Delayed Non-matching To Position Task Research Articles

Left−Right Asymmetry Defect in the Hippocampal Circuitry Impairs Spatial Learning and Working Memory in iv Mice

Although left-right (L−R) asymmetry is a fundamental feature of higher-order brain function, little is known about how asymmetry defects of the brain affect animal behavior. Previously, we identified structural and functional asymmetries in the circuitry of the mouse hippocampus resulting from the asymmetrical distribution of NMDA receptor GluR ε2 (NR2B) subunits. We further examined the ε2 asymmetry in the inversus viscerum (iv) mouse, which has randomized laterality of internal organs, and found that the iv mouse hippocampus exhibits right isomerism (bilateral right-sidedness) in the synaptic distribution of theε2 subunit, irrespective of the laterality of visceral organs. To investigate the effects of hippocampal laterality defects on higher-order brain functions, we examined the capacity of reference and working memories of iv mice using a dry maze and a delayed nonmatching-to-position (DNMTP) task, respectively. The iv mice improved dry maze performance more slowly than control mice during acquisition, whereas the asymptotic level of performance was similar between the two groups. In the DNMTP task, the iv mice showed poorer accuracy than control mice as the retention interval became longer. These results suggest that the L−R asymmetry of hippocampal circuitry is critical for the acquisition of reference memory and the retention of working memory.

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.

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.

Evidence that muscarinic receptors are involved in nicotine-facilitated spatial memory

A delayed nonmatching-to-position task (DNMPT) in a water maze (nine trials per day, 10 days) was used to investigate the role of muscarinic acetylcholinergic receptor (mAChR) in nicotine-facilitated spatial memory in Wistar rats. The index of spatial memory was determined by the number of correct choices made in choice swim (CS) and the time taken to complete the swim in the correct CS. Diazepam (6 mg kg −1 ip, daily) significantly impaired choice accuracy and increased the swim time for correct CS. In contrast, when nicotine (2 mg kg −1 sc, twice daily) and diazepam were administered simultaneously in the last three sessions of training, the choice accuracies of CS were similar to controls and significantly higher than in the diazepam group. However, the swim times for correct CS were longer in the nicotine+diazepam group than in controls. Atropine (30 mg kg −1 ip, daily) significantly decreased the choice accuracies of CS. The choice accuracies of CS swim times for correct CS in the atropine group did not differ significantly from those in the nicotine+atropine group, in which nicotine (2 mg kg −1 sc, twice daily) and atropine were given simultaneously. These results show that nicotine improves memory performance when the functions of mAChRs are normal; when the mAChRs are blocked, nicotine does not enhance spatial memory. Therefore, mAChRs are involved in the spatial memory-enhancing effect of nicotine.

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.

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.

Use of a delayed non-matching to position task to model age-dependent cognitive decline in the dog

Spatial learning and memory in young and old dogs was studied in a series of experiments using a delayed non-matching to position (DNMP) paradigm. Past research from our laboratory has suggested that aged dogs perform more poorly on a version of the DNMP task compared to young dogs [Head et al., Spatial learning and memory as a function of age in the dog, Behav. Neurosci. 1995;109(5):851–585]. We have now extended these findings by testing a large number of dogs on three different variations of the DNMP paradigm to evaluate different aspects of spatial learning and memory. Our results indicate that: (1) aged dogs show impaired spatial learning compared to young dogs, (2) aged dogs display spatial working memory deficits compared to young dogs, (3) young dogs have a greater maximum working spatial memory capacity than old dogs and (4) we can use the DNMP paradigm to cognitively categorize different subsets of aged dogs. These data indicate that the DNMP paradigm can serve as a valuable tool to evaluate age-dependent cognitive dysfunction in the canine.

The acetylcholinesterase inhibitor, ENA 713 (Exelon), attenuates the working memory impairment induced by scopolamine in an operant DNMTP task in rats.

The disruption of working memory in the delayed non-matching to position (DNMTP) task by the muscarinic antagonist, scopolamine, is considered to be a model of the spatial working memory deficit in Alzheimer's disease (AD) patients. To investigate whether ENA 713 (Exelon) (0.1, 0.5 mg/kg, IP), an acetylcholinesterase inhibitor, would reverse the effects of scopolamine in the DNMTP task. Male Lister Hooded rats were trained to criterion in an operant DNMTP task (0- to 16-s delay intervals) before receiving vehicle, scopolamine (0.05 mg/kg, SC) alone, ENA 713 (0.1, 0.5 mg/kg, IP) alone, or combinations of scopolamine and ENA 713, in two variations of the task - with and without barriers inserted between the food magazine and the two levers. Barriers were inserted to prevent the use of positional strategies to perform the task, since this behaviour may confound the conclusions of the effect of drugs on working memory. It was found that: (i) scopolamine significantly reduced choice accuracy delay-dependently in both test situations while modifying non-mnemonic measures of task performance delay-independently, indicating an impairment of working memory; (ii) ENA 713 (0.5 mg/kg) significantly attenuated the scopolamine-induced impairment of working memory and significantly reduced the scopolamine-induced changes in some non-mnemonic measures of task performance; (iii) the presence of barriers did not alter the effects of scopolamine and ENA 713 on working memory. ENA 713 reversed the working memory deficit induced by scopolamine. These results are consistent with the attenuation of learning and memory disruptions due to cholinergic dysfunction by ENA 713 in other preclinical assays, and predict a drug-induced improvement in working memory in AD patients.

Analysis of the automated delayed nonmatching-to-position task: The effects of changing contiguity between stimulus, response and reinforcement, and of providing a salient spatial cue within the apparatus

The present report examines two factors that may affect the acquisition and performance of a delayed nonmatching to position (DNMP) task. Both of these concern the design and layout of the apparatus. The first is the contiguity between stimulus, response and reinforcement while the second concerns the impact of asymmetry within the behavioural apparatus. In the standard version of the task, food rewards are dispensed at a central well, equidistant from the stimuli to be discriminated and from the site of the animals' responses. The present experiment demonstrated that acquisition of the task is significantly quicker when there is greater continguity between the stimuli and rewards i.e. when rats are reinforced in the same location as where they respond. We also studied the potential impact of the fact that the standard two-lever operant chamber is asymmetrical as the transparent access door is typically at the side of the box i.e. adjacent to one lever. By comparing test chambers with or without single Plexiglas walls we found clear evidence that the door/wall provides a salient cue that aids DNMP performance. This casts light on the nature of the actual memory demands in the DNMP task.

Differential effects of three 5-HT receptor antagonists on the performance of rats in attentional and working memory tasks

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-HT 1 and 5-HT 2 as well as the 5-HT 5–7 receptors, with varying degrees of selectivity, and ketanserin binds at the 5-HT 2A receptors rather selectively. None of these agents bind to any significant extent to 5-HT 3 or 5-HT 4 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-HT 2A 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.

Contrasting effects of systemic and intracerebral infusions of the 5-HT 1A receptor agonist 8-OH-DPAT on spatial short-term working memory in rats

The present study compared the effects of systemic 8-OH-DPAT (0.05, 0.1 and 1.0 mg/kg) with intra-raphe and intra-hippocampul infusions of 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT) (10, 30 100 ng) on delayed non-matching-to-position (DNMP) performance in rats. The highest dose of 8-OH-DPAT administered systemically impaired DNMP performance in a delayindependent manner, increased premature responding and increased response bias. Infusions of 8-OH-DPAT (100 ng) into the median raphé nucleus improved performance accuracy, independent of delay whilst having no effect on any other response measure. Infusions of 8-OH-DPAT into the dorsal raphe nucleus had no effect on performance at any dose tested. Infusions of 8-OH-DPAT into the dorsal hippocampus produced a small impairment in performance which was also independent of delay. However, this decrement in performance accuracy was not accompanied by any changes in other response measures. These findings demonstrate a dissociation between the effects of stimulation of pre- and post-synaptic 5-HTIA receptors on performance of a DNMP task although the changes in performance cannot be accounted for by changes in mnemonic function.