Timing of conditioned responses utilizing electrical stimulation in the region of the interpositus nucleus as a CS

A large body of evidence indicates that the cerebellum is essential for the acquisition, retention, and expression of the standard delay conditioned eyeblink response and that the basic memory trace appears to be established in the anterior interpositus nucleus (IP). Adaptive timing of the conditioned response (CR) is a prominent feature of classical conditioning—the CR peaks at the time of onset of the unconditioned stimulus (US) over a wide range of CS-US interstimulus intervals (ISI). A key issue is whether this timing is established by the cerebellar circuitry or prior to the cerebellum. In this study timing of conditioned eyeblink responses established via electrical stimulation of the interpositus nucleus as a conditioned stimulus (CS) was analyzed prior to and following modification of the CS-US interval in well-trained rabbits. Consistent with previous results, learning under these conditions is very rapid and robust. The CR peak eyeblink latencies are initially timed to the US onset and adjust accordingly to lengthening or shortening of the CS-US interval, just as with peripheral CSs. The acquisition of conditioned eyeblink responses by direct electrical stimulation of the IP as a CS thus retains temporal flexibility following shifts in the CS-US delay, as found in standard classical eyeblink conditioning procedures.     

Timing of Conditioned Responses Utilizing Electrical Stimulation in the Region of the Interpositus Nucleus as a CS

A large body of evidence indicates that the cerebellum is essential for the acquisition, retention, and expression of the standard delay conditioned eyeblink response and that the basic memory trace appears to be established in the anterior interpositus nucleus (IP). Adaptive timing of the conditioned response (CR) is a prominent feature of classical conditioning-the CR peaks at the time of onset of the unconditioned stimulus (US) over a wide range of CS-US interstimulus intervals (ISI). A key issue is whether this timing is established by the cerebellar circuitry or prior to the cerebellum. In this study timing of conditioned eyeblink responses established via electrical stimulation of the interpositus nucleus as a conditioned stimulus (CS) was analyzed prior to and following modification of the CS-US interval in well-trained rabbits. Consistent with previous results, learning under these conditions is very rapid and robust. The CR peak eyeblink latencies are initially timed to the US onset and adjust accordingly to lengthening or shortening of the CS-US interval, just as with peripheral CSs. The acquisition of conditioned eyeblink responses by direct electrical stimulation of the IP as a CS thus retains temporal flexibility following shifts in the CS-US delay, as found in standard classical eyeblink conditioning procedures.     

Time course of cardiac conditioned responses in restrained rats as a function of the trace CS-US interval

Two experiments aimed at understanding the temporal characteristics of trace-conditioned heart-rate responses to a 0.5-s tone (conditioned stimulus [CS]) in restrained rats. A CS paired with a tail-shock (unconditioned stimulus [US]) elicited lasting bradycardiac responses. The magnitude and extinction rate of conditioned responses (CR) were independent of the CS-US interval (interstimulus interval [ISI], 3 s to 20 s). Unreinforced test trials were analyzed for CR topography. Responding was delayed in groups with longer ISIs, but CR latencies, peak and decay times were not proportional to the ISI. Response peaks tended to cluster either about 6 s after CS onset, or about 10 s with a slow decay, depending on the ISI. The authors postulated 2 components of auditory stimulus traces involved in cardiac conditioning, maximally active 6 s and 10 s respectively after CS onset. The topography of the CR could be constrained to combinations of associative strength and instantaneous activity of these 2 components.     

Classical conditioning of the rabbit's nictitating membrane response under fixed and mixed CS-US intervals

The rabbit's nictitating membrane response was classically conditioned to a tone CS, followed by an electric shock US, at two randomly alternating CS-US interstimulus intervals (ISIs). Different groups were exposed to different proportions of 200- and 700-msec ISIs. The study revealed: (a) CR percentage was a direct function of the proportion of 200-msec ISIs; (b) trials to the first test-trial CR were an inverse function of the proportion of 200-msec ISIs; (c) CR onset latencies decreased over training; (d) CR peak latencies coincided with the temporal loci of the US; and (e) groups exposed to both ISIs acquired double-peaked CRs. Moreover, the amplitudes of nictitating membrane responses in the present experiment paralleled certain quantitative aspects of the free operant key peck response rates of pigeons trained under two mixed inter-reinforcement intervals. The results were discussed with respect to the micromolar response shaping and macromolecular CS-trace accounts of classical conditioning.     

Purkinje cell activity in the cerebellar anterior lobe after rabbit eyeblink conditioning

The cerebellar anterior lobe may play a critical role in the execution and proper timing of learned responses. The current study was designed to monitor Purkinje cell activity in the rabbit cerebellar anterior lobe after eyeblink conditioning, and to assess whether Purkinje cells in recording locations may project to the interpositus nucleus. Rabbits were trained in an interstimulus interval discrimination procedure in which one tone signaled a 250-msec conditioned stimulus-unconditioned stimulus (CS-US) interval and a second tone signaled a 750-msec CS-US interval. All rabbits showed conditioned responses to each CS with mean onset and peak latencies that coincided with the CS-US interval. Many anterior lobe Purkinje cells showed significant learning-related activity after eyeblink conditioning to one or both of the CSs. More Purkinje cells responded with inhibition than with excitation to CS presentation. In addition, when the firing patterns of all conditioning-related Purkinje cells were pooled, it appeared that the population showed a pattern of excitation followed by inhibition during the CS-US interval. Using cholera toxin-conjugated horseradish peroxidase, Purkinje cells in recording areas were found to project to the interpositus nucleus. These data support previous studies that have suggested a role for the anterior cerebellar cortex in eyeblink conditioning as well as models of cerebellar-mediated CR timing that postulate that Purkinje cell activity inhibits conditioned response (CR) generation during the early portion of a trial by inhibiting the deep cerebellar nuclei and permits CR generation during the later portion of a trial through disinhibition of the cerebellar nuclei.     

Hippocampal and cerebellar single-unit activity during delay and trace eyeblink conditioning in the rat

In delay eyeblink conditioning, the CS overlaps with the US and only a brainstem-cerebellar circuit is necessary for learning. In trace eyeblink conditioning, the CS ends before the US is delivered and several forebrain structures, including the hippocampus, are required for learning, in addition to a brainstem-cerebellar circuit. The interstimulus interval (ISI) between CS onset and US onset is perhaps the most important factor in classical conditioning, but studies comparing delay and trace conditioning have typically not matched these procedures in this crucial factor, so it is often difficult to determine whether results are due to differences between delay and trace or to differences in ISI. In the current study, we employed a 580-ms CS-US interval for both delay and trace conditioning and compared hippocampal CA1 activity and cerebellar interpositus nucleus activity in order to determine whether a unique signature of trace conditioning exists in patterns of single-unit activity in either structure. Long-Evans rats were chronically implanted in either CA1 or interpositus with microwire electrodes and underwent either delay eyeblink conditioning, or trace eyeblink conditioning with a 300-ms trace period between CS offset and US onset. On trials with a CR in delay conditioning, CA1 pyramidal cells showed increases in activation (relative to a pre-CS baseline) during the CS-US period in sessions 1-4 that was attenuated by sessions 5-6. In contrast, on trials with a CR in trace conditioning, CA1 pyramidal cells did not show increases in activation during the CS-US period until sessions 5-6. In sessions 5-6, increases in activation were present only to the CS and not during the trace period. For rats with interpositus electrodes, activation of interpositus neurons on CR trials was present in all sessions in both delay and trace conditioning. However, activation was greater in trace compared to delay conditioning in the first half of the CS-US interval (during the trace CS) during early sessions of conditioning and, in later sessions of conditioning, activation was greater in the second half of the CS-US interval (during the trace interval). These results suggest that the pattern of hippocampal activation that differentiates trace from delay eyeblink conditioning is a slow buildup of activation to the CS, possibly representing encoding of CS duration or discrimination of the CS from the background context. Interpositus nucleus neurons show strong modeling of the eyeblink CR regardless of paradigm but show a changing pattern across conditioning that may be due to the necessary contributions of forebrain processing to trace conditioning.     

Comparison of timing and classical conditioning

Four experiments with rats investigated if the timing of a stimulus (sound) correlated with the strength of a conditioned response (CR) to the stimulus. The timing (effective duration) of the stimulus was measured using the peak procedure, similar to a discrete-trials fixed-interval procedure. The rats were trained so that their response rate reached a maximum about 40 s or 60 s after the onset of a light; the time of the maximum measured from the start of the light (peak time) was the measure of timing. On some trials, the light was preceded by a short (5 s) or long (20 s or 30 s) interval of sound. We assumed that the difference in peak time after long and short sounds reflected the timing of the sound--if the sound was timed, the longer sound would produce a lower peak time; if the sound was not timed, the two durations of sound would produce the same peak time. The CR was lever-pressing during the sound. The sound was treated in various ways: presented alone (Experiments 1, 3, and 4), followed by food (Experiments 1, 3, and 4), preceded by food (Experiment 3), and followed by food after 20 s (Experiment 4). Treatments that produced no timing of sound produced no CR, and treatments that increased (or diseased) timing also increased (or decreased) the CR. The results suggest that there is overlap between the mechanisms that produce time discrimination and the mechanisms that produce classical conditioning.     

Temporal specificity in cross-modal transfer of the rabbit nictitating membrane response

Two experiments examine cross-modal transfer of response features specific to the interstimulus interval (ISI) between a conditioned stimulus (CS) and an unconditioned stimulus. Rabbits were given initial training with a stimulus (CSA) in one modality (e.g., tone) at a designated ISI (e.g., 600 ms). Training was then shifted to a new stimulus (CSB) in another modality (e.g., light) at a new ISI (e.g., 400 ms). The timing of early conditioned responses (CRs) to CSB reflected the ISI of CSA. Ultimately, CRs to CSB shifted to a temporal location conforming to the ISI of CSB. When the ISI of CSB was shorter than that of CSA, CRs to CSA also shifted to a locus conforming to the ISI of CSB. The present results confirmed previous findings that training in one CS modality accelerates CR acquisition to a CS in another modality. The findings are compared with the transfer of response patterns in instrumental learning sets and are discussed regarding their implications for theories of cross-modal transfer.     

Timing at the Start of Associative Learning

Some theories of associative learning imply that time plays a fundamental role in the acquisition process. Consistent with these theories, this paper presents evidence that the time from the onset of a conditioned stimulus (CS) until presentation of the unconditioned stimulus (US) is learned very rapidly at the start of training. We report two autoshaping studies and a study on aversive conditioning in goldfish in which we examine timing at the start of conditioning. We also review data from a number of other conditioning preparations, including fear-potentiated startle, appetitive conditioning in rats, and eyeblink conditioning in rabbits, that report conditioned response (CR) timing early in training. Acquisition speed and the very first expressions of conditioned responding often show sensitivity to the time of US presentation. In instances where temporal control is slowly expressed, it is likely due to performance factors, not to slow learning about time. In fact, the learning about time may be a necessary condition for associative learning.     

A portable solid-state stimulus programmer

This paper describes a miniature solid-state timing device particularly useful for presenting repetitive signal sequences in classical conditioning experiments. The device uses transistors, silicon-controlled rectifiers, and four-layer diodes, and is powered by 20-hour rechargeable nickel-cadmium batteries. Visual monitoring is provided for the unelapsed ITI and battery charge. Ranges are; ITI, 15 sec. to 5 min., ISI, 0–50 secs., CS duration, 0.5 to 30 sec., US duration, 0.5 to 30 sec. The CS and US durations are adjustable and the onset of the latter may be at any time after the CS onset. Cycling is continuous and automatic; the outputs are in the form of relay closures.     

Posttraining prefrontal lesions impair jaw movement conditioning performance,but have no effect on accompanying heart rate changes

This experiment examined the role of the medial prefrontal cortex (mPFC) in regulating learned autonomic and somatomotor responses in rabbits using appetitive Pavlovian conditioning. Interstimulus interval (ISI) duration [i.e., the time between the onset of the conditioned stimulus (CS) and unconditioned stimulus (US)] was manipulated in order to determine whether ISI duration was related to the heart rate (HR) responses obtained during conditioning. Two groups received either a 1- or a 4-s ISI, with a tone as the CS and an intraoral pulse of water as the US. Another two groups received explicitly unpaired presentations of either the 1- or 4-s tone CS and water US. Few conditioned jaw movement (JM) or HR conditioned responses (CRs) were observed in the unpaired conditions. Significant JM conditioning was, however, elicited by the paired conditions, especially to the 4-s ISI. Consistent CS-evoked HR accelerations were observed in both ISI conditions. After five sessions of training, the mPFC was lesioned in half the animals. A separate group of paired animals received sham lesions. After surgical recovery, all animals received 3 days of postoperative training. During the first postoperative training session, JM CRs significantly declined in both groups with mPFC lesions in comparison to the groups with sham lesions. The mPFC lesions, however, did not affect the CS-evoked cardiac accelerations, which again occurred during postoperative training.     

Speed-accuracy tradeoff in double stimulation: Effects on the first response

A single-stimulation and two double-stimulation response conditions were compared using explicit payoff matrices to vary speed-accuracy tradeoff. Under accuracy payoff, response latency (RT(1)) to the first stimulus increased as ISI dropped but accuracy remained high and relatively constant. Under speed payoff, RT(1) was only slightly affected by ISI but accuracy dropped as ISI decreased. Transmitted information rates consistently reflected detrimental effects of short ISI. In double stimulation, but not in single stimulation, error response latency exceeded correct response latency. Furthermore, error response latencies were found to be far more variable and more sensitive to changes in speed-accuracy condition than were correct response latencies. Finally, under both speed and accuracy conditions, response latency to the first of two successive stimuli was faster if a response was also required to the second stimulus. Implications of the data for possible models of double-stimulation speed-accuracy tradeoff are considered.     

Galantamine facilitates acquisition of hippocampus-dependent trace eyeblink conditioning in aged rabbits

Cholinergic systems are critical to the neural mechanisms mediating learning. Reduced nicotinic cholinergic receptor (nAChR) binding is a hallmark of normal aging. These reductions are markedly more severe in some dementias, such as Alzheimer's disease. Pharmacological central nervous system therapies are a means to ameliorate the cognitive deficits associated with normal aging and aging-related dementias. Trace eyeblink conditioning (EBC), a hippocampus- and forebrain-dependent learning paradigm, is impaired in both aged rabbits and aged humans, attributable in part to cholinergic dysfunction. In the present study, we examined the effects of galantamine (3 mg/kg), a cholinesterase inhibitor and nAChR allosteric potentiating ligand, on the acquisition of trace EBC in aged (30–33 months) and young (2–3 months) female rabbits. Trace EBC involves the association of a conditioned stimulus (CS) with an unconditioned stimulus (US), separated by a stimulus-free trace interval. Repeated CS–US pairings results in the development of the conditioned eyeblink response (CR) prior to US onset. Aged rabbits receiving daily injections of galantamine (Aged/Gal) exhibited significant improvements compared with age-matched controls in trials to eight CRs in 10 trial block criterion (P = 0.0402) as well as performance across 20 d of training [F(1,21) = 5.114, P = 0.0345]. Mean onset and peak latency of CRs exhibited by Aged/Gal rabbits also differed significantly [F(1,21) = 6.120/6.582, P = 0.0220/0.0180, respectively] compared with age-matched controls, resembling more closely CR timing of young drug and control rabbits. Galantamine did not improve acquisition rates in young rabbits compared with age-matched controls. These data indicate that by enhancing nicotinic and muscarinic transmission, galantamine is effective in offsetting the learning deficits associated with decreased cholinergic transmission in the aging brain.     

Consequences of response-contingent change in unconditioned stimulus intensity upon the rabbit (Oryctolagus cuniculus) nictitating membrane response.

In a between-groups design, an instrumental contingency was superimposed on classical conditioning of the rabbit nictitating membrane response. Subjects were exposed to a tonal conditioned stimulus (CS) and, if no conditioned response (CR) occurred, a 5.0-ma. paraorbital electric shock unconditioned stimulus (US). USs of 5.0, 3.3, 1.7, and 0.0 ma., respectively, were contingent on occurrence of a CR in the CS-US interval for subjects in the 4 groups of the experiment. The group exposed to contingent US omission differed from the other 3 groups in percentage CR, onset latency, amplitude, and 2 indices of CR form, and those 3 groups generally did not differ significantly among themselves on these dependent variables. Results were interpreted to be contrary to "law of effect" formulations of classical conditioning.     

Discriminability and central intermittency in same-different judgements

Four sets of paired visual stimuli (OO, XX, XO, or OX) were judged by 48 subjects to be either “same” or “different.” Decision latencies of the same and different judgement were studied as a function of the inter-stimulus interval (ISI). In Experiments I and II, in which stimulus durations were 70 millisec., decision latencies showed marked increases when the ISI was reduced to 100 millisec., but in Experiments III and IV, in which the stimulus durations were only 40 millisec., comparable increases did not occur until the ISI was reduced to 50 millisec. These increases were more marked for “same” than for “different” judgements, although overall decision latencies were generally shorter for “same” judgements. The effects of varying ISIs and stimulus durations are interpreted in terms of masking; they fail to support an hypothesis of central intermittency.     

言语工作记忆的保持对时间知觉的影响*

采用工作记忆和时间判断的双任务范式,探讨了言语工作记忆的保持过程对时间知觉的影响。研究中操作记忆负荷和任务之间的时间间隔(ISI:记忆刺激消失到时间判断任务开始之间的时间间隔)。结果发现,记忆负荷越大,知觉到的时间越短,韦伯比例越低,反应时间越长;ISI越短,知觉到的时间变短,反应时间越长,这表明知觉时间和反应决策是一致的,不存在累加时间和反应判断之间的trade-off。但是记忆负荷和ISI的交互作用不显著。结果表明记忆负荷和ISI以不同的方式影响时间判断,言语工作记忆的保持和时间加工共享工作记忆资源。     

Short-term recognition memory of tones

Four Os participated in a recognition memory experiment for a period of 5 weeks. The task required O to judge whether two temporally sequenced tones (ISI = 0.5, 2.0, or 8.0 sec) were the “same” or “different ” Latencies and confidence ratings were obtained for each judgment. TSD analyses applied to individual O’s data indicated consistent and rapidly decreasing d’s as a function of ISI. ROC functions generated from the latencies and ratings produced comparable results, indicating the feasibility of using latency measures along with the type of judgments made to obtain sensitivity measures. Response bias, as indicated by the differences in the latencies between “same” and “different” judgments, did not produce consistent trends.     

Unconscious learning. Conditioning to subliminal visual stimuli

The role of consciousness in Pavlovian conditioning was examined in two experiments in which visually masked neutral words were used as the conditioned stimuli (CS) and an electric shock as the unconditioned stimulus (US). The inter-stimulus interval (ISI) was established individually. A detection threshold was used in Experiment 1 and an identification threshold in Experiment 2. The primary dependent variable was the skin conductance response (SCR). Results showed that the conditioned response (CR) was acquired by 58% of participants who perceived stimuli above the identification threshold, 50% of participants who perceived stimuli below the detection threshold, and 11% of participants who perceived stimuli below the identification threshold, but above the detection threshold. These results suggest that consciousness of the CS-US contingency is not a necessary condition for acquiring a CR of the autonomous nervous system (ANS).     

In the blink of an eye: Real-time stimulus factors in delay and trace conditioning of the rabbit's nictitating membrane response

Since Pavlov, theories of conditioning have assumed that CR evocation is governed by a series of internal stimuli generated by the CS. This hypothesis was tested in conditioning of the rabbit's nictitating membrane (NM) response by attempting to manipulate the internal sequence through truncating a delay CS and extending a trace CS on test trials. These perturbations of CS duration produced large deficits in CR likelihood and smaller alterations in the CR's time course. As predicted by many models of conditioning, the onset of the CS appeared to play a large but not exclusive role compared to CS duration and CS offset in both evocation and timing of the CR. The results are discussed with respect to their implications for real-time models of conditioning.     

Exploring the time course of semantic interference and associative priming in the picture-word interference task

The picture-word interference (PWI) task is a widely used technique for exploring effects of semantic context on lexical access. In this task, printed words are superimposed over pictures to be named, with the timing of the interfering word relative to the picture systematically manipulated. Two experiments (N = 24 adults in each) explored the time course of effects of associates (e.g., CARROT superimposed on a picture of a rabbit) versus coordinates (e.g., CHIPMUNK superimposed on a picture of a rabbit) on naming latencies. Associates led to faster picture naming than did unrelated words, with facilitative effects occurring at stimulus onset asynchronies (SOAs, in ms) ranging from -450 to 0. Coordinates led to slower naming latencies, with the interference effect restricted to SOAs of -150 and 0. The overlapping time course of associative priming and coordinate interference provides important constraints on models of lexical access in speech production.