Delayed Non-matching To Position Research Articles

JNJ-10181457, a selective non-imidazole histamine H 3 receptor antagonist, normalizes acetylcholine neurotransmission and has efficacy in translational rat models of cognition

Histamine 3 (H 3) receptors are distributed throughout the brain and regulate histamine as well as the activity of other neurotransmitters including acetylcholine (ACh). Impaired ACh neurotransmission is associated with deficits of cognitive-related functioning in many species including humans. The goal of these studies was to evaluate the behavioral and neurochemical effects of JNJ-10181457, a selective non-imidazole histamine H 3 receptor antagonist, in rats. The pharmacokinetic profile and receptor occupancy of JNJ-10181457 were tested. The efficacy of JNJ-10181457 was evaluated, acutely, in the imetit-induced water licking model, delayed non-matching to position (DNMTP) task and microdialysis studies. In addition, the effects of repeated administration of JNJ-10181457 were evaluated in the reversal learning task. A single administration of JNJ-10181457 (10 mg/kg, i.p.) resulted in significant plasma and brain exposure and maximal H 3 receptor occupancy. In addition, JNJ-10181457 reversed imetit-induced water licking, similarly to thioperamide (10 mg/kg, i.p.). In the DNMTP task, scopolamine (0.06 mg/kg, i.p.) significantly decreased percentage correct responding. These effects were significantly reversed by JNJ-10181457 (10 mg/kg, i.p.) and also by donepezil (1 mg/kg, i.p.), an acetylcholinesterase inhibitor, and were associated with normalization of ACh neurotransmission in the cortex. Repeated administration of JNJ-10181457 (10 mg/kg, i.p.) significantly increased percentage correct responding in the reversal learning task. Treatment discontinuation was not associated with rebound effects on cognition. These results indicate that selective blockade of histamine H 3 receptors might have therapeutic utility for the treatment of working memory deficits and learning disorders, especially those in which ACh neurotransmission is compromised.

SB‐269970, a selective 5‐HT7 antagonist, reverses working memory deficits in rats by normalizing glutamate neurotransmission

5‐HT7 antagonists have been shown to have efficacy in animal models of cognition. However, the mechanism by which these procognitive effects occur is not well understood. The goal of these studies was to evaluate the effects of SB‐269970, a selective 5‐HT7 antagonist, in translational models of cognition and establish whether it modulates glutamate neurotransmission. The effects of SB‐269970 (10 mg/kg, i.p.), were evaluated in the delayed non‐matching to position (DNMTP) task alone and in combination with MK‐801 (0.1 mg/kg, i.p.), a non‐competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine (0.06 mg/kg, i.p.), a non‐selective muscarinic antagonist. Also, the ability of SB‐269970 (10 mg/kg, i.p.) to modulate MK‐801 (0.1 mg/kg, i.p.)‐induced glutamate and dopamine cortical release was evaluated using microdialysis in freely moving rats. MK‐801 and scopolamine significantly reduced percentage correct responding in the DNMTP task without affecting number of trials. SB‐269970 significantly reversed the deficits induced by MK‐801, but not by scopolamine. SB‐269970 normalized MK‐801‐induced glutamate but not dopamine release in the cortex and these effects were similar to LY379268, a group II mGluR agonist. These results indicate that blockade of 5‐HT7 receptors selectively normalizes glutamatergic neurotransmission.

Effects of mGlu1 receptor blockade on working memory, time estimation, and impulsivity in rats

Metabotropic glutamate 1 (mGlu1) receptor antagonists were reported to induce cognitive deficits in several animal models using aversive learning procedures. The present study aimed to further characterize behavioral effects of mGlu1 receptor antagonists using appetitively motivated tasks that evaluate working memory, timing, and impulsivity functions. Separate groups of adult male Wistar rats were trained to perform four food-reinforced operant tasks: delayed non-matching to position (DNMTP), differential reinforcement of low rates of responding 18 s (DRL 18-s), signal duration discrimination (2-s vs 8-s bisection), and tolerance to delay of reward. Before the tests, rats were pretreated with (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM; 2.5-10 mg/kg, i.p.; JNJ16567083). In DNMTP task, EMQMCM produced delay-dependent increases in performance accuracy so that, at 10 mg/kg dose level, percentage of correct lever choices was enhanced at 8- and 16-s delays. In DRL task, at all three tested doses, response rates were higher, and reinforcement rates were lower than under control conditions. In signal duration discrimination tasks, EMQMCM did not have any specific effects on temporal control. In tolerance to delay of reward, EMQMCM (5 and 10 mg/kg) facilitated choice of the lever associated with large reward at longer delay levels. Blockade of mGlu1 receptors improves working memory and reduces impulsive choice at the doses that have no effects on time perception but appear to facilitate impulsive action.

P.1.d.008 Effects on the adult behavioral changes of early maternal separation during the stage of development in the rat

The effects of three different serotonin (5-HT) receptor antagonists (ketanserin, methysegide, methiothepin) in the modulation of attention, working memory and behavioural activity were investigated in this study by assessing the performance of rats in two separate cognitive models; the 5-choice serial reaction time (5-CSRT) task, which measures attention, and the delayed non-matching to position (DNMTP) task, which measures working memory. Methysergide and methiothepin bind at the 5-HT1 and 5-HT2 as well as the 5-HT5–7 receptors, with varying degrees of selectivity, and ketanserin binds at the 5-HT2A receptors rather selectively. None of these agents bind to any significant extent to 5-HT3 or 5-HT4 receptors. In the 5-CSRT task, neither methiothepin (0.15 mg/kg) nor ketanserin (1.0 and 3.0 mg/kg) impaired the choice accuracy of rats, although they induced sedation. The low doses of methysergide (1.5 and 3.0 mg/kg) slightly increased the behavioural activity of rats, whereas the high dose of methysergide (15.0 mg/kg) reduced behavioural activity and slightly reduced choice accuracy of the rats in the attentional task (monitoring of visual stimuli) under the baseline conditions or curtailed stimulus duration. This effect was not augmented at the reduced stimulus intensity. These findings suggest that the high dose of methysergide did not interfere with the visual discrimination of rats. Furthermore, methysergide did not reduce motivation for this task, since it did not increase food collection latencies. In the DNMTP task, methiothepin (0.15 mg/kg) induced a delay non-dependent deficit in choice accuracy. This could be due to an impaired alternation ability or akinesia, which increases an actual delay between sample and choice. Methiothepin (0.15 mg/kg) also interfered with behavioural activity of rats. Interestingly, ketanserin (1.0 mg/kg and 3.0 mg/kg) and methysergide (3.0–15.0 mg/kg) neither impaired the choice accuracy nor reduced the behavioural activity of rats in the DNMTP task. These results suggest that the blockade of 5-HT2A receptors does not interfere with attention and working memory per se. However, all three serotonin receptor antagonists interfered with behavioural activity of rats in the 5-CSRT task more severely than in the DNMTP task. The possible role of serotonin and non-serotonin receptors underlying the influence of these antagonists on behavioural activity will be discussed.

Interference effects by spatial proximity and age-related declines in spatial memory by Japanese monkeys (Macaca fuscata): Deficits in the combined use of multiple spatial cues.

Spatial information processing was assessed in 3 young (4-10 years old) and 4 aged (24-25 years old) Japanese monkeys (Macaca fuscata) on 3 delayed nonmatching-to-position (DNMP) tests with relatively short delays of 5 s. Each test had 3 conditions of different horizontal distances between sample and to-be-nonmatched positions. Experiment 1 demonstrated that the performance on the DNMP test in both age groups was impaired when 2 stimulus positions were located next to each other; however, it was fairly accurate when they were located farther apart, suggesting that interference is introduced by spatial proximity. Experiment 2 revealed age-related differences in the situation in which an additional spatial cue, depth information, was available by extending the stimulus array of the DNMP test to a 4 x 2 matrix. In this test, young monkeys performed accurately irrespective of position distance between stimuli, whereas the aged monkeys' performance remained the same as before. Experiment 3 confirmed that the recognition ability in aged monkeys was well preserved on DNMP tests with different objects. These patterns of results indicate that the ability to use information from multiple spatial cues is not accessible to the aged monkeys.

Visuospatial function in the beagle dog: An early marker of cognitive decline in a model of human aging and dementia

Visuospatial learning and memory impairments are an early marker for age-related cognitive decline and Alzheimer’s disease. Similar to humans, aged dogs show visuospatial learning and memory deficits ( Adams et al., 2000b). One hundred and nine beagle dogs ranging between 0.25 and 11.99 years were tested on a visuospatial delayed non-matching to position (DNMP) task to better characterize the progression of visuospatial deficits in the dog. Age predicted 48.2% of the variability in learning the DNMP, with dogs ranging from 1 to 11.99 years generally making more errors with increasing age. By contrast, puppies (<1 year) likely were showing developmental deficits, possibly due to an immature prefrontal cortex. Mild visuospatial deficits were detected by 6 years, which precedes the typical onset of amyloid-β (Aβ) accumulation in the dog brain by two years, and can serve as an early marker for cognitive decline in the dog. These findings suggest that (1) age-related changes in visuospatial function in the dog models that seen in humans, further validating the dog as a model for human aging and dementia; and (2) other mechanisms, such as oxidative stress, soluble Aβ oligomers or cholinergic deficits, are likely contributing to the early impairment.

Galanin and perseveration

Galanin is a 29/30 amino acid neuropeptide that has been shown to impair learning and memory task performance and also have roles in somatosensation, stress responses, sexual behavior, and feeding regulation. However, little is known about galanin involvement in higher cognitive processes, especially executive processes. Perseveration is a classic sign of frontal cortex damage and failure of executive control. Galanin has been shown to disrupt the performance of maze delayed alternation tasks and the operant, spatial delayed nonmatch-to-position (DNMTP) working memory task, tests especially sensitive to perseverative responding. To better understand this potential involvement of galanin in executive control, the present study tested the hypothesis that galanin induces perseveration. The first experiment examined the effects of galanin (10, 20 μg i.c.v.) on the performance of a simple operant response alternation task in which stimuli were assigned to one of two spatially distinct locations to produce extended sequences of presentations to one location, separated by a 10-s intertrial interval. The second experiment looked at the effects of galanin (5, 20 μg i.c.v.) on the performance of non-delayed match-to-position and nonmatch-to-position conditional discrimination operant tasks in which a minimal 1.0 s time interval separated responses. Finally, the effects of galanin (10, 20 μg i.c.v.) on delayed match-to-position (DMTP) performance were examined to determine whether response alternation (i.e., nonmatching) was critical to observing a galanin-induced impairment in this task. Galanin reduced the rate of trial completion in all the tasks, but did not alter simple or conditional discrimination accuracy. Galanin (10 μg) impaired DMTP performance in a delay-independent manner. Together, these data suggest that galanin does not produce perseveration, but are consistent with a galanin-induced decrease in reinforcer strength.

Intracerebroventricular administration of galanin decreases free water intake and operant water reinforcer efficacy in water-restricted rats

The 29/30 amino acid neuropeptide galanin coexists with vasopressin in the hypothalamus and has been shown to inhibit the actions of vasopressin and aldosterone, suggesting an inhibitory role for galanin in physiological water retention mechanisms and water seeking and water consumption behavior. Little work, however, has examined a role for galanin in water intake regulation. Furthermore, many experiments that have reported galanin-induced impairments in the performance of tasks thought to measure learning and memory have used water restriction routines and water reinforcers to maintain responding. Therefore, the present study examined the effects of intracerebroventricularly administered galanin (5.0-20.0 microg/5 microl) on free water consumption during a 10 min test session and a follow up open field exploration, an operant progressive ratio (PR) schedule, a test used to assess reinforcer strength, and an operant fixed time schedule (FT 20) in 23.5h water restricted rats. Finally, in an additional experiment that was designed to simulate the effects of a galanin-induced decrease in water reinforcer efficacy, the rats were allowed access to water prior to testing in an operant delayed non-matching to position (DNMTP) task. A galanin-induced decrease in water consumption was observed in both the free access test and the FT 20 at the 20 microg dose, but no significant galanin-induced alterations in open field behavior. A decrease in responses emitted and rewards received was observed on the PR schedule at the 5, 10, and 20 microg doses. Pre-session access to water significantly reduced the number of trials per session in the DNMTP but did not reduce accuracy. This study is the first to observe a galanin-induced reduction in water intake and reinforced operant behavior, and suggests that galanin may play a role in regulating water intake and reinforcement. However, the present data also suggest that DNMTP choice accuracy deficits observed previously cannot be attributed to a galanin-induced change in reinforcer efficacy.

Effects of pre-training pedunculopontine tegmental nucleus lesions on delayed matching- and non-matching-to-position in a T-maze in rats

Lesions of the pedunculopontine tegmental nucleus (PPTg) can impair spatial learning tasks, but it is not clear whether those detrimental effects depend on the specific training conditions (for example, number of response choices available) or are secondary to enhanced anxiety. In the present work, rats with either bilateral excitotoxic (ibotenate) lesions of the PPTg (lesion group) or with vehicle infusions (control group) were tested in an elevated plus-maze, in order to measure anxiety-like behaviours and spontaneous locomotion. Subsequently, they were trained in a delayed matching-to-position (DMTP) task in a T-maze (a two-response choice task). After reaching a predefined learning criterion, or after a maximum of 30 training sessions, the animals were trained in a delayed non-matching-to-position (DNMTP) task. Lesioned animals made less grooming episodes, stretch-attend postures and closed arm entries than controls in the elevated plus-maze, suggesting slightly lower anxiety levels. None of the lesioned rats reached the learning criterion for the DMTP, and overall accuracy levels were significantly lower in those rats, compared to controls. In the DNMTP task, lesioned animals showed lower accuracy levels and higher side bias than controls in some of the sessions, but there were no significant differences between the two groups in the proportion of animals reaching the learning criterion. It is concluded that spatial learning deficits induced by damage to the PPTg are not secondary to enhanced anxiety. Instead, those deficits seem to be influenced by several conditions that modify task demands, the number of response choices being only one of such conditions.

P4.029 A comparison of wildtype and APP transgenic mice on titrating delayed non-match to position (DNMTP) and differential reinforcement of low rates (DRL) performance

P4.029 A comparison of wildtype and APP transgenic mice on titrating delayed non-match to position (DNMTP) and differential reinforcement of low rates (DRL) performance

Modafinil facilitates performance on a delayed nonmatching to position swim task in rats

Modafinil is a wake-promoting drug approved by the FDA for the treatment of narcolepsy. Recent evidence suggests that modafinil may improve learning and memory processes. To further evaluate possible cognitive properties associated with modafinil, male Sprague–Dawley rats were tested in a delayed nonmatching to position (DNMTP) task. A modified water maze allowed animals to make one of two choices for the location of the escape platform. Each trial consisted of two swims. On the information swim (IS), only one choice was open to the animal for escape. One minute later, a choice swim (CS) presented the animal with two choices with the escape platform in the opposite position. There were 10 trials per day for 10 days. Rats received 0, 30, 55, or 100 mg/kg ip of modafinil 30 min prior to testing. Locomotor activity was also assessed. Animals that received 55 and 100 mg/kg made significantly more correct choices, indicating that higher doses of modafinil learned the task faster than did controls. While animals that received 100 mg/kg did exhibit an enhancement of locomotor activity, this effect did not result in more efficient goal-directed behavior. The evidence is consistent with previous research showing that modafinil facilitates cognitive processes.

Delayed non-matching to position performance in aged hybrid Fischer 344 × Brown Norway rats: a longitudinal study

In this study, the effects of aging on the performance in a delayed non-matching to position (DNMTP) task were investigated longitudinally in hybrid Fischer 344 × Brown Norway rats. The rats were first trained to perform the task. Subsequently, their performance was assessed monthly from 28 to 34 months of age. The measures of responding on the DNMTP schedule did not decrease in the course of the study. After the last DNMTP test, choline acetyltransferase (ChAT) activity and glial fibrillary acidic protein (GFAP) content were measured in frontal cortex and hippocampus. We found that higher levels of GFAP in the frontal cortex, but not hippocampus, were associated with a poorer performance in the DNMTP task. Our findings support the notion that repeated testing prevents the age-related decline in cognitive functions that has been reported in cross-sectional studies. Pathology of the frontal cortex seems to predict a faster rate of forgetting in aging rats.

Dose-specific effects of scopolamine on canine cognition: impairment of visuospatial memory, but not visuospatial discrimination.

The cholinergic system is linked extensively to memory, but its exact role remains controversial. In particular, scopolamine-induced impairment in rodents is not task specific, which may be due to difficulty in developing rodent protocols to assess deficits in recent memory, in which the remembered event is brief and distinct, and/or to non-specific behavioral impairment. The present study sought to determine whether scopolamine-induced deficits in recent memory, using a working memory task, could be dose-specifically dissociated from deficits in associative memory in dogs. A Latin-square design was used to determine the effect of scopolamine (5, 10 and 15 microg/kg; SC) on a variable delayed-non-matching-to-position (DNMP) task, which assesses visuospatial working memory. Subsequently, the minimal effective dose (15 microg/kg; SC) was administered prior to testing on a landmark discrimination task, which provides a measure of allocentric spatial ability, a black-white discrimination task, an oddity discrimination task and tests of exploratory behavior. We also investigated the effects of a 30 microg/kg dose (SC) on tests of oddity discrimination and behavioral activity. A 15 microg/kg dose produced significant impairment on the DNMP task, but did not affect performance of any discrimination task and did not alter behavior on tests of open field or curiosity. A 30 microg/kg dose caused disruption on discrimination performance and on open field measures. Working memory performance is most sensitive to scopolamine-induced impairment and can be dissociated from scopolamine-induced deficits in discrimination performance and non-cognitive behaviors. The present results indicate that scopolamine-induced impairments of working memory in the dog can serve as a model of age-related cholinergic dysfunction.

The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates PCP-induced cognitive deficits in rats.

Recent studies have shown that metabotropic glutamate receptor 5 (mGluR5) can modulate N-methyl-D-aspartate (NMDA) receptor function in vivo. For example, the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP) can potentiate PCP (phencyclidine)-evoked hyperactivity and PCP-induced disruptions in pre-pulse inhibition (PPI) in rats. To extend these previous behavioral findings and determine whether the mGluR5 antagonist MPEP can modulate the disruptions in learning and memory induced by PCP in rats. The effects of MPEP, alone and in combination with PCP, were evaluated in rats trained to perform a repeated acquisition procedure (learning) or a delayed non-matching to position (DNMTP) radial maze task (spatial memory). In the repeated acquisition task, MPEP (0-10 mg/kg, IP) dose-dependently decreased response rates but had no effect on response accuracy. In contrast, PCP (0.625-1.25 mg/kg, SC) reduced response rate and response accuracy in a dose-dependent manner. Although MPEP (10 mg/kg, IP) had no effect when administered alone, the mGluR5 antagonist potentiated the disruptions in learning induced by a low dose of PCP (0.625 mg/kg, SC). In the DNMTP maze task, MPEP (0-10 mg/kg, IP) had no effect on spatial memory, whereas PCP (1.25-2.5 mg/kg, SC) produced a dose-dependent disruption. MPEP (10 mg/kg, IP) potentiated the impairments in memory induced by PCP (1.25 mg/kg, SC). The mGluR5 antagonist, MPEP, potentiated the disruptions in learning and memory induced by PCP. These behavioral data extend previous behavioral findings and further suggest that mGluR5 can modulate NMDA receptor function in vivo.

Adrafinil disrupts performance on a delayed nonmatching-to-position task in aged beagle dogs

Previous studies in humans and dogs have reported beneficial effects of adrafinil on specific cognitive functions. The effects in dogs are limited to a single study examining discrimination learning. We wanted to further explore the cognitive effects of adrafinil in dogs. The purpose of the present study was to determine the effect of oral administration of adrafinil on visuospatial function in dogs. Eighteen aged beagle dogs were tested on a delayed nonmatching-to-position (DNMP) task 2 h following one of three possible treatments; 20 mg/kg of adrafinil, 10 mg/kg of adrafinil or a placebo control. All dogs were tested under each treatment for eight test sessions. A 2-day washout period was given between treatments and the order of treatments was varied. Treatment with 20 mg/kg of adrafinil produced a significant impairment in working memory as indicated by an increase in the number of errors over the 8-day test period. The disturbance of memory functions from adrafinil could be a result of increased noradrenergic transmission in the prefrontal cortex.

Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats

Rationale. Hypertension is considered a risk factor for the development of cognitive disorders, because of its negative effects on cerebral vasculature and blood flow. Genetically induced hypertension in rats has been associated with a range of cognitive impairments. Therefore, spontaneously hypertensive rats (SHR) can potentially be used as a model for cognitive deficits in human subjects. Consecutively, it can be determined whether certain food components can improve cognition in these rats. Objective. The present study aimed to determine whether SHR display specific deficits in attention, learning, and memory function. Additionally, effects of chronic uridine and choline administration were studied. Methods. 5–7 months old SHR were compared with normotensive Wistar–Kyoto (WKY) and Sprague–Dawley (SD) rats. (a) The operant delayed non-matching-to-position (DNMTP) test was used to study short-term memory function. (b) The five-choice serial reaction time (5-CSRT) task was used to assess selective visual attention processes. (c) Finally, the Morris water maze (MWM) acquisition was used as a measure for spatial learning and mnemonic capabilities. Results. (1) SHR exhibited significantly impaired performance in the 5-CSRT test in comparison with the two other rat strains. Both the SHR and WKY showed deficits in spatial learning when compared with the SD rats. (2) Uridine and choline supplementation normalized performance of SHR in the 5-CSRT test. (3) In addition, uridine and choline treatment improved MWM acquisition in both WKY and SHR rats. Conclusion. The present results show that the SHR have a deficiency in visual selective attention and spatial learning. Therefore, the SHR may provide an interesting model in the screening of substances with therapeutic potential for treatment of cognitive disorders. A combination of uridine and choline administration improved selective attention and spatial learning in SHR.

Cholinergic blockade impairs performance in operant DNMTP in two inbred strains of mice

Cholinergic blockade has been shown to impair performance in delayed nonmatching to position (DNMTP) paradigms in rats. In this study, a murine operant DNMTP task was used to assess the effects of cholinergic antagonism in two strains of mice (DBA/2 and C57BL/6) differing in spatial learning abilities. DNMTP was scheduled in operant chambers with retractable levers, where mice were trained until high levels of accuracy. Subsequently, proactive interference effects were assessed by manipulation of the intertrial interval (ITI), and animals were tested in this task under scopolamine (0.1–1.0 mg/kg) and mecamylamine (0.5–2.0 mg/kg) treatment. Data were analyzed according to the methods of signal detection theory. ITI manipulation decreased accuracy when the time between trials was reduced to 5 s. Cholinergic blockade failed to induce a pure mnemonic impairment but distinguishable effects of both receptor antagonists could be detected: scopolamine disrupted accuracy in a dose-dependent but delay-independent manner, whereas mecamylamine failed to impair accuracy, but decreased responsivity delay- and dose-dependently. Strains mainly differed in responsivity, with DBA/2 showing higher latencies to respond to the levers. These results are comparable to those obtained in rats. Thus, operant DNMTP can be applied to assess working memory in mice.

The α 2 adrenoceptor antagonists RX 821002 and yohimbine delay-dependently impair choice accuracy in a delayed non-matching-to-position task in rats

alpha 2 adrenoceptor mechanisms appear to play a role in the performance of delayed response working memory tasks but there are contradictory results. To investigate whether RX 821002 (2-methoxy-idazoxan) and yohimbine and would affect the performance of the delayed non-matching-to-position (DNMTP) task in rats and compare the effects to those of the cholinergic antagonist scopolamine. Male Lister Hooded rats trained to criterion in an operant DNMTP task (0-48 s delay intervals) were administered vehicle, RX 821002 (0.3, 1, 3 mg/kg s.c.), yohimbine (1, 3 mg/kg. s.c.) or scopolamine (0.05 mg/kg, s.c.). Together with choice accuracy, the motor performance of the task was measured. It was found that: (1) both RX 821002 and yohimbine statistically significantly reduced choice accuracy dose- and delay-dependently and in a similar magnitude to that of scopolamine while modifying the motor aspects of task performance delay-independently and (2) RX 821002 produced mainly rate-decreasing effects. Yohimbine exerted stimulatory effects at the lowest dose and rate-decreasing effects at the highest dose, a profile consistent with that already described in operant tasks. The results confirm that alpha 2 antagonists delay-dependently impair choice accuracy in a delayed-response paradigm.

Effects of cholinergic manipulation on operant delayed non-matching to position performance in two inbred strains of mice

With the increasing demand on phenotyping of mouse mutants there is a clear need to develop novel paradigms for testing mice. Mice are able to learn a non-matching to position rule to high accuracy in a variety of maze paradigms, but an operant version of this task is desirable. In the present study, mice of the C57BL/6 and DBA/2 strains were trained and tested on an operant delayed non-matching to position (DNMTP) paradigm. Data were analysed according to the methods of signal detection theory (SDT), which allows conclusions as to whether strain differences in DNMTP performance are more related to changes in accuracy or in motivational factors. Mice can learn to respond on an operant DNMTP paradigm with high accuracy, and accurate performance depends on the duration of the delay-period, i.e. forgetting curves can be generated. Comparison between the two strains of mice revealed that DBA/2 mice learned faster than C57BL/6 mice to associate the lever press with food during initial shaping, but no further strain differences were observed in accurate responding during later stages of the experiment. However, differences in biased responding and, in particular, responsivity were observed between the two strains. Muscarinic blockade with scopolamine (0.1–1.0 mg/kg) failed to affect accuracy in the two strains, but altered responsivity. This task should be of great value for a more in-depth analysis of cognitive function in mutant mice as it allows a better dissociation between mnemonic and non-mnemonic factors. In particular, such paradigm may be of interest for testing conditional mutants, which allow time-sensitive induction or inhibition of gene expression, i.e. where animals can be trained while non-impaired to stable baseline and then tested once the gene is activated or inhibited.

Preferential responses on a positional recognition task in aged and young monkeys

The present experiment assessed learning and memory of five young and three aged monkeys in a spatial recognition task. Subjects were tested in a delayed non-matching to position (DNMP) task evaluating preferential response as well as accuracy of the task. There was no clear difference between the two age groups in the number of trials to reach the learning criterion. This result is consistent with the previous studies using non-spatial tasks. However, analysis of the process of learning revealed differential patterns in the emergence of preferential responses in both groups. While four patterns were observed in the young monkeys, in contrast, only one of the four was observed in the aged monkeys. The aged monkeys showed preferential responses in the early phase of learning, followed by rapid learning. This analysis of preferential response suggests that position preference behavior was effective in learning for the aged monkeys but not for the young monkeys. After reaching a criterion, the monkeys were subjected to longer retention intervals of 10-60 seconds. In this task, two aged monkeys performed as accurately as young monkeys did, while another one showed severe impairment. As has been shown previously for the non-spatial task, considerable individuality was found again in a memory task with the aged monkeys, with respect to spatial task as well.