Brain mechanisms of extinction of the classically conditioned eyeblink response

It is well established that the cerebellum and its associated circuitry are essential for classical conditioning of the eyeblink response and other discrete motor responses (e.g., limb flexion, head turn, etc.) learned with an aversive unconditioned stimulus (US). However, brain mechanisms underlying extinction of these responses are still relatively unclear. Behavioral studies have demonstrated extinction as an active learning process distinct from acquisition. Experimental data in eyeblink conditioning suggest that plastic changes specific to extinction may play an important role in this process. Both cerebellar and hippocampal systems may be involved in extinction of these memories. The nature of this phenomenon and identification of the neural substrates necessary for extinction of originally learned responses is the topic of this review.     

Blocking cholesterol synthesis impairs acquisition of the classically conditioned eyeblink response

Smith-Lemli-Opitz (SLO) syndrome is a congenital disorder characterized by severe mental retardation. Patients with SLO lack 7-dehydrocholesterol (7 dH) reductase, which catalyzes the last step of cholesterol synthesis. Administration of an agent that blocks 7 dH cholesterol reductase, BM 15.966 (BM), leads to a biochemical profile which resembles that of SLO patients, i.e., lower plasma, live and brain cholesterol levels accompanied by the appearance of the precursors 7 dH and 8 dH cholesterol. In this article we address the functional consequences of chronic BM treatment on new motor learning by assessing acquisition of the classically conditioned eyeblink response. Just-weaned rats were fed BM by gavage for four months, with half of these rats given exogenous cholesterol during the last two months of BM treatment. Acquisition of the eyeblink response was impaired in BM-treated rats. Impaired acquisition of the eyeblink response was not accompanied by alterations in responsiveness to either the conditioned or unconditioned stimulus. Exogenous cholesterol, a clinically relevant countertreatment, failed to correct for the learning impairment produced by BM treatment. Chronic treatment with a cholesterol synthesis-blocking agent impaired associative learning in just-weaned rats.     

Acquisition of the classically conditioned eyeblink response in humans over the life span

Human subjects ranging in age from 18 to 85 years underwent classical conditioning of the eyeblink response to a tone conditioned stimulus (CS) and an air-puff unconditioned stimulus (UCS). There was a decline in percentage of conditioned responses with age. This decline was most noticeable in subjects over age 50. These conditioning deficits were not due to age-related changes in sensitivity to the tone CS or the air-puff UCS, nor could the conditioning deficits be attributed to an age-related decline in general cognitive abilities or to changes in spontaneous blink rates. The results are discussed in terms of using the classically conditioned eyeblink in humans in conjunction with the classically conditioned nictitating membrane response in rabbits as a model system for studying the neurobiology of age-related conditioning deficits.     

Blocking cholesterol synthesis impairs acquisition of the classically conditioned eyeblink response.

Smith-Lemli-Opitz (SLO) syndrome is a congenital disorder characterized by severe mental retardation. Patients with SLO lack 7-dehydrocholesterol (7 dH) reductase, which catalyzes the last step of cholesterol synthesis. Administration of an agent that blocks 7 dH cholesterol reductase, BM 15.766 (BM), leads to a biochemical profile which resembles that of SLO patients, i.e., lower plasma, liver, and brain cholesterol levels accompanied by the appearance of the precursors 7 dH and 8 dH cholesterol. In this article we address the functional consequences of chronic BM treatment on new motor learning by assessing acquisition of the classically conditioned eyeblink response. Just-weaned rats were fed BM by gavage for four months, with half of these rats given exogenous cholesterol during the last two months of BM treatment. Acquisition of the eyeblink response was impaired in BM-treated rats. Impaired acquisition of the eyeblink response was not accompanied by alterations in responsiveness to either the conditioned or unconditioned stimulus. Exogenous cholesterol, a clinically relevant countertreatment, failed to correct for the learning impairment produced by BM treatment. Chronic treatment with a cholesterol synthesis-blocking agent impaired associative learning in just-weaned rats.     

Inhibitory stimulus control of the classically conditioned nictitating membrane response of the rabbit

Pavlovian conditioned inhibition training provides a method for investigating inhibitory dimensional stimulus control of the rabbit’s conditioned nictitating membrane response. The basic technique consists of reinforcing a burst of white noise while a compound made up of white noise and a tone is systematically not reinforced. Generalization tests to the white noise and a series of test tones result in a U-shaped gradient which remains relatively stable over a series of training-test phases.     

Changes in spinal reflex excitability in a countermanded timed response task

Subjects (N = 8) performed a timed response task in which they attempted to synchronize an impulsive foot-press response with the last in a series of four regularly spaced tones. In Experiment 1, the response was countermanded on one third of the trials (stop trials) by a stop signal that appeared at a predetermined delay after the third tone. No stop signal appeared on the remaining trials (go trials). All subjects showed a systematic transition from withholding the response on stop trials in which the stop signal appeared shortly after the third tone to executing the response on trials in which a single stop signal delay had been chosen so that a response would be made on about 50% of the stop trials. We elicited Hoffmann (H) reflexes from the soleus muscle on all trials to determine whether the reflexes were augmented on occasions on which a response was prepared but withheld. Mean H-reflex amplitudes on go trials and on stop trials on which the response was executed were similar and showed a marked augmentation beginning about 250 ms before response onset; mean H-reflex amplitudes on stop trials on which the response was withheld showed less pronounced augmentation. Inspection of individual H-reflex amplitudes revealed that on stop trials on which the response was withheld the reflexes could be augmented to the same extent as on trials on which the response was executed. This dissociation of H-reflex augmentation and response execution shows that H-reflex augmentation reflects a controlled response process. Ballistic response processes therefore must be limited to a brief duration.     

Retention of conditioned inhibition in a bar-press suppression paradigm

In three experiments, the retention of conditioned inhibition in rats was examined over long intervals. Retention deficits of conditioned inhibition were found at 21 days, although conditioned excitation was relatively stable over time. This loss of conditioned inhibition was demonstrated using both the summation and the retardation of learning techniques in a bar-press suppression paradigm. Furthermore, retention differences were found between within-groups and between-groups generalization tests of conditioned inhibition, using the summation procedure. These differences were interpreted within a retrieval-oriented model of memory.     

Modulation of a discrete Pavlovian conditioned reflex by a putative emotive Pavlovian conditioned stimulus

Three experiments showed the modulation of a rabbit eyeblink conditioned response (CR) to a Pavlovian conditioned stimulus (CS) by 30-s stimuli (A & B) that had been differentially paired with paraorbital shock. The CS (Y) was a 1,050-ms cue that had been paired with paraorbital shock outside A or B. In testing, the amplitude of CRs was greater when Y was presented within A than within B. Differential modulation occurred whether shock in A had been preceded by another 1,050-ms cue, X(AX+,BX-;Experiment 1) or not (A+B-;Experiment 2). Experiment 3 compared the technique of Experiment 1 (AX+) with that of Experiment 2 (A+) and found the latter to be advantageous for facilitation of CRs to Y by A. These data are consistent with the predictions of a model of Pavlovian conditioning (AESOP, Wagner & Brandon, 1989) that distinguishes between emotive and sensory conditioning as did Konorski (1967).     

Cardiac arrhythmias in the monkey during classically conditioned fear and excitement

Rhesus monkeys(Macaca mulatto) were tested in classic aversive and appetitive conditioning paradigms following complete coronary artery occlusion (CO) to test the hypothesis that “emotional stress” induces ventricular arrhythmias. Findings were based upon conditioning trials conducted for one or more weeks after occlusion in 13 animals. When all data from each animal for the week following CO were considered, there was no demonstrable tendency for arrhythmias to increase during “fear” conditioned to unavoidable electric shock or during “excitement” in anticipation of food. However, selected trials from six monkeys did reveal instances when changes in the frequency of occurrence of arrhythmias were coupled with behavioral conditioning. While analysis of these trials did not reveal any simple relationship between emotional stress and the development of ventricular arrhythmias after myocardial infarction, certain of the behavioral situations may be more potentially arrhythmogenic than others. For these selected trials, with respect to control, the number of arrhythmias may have increased or decreased upon presentation of the conditional stimulus; the exact response appears to depend upon the immediate physiologic status of the animal as well as on the behavioral condition. “More stressful” situations, such as aversive conditioning, are not necessarily associated with greater numbers of arrhythmias than were “less stressful” situations, such as appetitive conditioning. Arrhythmias appear to occur more frequently when an animal’s heart rate is within a given range; this may reflect underlying cardiac sympathetic and parasympathetic nerve activity.     

Extinction of a classically conditioned G.S.R. as a function of awareness

Insight, defined as the ability to verbalize the stimulus-response contingency of acquisition has bsen found to be unrelated to the extinction of an operantly conditioned verbal response. In the present study, the authors classically conditioned a GSR response in thirty Ss without insight, divided them into insight and no-insight groups following acquisition, and ran extinction trials which demonstrated a positive relationship (P< 0.001) under these particular conditions. It was concluded that the role of insight in extinction is a complex function of mode of conditioning (classical vs. operant) and/or mode of response (voluntary vs. involuntary), and that further studies utilizing the classical-voluntary and operant-involuntary combinations will be needed to define that function.