Todd R. Schachtman

Recovery of an overshadowed association achieved by extinction of the overshadowing stimulus

Abstract Three experiments are reported in which conditioned lick suppression by water-deprived rats was used as an index of associative strength. In Experiment 1, overshadowing of a light by a tone was observed when the light-tone compound stimulus was paired with foot shock. After initial compound pairings, the tone-shock association was extinguished in one group of subjects. Subsequently, these animals demonstrated significantly higher levels of suppression to the light relative to a control group in which the tone had not been extinguished. Experiment 2 replicated this effect while failing to find evidence to support the possibilities that extinction presentations of the overshadowing tone act as retrieval cues for the light-shock association, or that, via second-order conditioning, the light-shock association is actually formed during extinction of the tone. Experiment 3 determined that the recovery from overshadowing observed in Experiments 1 and 2 was specific to the extinction of the overshadowing stimulus rather than the extinction of any excitatory cue. Collectively, these results suggest that the debilitated response to an overshadowed stimulus does not represent an acquisition failure, but rather the failure of an acquired association to be manifest in behavior.

The comparator hypothesis of conditioned response generation: manifest conditioned excitation and inhibition as a function of relative excitatory strengths of CS and conditioning context at the time of testing.

In the present research water-deprived rats were used in a conditioned lick suppression paradigm to test and further develop Rescorlas (1968) contingency theory, which posits that excitatory associations are formed when a conditioned stimulus (CS) signals an increase in unconditioned stimulus (US) likelihood and that inhibitory associations develop when the CS signals a decrease in US likelihood. In Experiment 1 we found that responding to a CS varied inversely with the associative status of the context in which the CS was trained and that this response was unaltered when testing occurred in a distinctively dissimilar context with a different conditioning history, provided associative summation with the test context was minimized. These results suggest that manifest excitatory and inhibitory conditioned responding is modulated by the associative value of the training context rather than that of the test context. In Experiment 2 it was demonstrated that postconditioning decreases in the associative value of the CS training context reduced the effective inhibitory value of the CS even when testing occurred outside of the training context. Moreover, this contextual deflation effect was specific to the CS training context as opposed to any other excitatory context. Collectively, these studies support the comparator hypothesis, which states that conditioned responding is determined by a comparison of the associative strengths of the CS and its training context that occurs at the time of testing rather than at the time of conditioning. This implies that all associations are excitatory and that responding indicative of conditioned inhibition reflects a CS-US association that is below (or near) the associative strength of its comparator stimulus. It is suggested that response rules which go beyond a monotonic relation between associative value and response strength can partially relieve learning theories of their explanatory burdens, thereby allowing for simpler models of acquisition.

The effects of stress on the development of immunological memory following low-dose antigen priming in mice

Observable stress effects on immune responses may be a function of the quantitative and qualitative characteristics of the stressor, and the outcome measurement of immunity. Further, the effects of stress on humoral immunity, in particular, may be sensitive to the concentrations of antigen used to elicit a response. We have studied the effects of footshock stress during the time of priming with low concentrations of antigen on the secondary response to another low dose of antigen. The secondary humoral immune response of C3H/HeJ mice to the protein antigen keyhole limpet hemocyanin was examined following footshock, exposure to the apparatus without shock, or exposure to the home cage. Footshock reproducibly depressed the IgG anti-KLH response, and the effect on the IgM response was sporadic. Initially, footshock was administered for 7 days before and 7 days after priming with low amounts of antigen. Subsequent studies demonstrated that a single footshock session delivered 24 h after priming could suppress the IgG anti-KLH response.

Metabotropic glutamate receptor subtype 5 antagonism in learning and memory

The role of the metabotropic glutamate receptor 5 (mGlu(5) receptor) in learning and memory and other behaviors are reviewed by examining the influence of selective antagonists and genetic knockout on performance. This receptor is involved in spatial learning, contextual fear conditioning, inhibitory avoidance, fear potentiated startle, and conditioned taste aversion. However, mGlu(5) receptor antagonists have proven to be ineffective in other learning tasks, such as the delayed-match-to-position test and a three-hole spatial learning task. Locomotion is often decreased by mGlu(5) receptor antagonists; and other behaviors such as social interaction and consummatory responses can also be affected. In mGlu(5) receptor knockout mice, performance in contextual fear conditioning and spatial water maze tasks is impaired. Although the available evidence is suggestive of an important contribution of mGlu(5) receptors to cognitive functions, further studies are needed, particularly those with in vivo evaluation of the role of mGlu(5) receptors in selective brain regions in different stages of memory formation.

Attenuation of latent inhibition by post-acquisition reminder.

Using lick suppression by water-deprived rats as an associative index, white noise-footshock pairings resulted in less manifest conditioning when repeated non-reinforced presentations of the white noise preceded conditioning than when no stimulus pre-exposure was given, i.e., latent inhibition was observed. However, the latent inhibition deficit was reduced in animals who received as a reminder treatment shock-alone presentations in another context during the retention interval. Animals conditioned without prior stimulus pre-exposure and those exposed to the white noise and shock unpaired during the conditioning phase of the study showed no change in lick suppression as a result of the reminder treatment. These results suggest that the behavioural deficit produced by non-reinforced pre-exposure to the to-be-conditioned stimulus arises at least in part from a reversible retrieval failure rather than a lack of acquisition.

Spatial learning and memory impairment and increased locomotion in a transgenic amyloid precursor protein mouse model of Alzheimer's disease

This study provides an examination of spatial learning and a behavioral assessment of irritability and locomotion in TgCRND8 mice, an amyloid precursor protein transgenic model of Alzheimers disease. Performance was assessed using the Barnes maze, the touch escape test, and an open-field test. While past research focused primarily on 2-5-month-old TgCRND8 mice, the present study used an older age cohort (9-month-old female mice), in addition to a 4-month-old cohort of both transgenic (Tg) and wildtype female mice. Both younger and older Tg mice displayed poor spatial learning in the Barnes maze task compared to their wildtype littermates, as demonstrated by significantly longer latencies and more errors both during acquisition and at a 2-week retest. No differences in irritability were found between Tg and control mice in the younger cohort; however, older Tg mice displayed significantly higher irritability compared with wildtype littermates, as measured by the touch escape test. Additionally, Tg mice of both age cohorts showed increased locomotion and slowed habituation during a 60-min open-field test over 3 days of testing. These results demonstrate that TgCRND8 mice show significant deficits in spatial and nonspatial behavioral tasks at advanced stages of amyloid pathology.

Effect of signaled reinforcement on the formation of behavioral units.

Experiments examined the influence of a brief reinforcement signal on the acquisition of a response sequence and investigated whether such sequences serve as behavioral nits. In Experiment 1, hungry rats emitted 2 responses on each of 2 levers to earn food reward. There was no constraint on the sequence in which the 2 responses per lever could be emitted, but rats came to emit 1 of the permitted 4-response sequences to a greater degree than the others. Signaled reinforcement promoted emission of the dominant response sequence. In Experiments 2 and 3, rats with signaled reinforcement displayed facilitated acquisition of the required response sequence, and emission of the sequence persisted after the schedule, reinforcing the required sequence, which was shifted to a variable interval 45-s schedule

SLOW REACQUISITION OF A CONDITIONED TASTE AVERSION

Rats were used to examine the extent to which extinction of an acquired conditioned taste aversion retards subsequent reacquisition. A saccharin-flavored solution (sac) was paired with LiCl and then followed by CS-alone extinction trials with this flavor. A control group received a different flavor, decaffeinated-coffee (coff), during initial conditioning and extinction. Sac was then paired with LiCl for all rats during a second conditioning phase. Reacquisition of the aversion to sac was retarded relative to the acquisition of an aversion to sac by the control group. A similar experiment with fewer extinction trials, but still with complete loss of the initial aversion, did not obtain slow reacquisition. The results are discussed with respect to an interference view of extinction and the slow-reacquisition effect.

Functional interaction of mGlu5 and NMDA receptors in aversive learning in rats

Metabotropic glutamate receptor 5 (mGlu5) has been implicated in a variety of learning processes and is important for inhibitory avoidance and conditioned taste aversion learning. MGlu5 receptors are physically connected with NMDA receptors and they interact with, and modulate, the function of one another in several brain regions. The present studies used systemic co-administration of an mGlu5 receptor positive allosteric modulator, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and an NMDA receptor antagonist dizocilpine maleate (MK-801) to characterize the interactions of these receptors in two aversive learning tasks. Male Sprague-Dawley rats were trained in a single-trial step-down inhibitory avoidance or conditioned taste aversion task. CDPPB (3 or 10mg/kg, s.c.), delivered by itself prior to the conditioning trial, did not have any effect on performance in either task 48 h after training. However, CDPPB (at 3mg/kg) attenuated the MK-801 (0.2mg/kg, i.p.) induced learning deficit in both tasks. CDPPB also reduced MK-801-induced hyperactivity. These results underlie the importance of mGlu5 and NMDA receptor interactions in modulating memory processing, and are consistent with findings showing the efficacy of positive allosteric modulators of mGlu5 receptors in reversing the negative effects of NMDA receptor antagonists on other behaviors such as stereotypy, sensorimotor gating, or working, spatial and recognition memory.

Beneficial Effects of Dietary EGCG and Voluntary Exercise on Behavior in an Alzheimer's Disease Mouse Model

Alzheimers disease (AD) is a progressive, age-dependent neurodegenerative disorder affecting specific brain regions that control memory and cognitive functions. Epidemiological studies suggest that exercise and dietary antioxidants are beneficial in reducing AD risk. To date, botanical flavonoids are consistently associated with the prevention of age-related diseases. The present study investigated the effects of 4 months of wheel-running exercise, initiated at 2-months of age, in conjunction with the effects of the green tea catechin (-)-epigallocatechin-3-gallate (EGCG) administered orally in the drinking water (50 mg/kg daily) on: (1) behavioral measures: learning and memory performance in the Barnes maze, nest building, open-field, anxiety in the light-dark box; and (2) soluble amyloid-β (Aβ) levels in the cortex and hippocampus in TgCRND8 (Tg) mice. Untreated Tg mice showed hyperactivity, relatively poor nest building behaviors, and deficits in spatial learning in the Barnes maze. Both EGCG and voluntary exercise, separately and in combination, were able to attenuate nest building and Barnes maze performance deficits. Additionally, these interventions lowered soluble Aβ1-42 levels in the cortex and hippocampus. These results, together with epidemiological and clinical studies in humans, suggest that dietary polyphenols and exercise may have beneficial effects on brain health and slow the progression of AD.