditioning and adaptation of the vestibulo-ocular reflex, contributes to the well-established cerebellar functions of sensorimotor integration and control. Long-term depression of the parallel fiber-Purkinje cell synapse (which is often called 'cerebellar LTD') is a cellular phenomenon that has been suggested to underlie these forms of learning. However, it is clear that parallel fiber LTD, by itself, cannot account for all the properties of cerebellar motor learning. Here we review recent electrophysiological experiments that have described a rich variety of use-dependent plasticity in cerebellum, including long-term potentiation (LTP) and LTD of excitatory and inhibitory synapses, and persistent modulation of intrinsic neuronal excitability. Finally, using associative eyelid conditioning as an example, we propose some ideas about how these cellular phenomena might function and interact to endow the cerebellar circuit with particular computational and mnemonic properties.

Quantitative Evaluation of Atopic Blepharitis by Scoring of Eyelid Conditions and Measuring the Water Content of the Skin and Evaporation from the Eyelid Surface

To quantitatively evaluate the condition of the eyelid skin of patients with atopic blepharitis, their symptoms were scored and the water content of the skin and evaporation from the skin were measured. Forty patients with atopic blepharitis were examined. The condition of eyelid skin (erythema, edema/papulation/oozing/crust, excoriation/lichenification) was scored from 0 to 3 points. Water content and water evaporation were measured with a Moisture Checker and an evaporimeter, respectively. Eleven age-matched volunteers without atopic disorders were recruited as normal controls. The Moisture Checker values and water evaporation from lid skin were significantly correlated (r = -0.44, p = 0.006). The Moisture Checker values of the patients with atopic blepharitis was 35.5+/-8.2% (44.7 +/-10.6% in the normal controls, p = 0.009), and water evaporation from their lid skin was 3.6+/-0.9 g/cm2 per second (2.0+/-0.3 g/cm2 per second, p < 0.001); then, the patients were divided into four groups, from "asymptomatic" to "severe," according to the sum of their blepharitis scores. Patients with lower blepharitis scores tended to have higher Moisture Checker values and lower water evaporation values. Scoring of eyelid condition enabled us to objectively estimate the severity of atopic blepharitis. Measurements of the water content of lid skin and water evaporation from lid skin are useful in evaluation of the severity of this disease.

A comparison of the Rescorla-Wagner and Pearce models in a negative patterning and a summation problem

In two experiments, we examined two related conditioning problems previously investigated by Red-head and Pearce (1995a) and Pearce, Aydin, and Redhead (1997). Experiment 1 involved an A+, B+, C+, AB+, AC+, BC+, ABC2 discrimination. The Rescorla-Wagner model predicts that response to AB, AC, and BC will be greater than that to A, B, and C at asymptote, whereas the Pearce model makes the opposite prediction. In Experiment 2, we investigated the responding to a novel ABC compound in groups trained with either A+, B+, C+ or AB+, AC+, BC+. The Rescorla-Wagner model predicts greater response to ABC in the group trained with A+, B+, C+ than in the group trained with AB+, AC+, BC+, whereas the Pearce model makes the opposite prediction. In contrast to the findings of Redhead and Pearce (1995a) and Pearce et al. (1997) in pigeon autoshaping, our findings in rabbit eyelid conditioning support the Rescorla-Wagner model.

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.

Involvement of cerebral cortical structures in the classical conditioning of eyelid responses in rabbits

The classical conditioning of the eyelid motor system in alert behaving rabbits has been used to study the expression of Fos in the hippocampus, and in the occipital, parietal, piriform and temporal cortices. Animals were classically conditioned with both delay and trace conditioning paradigms. As conditioned stimulus, both short and long (20 and 100 ms) tones (600 Hz, 90 dB) or short, weak (20 ms, 1 kg/cm 2) air puffs were used. The unconditioned stimulus was always a long, strong (100 ms, 3 kg/cm 2) air puff that started 250–270 ms after the onset of the conditioned stimulus. The expression of Fos was significantly increased after both delayed and trace conditioning in the hippocampus, and in the parietal and piriform cortices contralateral to the unconditioned stimulus presentation side, compared with equivalent ipsilateral structures in conditioned animals, or with Fos production in the same contralateral structures in pseudo-conditioned and control animals. Fos expression in some cortical sites was specific to tone versus air puff stimuli when used as conditioned stimulus. Thus, Fos expression was significantly increased in the contralateral temporal lobe when tones were used as conditioned stimulus, for both delayed and trace conditioning paradigms, but not when animals were conditioned to short, weak air puffs. The present results indicate a specific Fos activation in several cerebral cortical structures during associative eyelid conditioning.

Ectropion and entropion.

This article reviews the etiology and classification of ectropion and entropion, two of the more common eyelid conditions seen by the ophthalmologist. The preoperative evaluation is important in determining the etiology of the lid malposition. Surgical correction should be directed to the anatomic changes present. A detailed discussion of the more useful surgical procedures to correct ectropion and entropion is presented.

Stimulus representations in human Pavlovian conditioning: implications of missing negative transfer across response systems.

Three Pavlovian conditioning experiments with human participants are reported, which investigated whether common or separate stimulus representations are involved in solving nonlinear discrimination tasks in different response systems. In our experiments we made use of a negative transfer effect between positive and negative patterning. Experiment 1 specified the conditions under which such a negative transfer effect occurs in human eyelid conditioning. Experiments 2 and 3 investigated whether a similar effect also occurs if two response systems--the eyelid and the skin conductance response system--are trained with trials of both types being randomly interleaved. The presence or absence of a negative transfer effect indicates whether or not the stimulus representations involved in the two conditioning processes overlap. The findings are discussed within the framework of a neuropsychological model of hippocampal function. The results suggest that the representations are distinct and thus support the idea of acquired equivalence and distinctiveness of stimulus representations.

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.

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.