Appetitive Trace Conditioning Research Articles

Ketamine facilitates appetitive trace conditioning in mice: Further evidence for abnormal stimulus representation in schizophrenia model animals.

Recent studies indicated that positive symptoms of schizophrenia, such as hallucination and delusion, can be modeled using Pavlovian conditioning procedures. Various schizophrenia model animals exhibit abnormally strong associative activations of absent stimuli (i.e., conditioned hallucination) and readily form further associations involving the absent cues (i.e., enhanced mediated conditioning). In the present study using mice, we examined whether the acquisition of appetitive trace conditioning, another Pavlovian task in which animals must form associations between two stimuli that never occur together, is facilitated by injections of ketamine, an N-methyl-D-aspartate-receptor antagonist and a known hallucinogen at low doses in humans and nonhuman animals. Ketamine administration before each conditioning session significantly enhanced the acquisition of 4-s trace conditioning but not delay conditioning. The trace conditioning-specific facilitatory effect of ketamine was replicated in subsequent experiments in which slightly modified procedures were used to enhance the overall levels of conditioned responses. Taken together, the current results demonstrated that low-dose ketamine promotes associative learning between stimuli over a temporal gap, which adds to existing literature illustrating aberrant learning involving absent stimuli in schizophrenia model animals. We discuss potential associative mechanisms through which ketamine promoted trace conditioning with reference to Wagner's (1981) Standard Operating Procedures model. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Supplemental Material for Ketamine Facilitates Appetitive Trace Conditioning in Mice: Further Evidence for Abnormal Stimulus Representation in Schizophrenia Model Animals

Supplemental Material for Ketamine Facilitates Appetitive Trace Conditioning in Mice: Further Evidence for Abnormal Stimulus Representation in Schizophrenia Model Animals

Training on an Appetitive Trace-Conditioning Task Increases Adult Hippocampal Neurogenesis and the Expression of Arc, Erk and CREB Proteins in the Dorsal Hippocampus.

Adult hippocampal neurogenesis (AHN) plays an essential role in hippocampal-dependent memory consolidation. Increased neurogenesis enhances learning, whereas its ablation causes memory impairment. In contrast, few reports suggest that neurogenesis reduces after learning. Although the interest in exploring the role of adult neurogenesis in learning has been growing, the evidence is still limited. The role of the trace- and delay-appetitive-conditioning on AHN and its underlying mechanism are not known. The consolidation of trace-conditioned memory requires the hippocampus, but delay-conditioning does not. Moreover, the dorsal hippocampus (DH) and ventral hippocampus (VH) may have a differential role in these two conditioning paradigms. Here, we have investigated the changes in: (A) hippocampal cell proliferation and their progression towards neuronal lineage; and (B) expression of Arc, Erk1, Erk2, and CREB proteins in the DH and VH after trace- and delay-conditioning in the rat. The number of newly generated cells significantly increased in the trace-conditioned but did not change in the delay-conditioned animals compared to the control group. Similarly, the expression of Arc protein significantly increased in the DH but not in the VH after trace-conditioning. Nonetheless, it remains unaltered in the delay-conditioned group. The expression of pErk1, pErk2, and pCREB also increased in the DH after trace-conditioning. Whereas, the expression of only pErk1 pErk2 and pCREB proteins increased in the VH after delay-conditioning. Our results suggest that appetitive trace-conditioning enhances AHN. The increased DH neuronal activation and pErk1, pErk2, and pCREB in the DH may be playing an essential role in learning-induced cell-proliferation after appetitive trace-conditioning.

Age-related differences in appetitive trace conditioning and novel object recognition procedures.

Appetitive trace conditioning (TC) was examined over 6 months in younger-adult (2-8 months) and middle-aged (12-18 months) male Wistar RccHan rats, to test for early age-related impairment in working memory. Novel object recognition (NOR) was included as a comparison task, to provide a positive control in the event that the expected impairment in TC was not demonstrated. The results showed that TC improved at both ages at the 2 s but not at the 10 s trace interval. There was, however, evidence for reduced improvement from one day to the next in the middle-aged cohort tested with the 2 s trace conditioned stimulus. Moreover, within the 10 s trace, responding progressively distributed later in the trace interval, in the younger-adult but not the middle-aged cohort. Middle-aged rats showed NOR discriminative impairment at a 24 h but not at a 10 min retention interval. Object exploration was overall reduced in middle-aged rats and further reduced longitudinally. At the end of the study, assessing neurochemistry by HPLC-ED showed reduced 5-HIAA/5-HT in the dorsal striatum of the middle-aged rats and some correlations between striatal 5-HIAA/5-HT and activity parameters. Overall the results suggest that, taken in isolation, age-related impairments may be overcome by experience. This recovery in performance was seen despite the drop in activity levels in older animals, which might be expected to contribute to cognitive decline.

Infusions of scopolamine in dorsal hippocampus reduce anticipatory responding in an appetitive trace conditioning procedure.

IntroductionTrace conditioning is impaired by lesions to dorsal hippocampus, as well as by treatment with the muscarinic acetylcholine antagonist scopolamine. However, the role of muscarinic receptors within hippocampus has received little attention.MethodsThe present study examined the effects of intra‐hippocampal infusion of scopolamine (30 µg/side) in an appetitive (2 vs. 10 s) trace conditioning procedure using sucrose pellets as the unconditioned stimulus (US). Locomotor activity (LMA) was examined in a different apparatus.ResultsIntra‐hippocampal scopolamine reduced responding to the 2 s trace conditioned stimulus (CS). Intra‐hippocampal scopolamine similarly depressed responding within the inter‐stimulus interval (ISI) at both 2 and 10 s trace intervals, but there was no such effect in the inter‐trial interval. There was also some overall reduction in responding when the US was delivered; significant at the 10 s but not at the 2 s trace interval. A similar pattern of results to that seen in response to the CS during acquisition was shown drug‐free (in the 5 s post‐CS) in the extinction tests of conditioned responding. LMA was increased under scopolamine.ConclusionsThe results suggest that nonspecific changes in activity or motivation to respond for the US cannot explain the reduction in trace conditioning as measured by reduced CS responding and in the ISI. Rather, the findings of the present study point to the importance of associative aspects of the task in determining its sensitivity to the effects of scopolamine, suggesting that muscarinic receptors in the hippocampus are important modulators of short‐term working memory.

Scopolamine Impairs Appetitive But Not Aversive Trace Conditioning: Role of the Medial Prefrontal Cortex.

The muscarinic acetylcholine receptor is an important modulator of medial prefrontal cortex (mPFC) functions, such as the working memory required to bridge a trace interval in associative leaning. Aversive and appetitive trace conditioning procedures were used to examine the effects of scopolamine (0.1 and 0.5 mg/kg, i.p.) in male rats. Follow-up experiments tested the effects of microinfusion of 0.15 μg of scopolamine (0.075 μg of in 0.5 μl/side) in infralimbic (IL) versus prelimbic regions of rat mPFC, in appetitive trace and locomotor activity (LMA) procedures. Systemic scopolamine was without effect in an aversive trace conditioning procedure, but impaired appetitive conditioning at a 2 s trace interval. This effect was demonstrated as reduced responding during presentations of the conditioned stimulus (CS) and during the interstimulus interval (ISI). There was no such effect on responding during food (unconditioned stimulus, US) responding or in the intertrial interval (ITI). In contrast, systemic scopolamine dose-relatedly increased LMA. Trace conditioning was similarly impaired at the 2 s trace (shown as reduced responding to the CS and during the ISI, but not during US presentations or in the ITI) after infusion in mPFC, whereas LMA was increased (after infusion in IL only). Therefore, our results point to the importance of cholinergic modulation in mPFC for trace conditioning and show that the observed effects cannot be attributed to reduced activity.SIGNIFICANCE STATEMENT Events are very often separated in time, in which case working memory is necessary to condition their association in “trace conditioning.” The present study used conditioning variants motivated aversively with foot shock and appetitively with food. The drug scopolamine was used to block muscarinic acetylcholine receptors involved in working memory. The results show that reduced cholinergic transmission in medial prefrontal cortex (mPFC) impaired appetitive trace conditioning at a 2 s trace interval. However, scopolamine was without effect in the aversive procedure, revealing the importance of procedural differences to the demonstration of the drug effect. The finding that blockade of muscarinic receptors in mPFC impaired trace conditioning shows that these receptors are critical modulators of short-term working memory.

Dopaminergic modulation of appetitive trace conditioning: the role of D1 receptors in medial prefrontal cortex.

RationaleTrace conditioning may provide a behavioural model suitable to examine the maintenance of ‘on line’ information and its underlying neural substrates.ObjectivesExperiment la was run to establish trace conditioning in a shortened procedure which would be suitable to test the effects of dopamine (DA) D1 receptor agents administered by microinjection directly into the brain. Experiment lb examined the effects of the DA D1 agonist SKF81297 and the DA D1 antagonist SCH23390 following systemic administration in pre-trained animals. Experiment 2 went on to test the effects of systemically administered SKF81297 on the acquisition of trace conditioning. In experiment 3, SKF81297 was administered directly in prelimbic (PL) and infralimbic (IL) sub-regions of medial prefrontal cortex (mPFC) to compare the role of different mPFC sub-regions.ResultsWhilst treatment with SCH23390 impaired motor responding and/or motivation, SKF81297 had relatively little effect in the pre-trained animals tested in experiment 1b. However, systemic SKF81297 depressed the acquisition function at the 2-s trace interval in experiment 2. Similarly, in experiment 3, SKF81297 (0.1 μg in 1.0 μl) microinjected into either PL or IL mPFC impaired appetitive conditioning at the 2-s trace interval.ConclusionsImpaired trace conditioning under SKF81297 is likely to be mediated in part (but not exclusively) within the IL and PL mPFC sub-regions. The finding that trace conditioning was impaired rather than enhanced under SKF81297 provides further evidence for the inverse U-function which has been suggested to be characteristic of mPFC DA function.

Selective hippocampal lesions impair acquisition of appetitive trace conditioning with long intertrial and long trace intervals.

Whereas hippocampal lesions clearly impair performance on aversive trace conditioning tasks, recent evidence suggests that such lesions do not affect performance on appetitive trace conditioning tasks with trace intervals from 2 seconds up to 20 seconds. The current study first demonstrated that intact rats can learn trace conditioning tasks with longer trace intervals (8 s) when the average intertrial interval (intertrial interval [ITI]) was lengthened from 150-s to 300-s. In two subsequent experiments with longer ITIs (420-s and 825-s), hippocampal-lesioned rats performed similarly to intact controls in an appetitive trace conditioning task with 20-s trace interval but were impaired in an appetitive trace conditioning task with a 60-s trace interval. These results suggest that the training ITI and the trace interval are important variables to consider in appetitive trace conditioning, and the hippocampus may play an important role in appetitive trace conditioning when the ITI and trace intervals are both sufficiently long.

Dorsal hippocampal involvement in appetitive trace conditioning and interval timing.

Involvement of the dorsal hippocampus (DHPC) in acquisition of Pavlovian trace conditioning and interval timing was examined in an appetitive preparation in which presentations of one conditioned stimulus (CS) were immediately followed by food (delay conditioning), and presentations of another CS were followed by food 15 seconds after its termination (trace conditioning). DHPC lesions did not disrupt acquisition of trace conditioning, but they selectively affected the distribution of conditioned responding over the course of the trace CS in the early stage of acquisition. In addition, lesions disrupted accuracy of timing the conditioned response (CR) for both delay and trace CSs: The control subjects showed maximum CR at the time of food delivery, but in the DHPC-lesioned subjects, the maximum CR was at an earlier time point. This timing deficit did not seem to be due to impulsive responding or deficits in response inhibition because, when the early portion of the delay CS was interrupted shortly by an empty interval, the difference in the time of maximum responding between the lesioned and control subjects was eliminated. Thus, although the involvement of the DHPC in appetitive trace conditioning was not found when a gross measure of conditioning was employed, it was revealed when the temporal distribution of conditioned responding was examined on a moment-by-moment basis as in eyeblink trace conditioning studies.

Differential acetylcholine release in the prefrontal cortex and hippocampus during pavlovian trace and delay conditioning

Pavlovian trace conditioning critically depends on the medial prefrontal cortex (mPFC) and hippocampus (HPC), whereas delay conditioning does not depend on these brain structures. Given that the cholinergic basal forebrain system modulates activity in both the mPFC and HPC, it was reasoned that the level of acetylcholine (ACh) release in these regions would show distinct profiles during testing in trace and delay conditioning paradigms. To test this assumption, microdialysis probes were implanted unilaterally into the mPFC and HPC of rats that were pre-trained in appetitive trace and delay conditioning paradigms using different conditional stimuli in the two tasks. On the day of microdialysis testing, dialysate samples were collected during a quiet baseline interval before trials were initiated, and again during performance in separate blocks of trace and delay conditioning trials in each animal. ACh levels were quantified using high-performance liquid chromatography and electrochemical detection techniques. Consistent with our hypothesis, results showed that ACh release in the mPFC was greater during trace conditioning than during delay conditioning. The level of ACh released during trace conditioning in the HPC was also greater than the levels observed during delay conditioning. While ACh efflux in both the mPFC and HPC selectively increased during trace conditioning, ACh levels in the mPFC during trace conditioning testing showed the greatest increases observed. These results demonstrate a dissociation in cholinergic activation of the mPFC and HPC during performance in trace but not delay appetitive conditioning, where this cholinergic activity may contribute to attentional mechanisms, adaptive response timing, or memory consolidation necessary for successful trace conditioning.

Alternative time representation in dopamine models

Dopaminergic neuron activity has been modeled during learning and appetitive behavior, most commonly using the temporal-difference (TD) algorithm. However, a proper representation of elapsed time and of the exact task is usually required for the model to work. Most models use timing elements such as delay-line representations of time that are not biologically realistic for intervals in the range of seconds. The interval-timing literature provides several alternatives. One of them is that timing could emerge from general network dynamics, instead of coming from a dedicated circuit. Here, we present a general rate-based learning model based on long short-term memory (LSTM) networks that learns a time representation when needed. Using a naïve network learning its environment in conjunction with TD, we reproduce dopamine activity in appetitive trace conditioning with a constant CS-US interval, including probe trials with unexpected delays. The proposed model learns a representation of the environment dynamics in an adaptive biologically plausible framework, without recourse to delay lines or other special-purpose circuits. Instead, the model predicts that the task-dependent representation of time is learned by experience, is encoded in ramp-like changes in single-neuron activity distributed across small neural networks, and reflects a temporal integration mechanism resulting from the inherent dynamics of recurrent loops within the network. The model also reproduces the known finding that trace conditioning is more difficult than delay conditioning and that the learned representation of the task can be highly dependent on the types of trials experienced during training. Finally, it suggests that the phasic dopaminergic signal could facilitate learning in the cortex.

Measuring Correlations and Interactions Among Four Simultaneously Recorded Brain Regions During Learning

Brain function depends on coordinated interactions in spatially distributed neuronal populations. Thanks to recent technological advances, it is now possible to monitor the activity of large groups of neurons. Although significant progress has been made in analyzing neuronal interactions across large samples of simultaneously recorded cells, most of the available approaches do not allow direct visualization of multidimensional correlations in the time domain. This study describes a novel analysis technique, termed four-dimensional spike-triggered joint histogram (4-d STJH) that permits the study of co-modulations of unit activity across four simultaneously recorded brain regions while preserving the time domain. To illustrate how this technique works, we recorded simultaneously from basolateral amygdala (BLA) and medial prefrontal (mPFC), as well as perirhinal and entorhinal neurons in animals learning an appetitive trace-conditioning task. Using the 4d-STJH, we show that coincident activity in the BLA and mPFC modulates the interactions between perirhinal and entorhinal neurons in a manner that cannot be explained by a linear combination of the individual BLA and mPFC-related modulations. We conclude with a discussion of the strengths and limitations of 4-d STJH and offer recommendations regarding optimal conditions for its use.

Additional evidence for intact appetitive trace conditioning in hippocampal-lesioned rats.

Hippocampal lesions impair aversive trace conditioning but do not interfere with appetitive Pavlovian trace conditioning of the licking response (LR). This experiment examined whether learning to discriminate the events occurring in the home cage and in the training chamber could account for the differential effects of hippocampal lesions on aversive and appetitive trace conditioning. Performance of rats with excitotoxic lesions of the hippocampus was compared to that of sham-operated rats in LR trace conditioning. The unconditional stimulus (US) "cola soft drink" was delivered only in the training chamber. Thus, as in aversive conditioning procedures, the hedonic properties of the US and the resulting behaviors and motivational states occurred only in that environment. The results failed to reveal learning differences between lesioned rats and controls. Our findings and those of other reports concur that trace conditioning with an appetitive US is independent of the hippocampal system.

A neurotensin agonist and antagonist decrease and increase activity, respectively, but do not preclude discrete cue conditioning

There is evidence to suggest that neurotensin (NT) may enhance cognitive function. For example, in aversive trace conditioning, the NT agonist PD149163 selectively increased trace conditioning (Grimond-Billa, et al., 2008). The present study, therefore, examined the role of NT in associative learning, tested using an appetitive trace conditioning procedure (0-s or 10-s inter-stimulus-interval [ISI]) with a mixed frequency noise as a conditioned stimulus (CS) and food delivery as the unconditioned stimulus (UCS). The effects of an NT agonist (PD149163, 0.125 and 0.25 mg/kg, Experiment 1) and an NT antagonist (SR142948A, 0.01 and 0.1 mg/kg, Experiment 2) were compared. To take nonspecific effects of these compounds into account, conditioning to the CS was measured as a percentage of total responding, during UCS deliveries and in the inter-trial-interval (ITI). In both experiments, associative learning to the contiguously (0-s) presented CS was demonstrated, although there was a relative reduction in this learning under 0.125 mg/kg PD149163. Counter to prediction, the only effect on trace conditioning was some overall reduction in responding to the CS in the 10-s group conditioned under 0.25 mg/kg PD149163. The NT antagonist was without any effect on appetitive conditioning. However, these NT compounds were not ineffective: decreases and increases in responding in the ITI, ISI and during UCS deliveries seen under PD149163 and SR142948A were dissociable from effects on discrete cue conditioning.

Dorsal, ventral, and complete excitotoxic lesions of the hippocampus in rats failed to impair appetitive trace conditioning

Three experiments examined appetitive trace and delay conditioning of the licking response (LR). In Experiment 1, normal rats were trained in trace conditioning using different trace intervals (2, 4, or 8 s) and in delay conditioning (i.e., with a 0-s trace) in order to determine an appropriate trace interval for the following lesion experiments. Only the rats trained with a 2-s trace interval ultimately reached the same level of learning as rats trained in delay conditioning. In Experiments 2A and 2B, the performance of rats with dorsal, ventral, and complete excitotoxic hippocampal lesions was compared to that of sham-operated rats in LR conditioning with a 2-s trace. In Experiment 2B, the performance of rats in trace LR conditioning was also compared to that of rats tested in the delay paradigm. In both experiments, acquisition did not differ in lesioned and sham-operated rats and, in Experiment 2B, it was faster in the delay than in the trace paradigm. These results contrast with those showing that aversive trace conditioning is impaired after hippocampal damage. Experiment 3 examined whether the differential effects of hippocampal lesions on aversive and appetitive trace conditioning could be related to a parametric difference, that is, the relative durations of the conditional stimulus and of the trace interval. Again, hippocampal damage failed to produce a learning impairment. It is suggested that the procedure of aversive, but not of appetitive, trace conditioning is context-specific and that an intact hippocampus is required only in these situations.

Emotional enhancement of memory via amygdala-driven facilitation of rhinal interactions

Emotions generally facilitate memory, an effect mediated by the basolateral amygdala (BLA). To study the underlying mechanisms, we recorded BLA, perirhinal and entorhinal neurons during an appetitive trace-conditioning task. We focused on the rhinal cortices because they constitute the interface between the hippocampus, a mediator of memory consolidation, and the neocortex, the storage site of declarative memories. We found that, after unexpected rewards, BLA activity increased impulse transmission from perirhinal to entorhinal neurons and that this effect decayed as the association between conditioned stimuli and rewards was learned. At this late phase of learning, the BLA effect occurred when the animals were anticipating the reward. By enhancing the processing of sensory cues, the BLA-mediated facilitation of rhinal interactions may explain how the amygdala promotes memory formation in emotional conditions.

Electrolytic lesions to nucleus accumbens core and shell have dissociable effects on conditioning to discrete and contextual cues in aversive and appetitive procedures respectively

The nucleus accumbens (n. acc.) has been implicated in conditioning to both discrete and contextual cues but its precise role is as yet controversial because conflicting patterns of effect have been reported. These inconsistencies may relate to the extent to which the lesions used encroach on different subfields of n. acc. and the use of different task variants. The present study compared the effects of selective lesions of shell and core subfields of nucleus accumbens (n. acc.) across aversive and appetitive trace conditioning variants. In both experiments, an auditory stimulus was contiguous with footshock or food, or presented at a trace interval. A continuous flashing light in each case provided an experimental background stimulus. Conditioning to the cues provided by the experimental chambers was also assessed. Rats with electrolytic lesions to the n. acc. shell and core showed different patterns of effect in aversive (Experiment 1) and appetitive (Experiment 2) variants of this procedure. In Experiment 1, the core lesion reduced the difference between trace and contiguously conditioned groups, in responding to the discrete noise stimulus. However, neither lesion had any detectable effect on contextual conditioning. In Experiment 2, the shell lesion clearly increased contextual conditioning, selectively in the trace conditioned group, but neither lesion had any detectable effect on discrete cue conditioning. Thus, whilst the shell and core lesions produced dissociable effects on discrete cue and contextual conditioning, the conclusions to be drawn depend on the procedural variant in use.