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 2s but not at the 10s trace interval. There was, however, evidence for reduced improvement from one day to the next in the middle-aged cohort tested with the 2s trace conditioned stimulus. Moreover, within the 10s 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 24h 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. [219 words

Data showing regional differences in rat brain monoaminergic function

Chemical neurotransmitters (such as dopamine) modulate cognitive function via ascending projections to various cortical and sub-cortical brain regions. This report describes and links to a relatively large dataset (up to N=112) compiled from control (untreated) brain samples taken during a series of experimental in vivo studies. The dataset is freely available, to explore the normal interrelationships between levels of neurotransmitter (e.g., dopamine, serotonin), across brain regions implicated in both normal reward and drug addiction, as well as in disorders such as schizophrenia (e.g., nucleus accumbens, frontal cortex). Most experimental studies run with a relatively small control group, so there is a lack of baseline data on the expected levels of neurotransmitters and their metabolites in different brain regions. Accordingly, the available dataset has been compiled from a number of studies run in the same laboratory, and using closely similar behavioural procedures, sampling selected brain regions of a priori interest. These collated data can be used to explore differences in the distribution of the monoamines and their metabolites, patterns of neurotransmitter intercorrelations, both between and within different brain structures and including some consideration of laterality effects

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

Trace 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. The present study examined the effects of intra-hippocampal infusion of scopolamine (30μg/side) in an appetitive trace conditioning procedure using sucrose pellets as the unconditioned stimulus (US). This treatment resulted in reduced responding to a trace conditioned stimulus (CS), an effect most clearly seen when the US was presented at a 2s trace (inter-stimulus-interval, ISI). Intra-hippocampal scopolamine similarly depressed responding within the ISI (at both 2 and 10s trace intervals), but there was no such effect in the inter-trial-interval (ITI). There was also some overall reduction in responding when the US was delivered; significant at the 10s but not at the 2s trace interval. A similar pattern of results to that seen in response to the CS during acquisition was shown drug-free (in the 5s post-CS) in the extinction tests of conditioned responding. Moreover, in a different apparatus, locomotor activity was increased under scopolamine. Thus the results suggest that non-specific 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

Intraperitoneal 8-OH-DPAT reduces competition from contextual but not discrete conditioning cues

The effects of the serotonergic (5-hydroxytryptamine, 5-HT) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.2 and 0.4 mg/kg i.p.) were examined in trace conditioning (Experiment 1) and overshadowing (Experiment 2) procedures. Both experiments used a fear conditioning procedure conducted off-the-baseline in water deprived male Wistar rats. 8-OH-DPAT was administered during conditioning and its effects were examined drug free as the suppression of an established licking response, both upon re-exposure to the cues provided by the conditioning chambers and upon presentation of experimental stimuli. There were no statistically significant effects of 8-OH-DPAT on conditioning to the discrete cue provided by a 5 s conditioned stimulus (CS), irrespective of the length of the trace interval used in Experiment 1, and irrespective of whether the CS took the form of a light alone, or a noise plus light compound in the Experiment 2 overshadowing procedure. The successful demonstration of overshadowing required the use of a second conditioning session which allowed further evaluation of the effects of 8-OH-DPAT in that neither a weak nor a strong overshadowing effect was modulated by either drug dose. Nonetheless conditioning to contextual cues was attenuated by treatment with 8-OH-DPAT at the 30 s trace interval. We therefore conclude that 8-OH-DPAT reduces competition from contextual but not discrete conditioning cues. This pattern of results lends further support to the view that contextual cue conditioning and discrete cue conditioning are modulated by different neuropharmacological mechanisms

The dopamine D1 receptor agonist SKF81297 has dose-related effects on locomotor activity but is without effect in a CER trace conditioning procedure conducted with two versus four trials

In an appetitively motivated procedure, we have previously reported that systemic treatment with the dopamine (DA) D1 receptor agonist SKF81297 (0.4 and 0.8 mg/kg) depressed acquisition at a 2s inter-stimulus-interval (ISI), suitable to detect trace conditioning impairment. However since DA is involved in reinforcement processes, the generality of effects across appetitively- and aversively-motivated trace conditioning procedures cannot be assumed. The present study tested the effects of SKF81297 (0.4 and 0.8 mg/kg) in an established conditioned emotional response (CER) procedure. Trace-dependent conditioning was clearly shown in two experiments: while conditioning was relatively strong at a 3-s ISI, it was attenuated at a 30-s ISI. This was shown after two (Experiment 1) or four (Experiment 2) conditioning trials conducted in - as far as possible - the same CER procedure. Contrary to prediction, in neither experiment was there any indication that trace conditioning was attenuated by treatment with 0.4 or 0.8 mg/kg SKF81297. In the same rats, locomotor activity was significantly enhanced at the 0.8 mg/kg dose of SKF81297. These results suggest that procedural details of the trace conditioning variant in use are an important determinant of the profile of dopaminergic modulation

Intraperitoneal sertraline and fluvoxamine increase contextual fear conditioning but are without effect on overshadowing between cues

Treatment with selective serotonin reuptake inhibitors (SSRIs) can reduce contextual conditioning. Since contexts present a variety of potentially competing cues, impaired overshadowing may provide an account of such effects. The present study therefore compared the effects of two SSRIs on overshadowing and contextual conditioning, testing suppression of an ongoing behavioral response (licking) by cues previously paired with foot shock. Conditioning to a 5s light stimulus was reduced when this was presented in compound with a 5s noise, thus overshadowing was demonstrated. In two experiments, this overshadowing was unaffected by treatment with either sertraline or fluvoxamine. However, unconditioned suppression to the noise (tested in the control group previously conditioned to the light alone) was reduced after sertraline (10mg/kg, i.p.). The successful demonstration of overshadowing required the use of a second conditioning session or an additional conditioning trial within the same conditioning session. Neither weak nor strong overshadowing (of the light by the tone) was affected by any drug treatment. Moreover, counter to prediction, conditioning to contextual cues was increased rather than impaired by treatment with sertraline (10mg/kg, i.p.) and fluvoxamine (30mg/kg, i.p.)

Effects of dopamine D1 modulation of the anterior cingulate cortex in a fear conditioning procedure

The anterior cingulate cortex (AC) component of the medial prefrontal cortex (mPFC) has been implicated in attention and working memory as measured by trace conditioning. Since dopamine (DA) is a key modulator of mPFC function, the present study evaluated the role of DA receptor agents in rat AC, using trace fear conditioning. A conditioned stimulus (CS, noise) was followed by an unconditioned stimulus (US, shock) with or without a 10s trace interval interposed between these events in a between-subjects design. Conditioned suppression of drinking was assessed in response to presentation of the CS or an experimental background stimulus (flashing lights, previously presented for the duration of the conditioning session). The selective D1 agonist SKF81297 (0.05 µg/side) or D1 antagonist SCH23390 (0.5 µg/side) was administered by intra-cerebral microinfusion directly into AC. It was predicted that either of these manipulations should be sufficient to impair trace (but not delay) conditioning. Counter to expectation, there was no effect of DA D1 modulation on trace conditioning as measured by suppression to the noise CS. However, rats infused with SKF81297 acquired stronger conditioned suppression to the experimental background stimulus than those infused with SCH23390 or saline. Thus, the DA D1 agonist SKF81297 increased conditioned suppression to the contextual background light stimulus but was otherwise without effect on fear conditioning

Ro 04-6790-induced cognitive enhancement: No effect in trace conditioning and novel object recognition procedures in adult male Wistar rats

The evidence for cognitively enhancing effects of 5-hydroxytryptamine6 (5-HT6) receptor antagonists such as Ro 04-6790 is inconsistent and seems to depend on the behavioural test variant in use. Trace conditioning holds promise as a behavioral assay for hippocampus-dependent working memory function. Accordingly, Experiment 1 assessed the effect of Ro 04-6790 (5 and 10 mg/kg i.p.) on associating a noise conditioned stimulus paired with foot shock (unconditioned stimulus) at a 3 or 30 s trace interval in adult male Wistar rats. Contextual conditioning was measured as suppression to the contextual cues provided by the experimental chambers and as suppression to a temporally extended light background stimulus which provided an experimental context. Experiment 2 assessed the effect of Ro 04-6790 (5 and 10 mg/kg i.p.) on recognition memory as tested by the exploration of novel relative to familiar objects in an open arena. In Experiment 1, Ro 04-6790 (5 and 10 mg/kg) was without effect on trace and contextual conditioning. In Experiment 2, there was no indication of the expected improvement under Ro 04-6790 at the same doses previously found to enhance recognition memory as measured in tests of novel object exploration. Thus, there was no evidence that treatment with the 5-HT6 receptor antagonist Ro 04-6790 acted as a cognitive enhancer in either trace conditioning or object recognition procedures. We cannot exclude the possibility that the experimental procedures used in the present study would have been sensitive to the cognitive enhancing effects of Ro 04-6790 in a different dose range, behavioral test variant, or in a different strain of rat. Nonetheless the drug treatment was not ineffective in that object exploration was reduced under 10 mg/kg Ro 04-6790

Potentiation rather than distraction in a trace fear conditioning procedure

Trace conditioning procedures are defined by the introduction of a trace interval between conditioned stimulus (CS, e.g. noise or light) offset and unconditioned stimulus (US, e.g. footshock). The introduction of an additional stimulus as a distractor has been suggested to increase the attentional demands of the task and to extend the usefulness of the behavioural model. In Experiment 1, the CS was noise and the distractor was provided by an intermittent light. In Experiment 2, the CS was light and the distractor was provided by an intermittent noise. In both experiments, the introduction of a 10s trace interval weakened associative learning compared with that seen in a 0s delay conditioned group. However, there was no consistent evidence of distraction. On the contrary, in Experiment 1, associative learning was stronger (in both trace and delay conditioned groups) for rats conditioned also in the presence of the intermittent light. In Experiment 2, there was no such effect when the roles of the stimuli were reversed. The results of Experiment 2 did however confirm the particular salience of the noise stimulus. The finding of increased associative learning dependent on salience is consistent with arousal-mediated effects on associative learning

Conditioned inhibition of emotional responses: retardation and summation with cues for IAPS outcomes

Conditioned inhibition occurs when a stimulus inhibits the responses that would normally occur to a conditioned stimulus that previously predicted an outcome of interest (the unconditioned stimulus, which elicits responding unconditionally). The present study tested inhibitory learning using emotionally salient cues provided by the use of pictures from the International Affective Picture System (IAPS). The procedure in use was adapted to confirm the demonstration of conditioned inhibition using two key transfer tests, retardation and summation. Experiment 1 showed the development of the predicted discrimination learning for negative outcomes but not for positive outcomes. Experiment 2 found evidence for retardation. Furthermore, this reduced learning was clearly related to the conditioned emotional response to the US images; individuals rated transfer images as positive if they had previously signalled the absence of a negative outcome. Experiment 3 showed that the conditioned inhibition was confirmed by summation test. Thus, inhibitory learning was confirmed by both retardation and summation tests, which between them control for alternative explanations of apparent conditioned inhibition, conducted on different participants but using the same discrimination learning procedure. Moreover, the use of emotionally salient cues as the unconditioned stimuli more closely resembles the traditional Pavlovian paradigm