N-methyl-D-aspartate receptor-dependent plasticity within a distributed corticostriatal network mediates appetitive instrumental learning.

The effect of microinfusion of the N-methyl-{d}-aspartate (NMDA) antagonist 2-amino-5-phosphonopentanoic acid (AP-5) into the amygdala, medial prefrontal cortex, and dorsal and ventral subiculum on acquisition of a lever-pressing task for food in rats was examined. Serial transmission between the basolateral amygdala and nucleus accumbens core was also examined in an asymmetric infusion design. AP-5 administered bilaterally into either the amygdala or medial prefrontal cortex markedly impaired learning, whereas administration into the dorsal or ventral subiculum had no effect. Unilateral infusion of AP-5 into either the nucleus accumbens core or amygdala was also sufficient to impair learning. These data provide novel evidence for NMDA receptor-dependent plasticity within corticostriatal networks in the acquisition of appetitive instrumental learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

NMDA and D2-like receptors modulate cognitive flexibility in a color discrimination reversal task in pigeons.

Reversal and extinction learning represent forms of cognitive flexibility that refer to the ability of an animal to alter behavior in response to unanticipated changes on environmental demands. A role for dopamine and glutamate in modulating this behavior has been implicated. Here, we determined the effects of intracerebroventricular injections in pigeons' forebrain of the D2-like receptor agonist quinpirole, the D2-like receptor antagonist sulpiride and the N-methyl-d-aspartate receptor antagonist AP-5 on initial acquisition and reversal of a color discrimination task. On day one, pigeons had to learn to discriminate two color keys. On day two, pigeons first performed a retention test, which was followed by a reversal of the reward contingencies of the two color keys. None of the drugs altered performance in the initial acquisition of color discrimination or affected the retention of the learned color key. In contrast, all drugs impaired reversal learning by increasing trials and incorrect responses in the reversal session. Our data support the hypothesis that D2-like receptor mechanisms, like N-methyl-d-aspartate receptor modulations, are involved in cognitive flexibility and relearning processes, but not in initial learning of stimulus-reward association. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Systemic and Prefrontal Cortical NMDA Receptor Blockade Differentially Affect Discrimination Learning and Set-Shift Ability in Rats.

The authors examined discrimination rule learning and extradimensional set-shifting ability in rats given systemic or intracranial injections of the N-methyl-D-aspartate (NMDA) receptor antagonist MK801. Pretraining systemic injections of MK801 impaired both the acquisition of the initial discrimination rule (Set 1) and the shift to the 2nd rule (Set 2). Pretraining intramedial prefrontal cortical (mPFC) administration of MK801 did not impair Set 1 acquisition. Intra-mPFC injection of MK801 was previously found to impair Set 2 acquisition. Impaired Set 2 performance was due to increased cognitive perseveration. The data suggest that discrimination learning in naive subjects requires NMDA receptors outside the mPFC, whereas NMDA receptors within the mPFC are selectively involved in the modification of previous knowledge and/or the inhibition of previously learned responses. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Operant learning requires NMDA-receptor activation in the anterior cingulate cortex and dorsomedial striatum, but not in the orbitofrontal cortex.

Previous research has shown that corticostriatal N-methyl-D-aspartate receptor (NMDAR) activation is necessary for operant learning. NMDAR activation induces plasticity-related intracellular signaling processes leading to gene expression, which are hypothesized to be important steps in codifying the content of learning. Operant learning induces immediate early gene (IEG) expression in key corticostriatal structures, namely the dorsomedial striatum (DMS), the orbitofrontal (OFC), and anterior cingulate cortices (ACC). Both the ACC and OFC send glutamatergic projections to the DMS, which is a crucial site for operant behavior. However, the role of NMDAR activation in these corticostriatal regions in operant learning is unknown. To test this hypothesis, the NMDA antagonist AP-5 (1 μg/0.5 μl) or saline was bilaterally microinjected into the ACC, OFC, and DMS of food-deprived rats just prior to operant learning sessions. NMDAR antagonism in the ACC and DMS impaired the acquisition of lever pressing for sucrose pellets but had no effect on lever pressing once learned. NMDAR blockade in OFC did not significantly impair operant learning, suggesting that NMDAR activation in operant learning is site-specific. These data extend our understanding of the role of NMDA receptors in operant learning and behavior throughout an extended corticostriatal network. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

NMDA receptor antagonism impairs reversal learning in developing rats.

Four experiments examined the effect of dizocilpine maleate (MK-801), a noncompetitive N-methyl-Daspartate (NMDA) receptor antagonist, on reversal learning during development. On postnatal days (PND) 21, 26, or 30, rats were trained on spatial discrimination and reversal in a T-maze. When MK-801 was administered (intraperitoneally) before both acquisition and reversal, 0.18 mg/kg generally impaired performance, whereas doses of 0.06 mg/kg and 0.10 mg/kg, but not 0.03 mg/kg, selectively impaired reversal learning (Experiments 1 and 3). The selective effect on reversal was not a result of sensitization to the second dose of MK-801 (Experiment 2) and was observed when the drug was administered only during reversal in an experiment addressing state-dependent learning (Experiment 4). Spatial reversal learning is more sensitive to NMDA-receptor antagonism than is acquisition. No age differences in sensitivity to MK-801 were found between PND 21 and 30. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spatial learning and performance in the radial arm maze is impaired after N-methyl-{d}-aspartate (NMDA) receptor blockade in striatal subregions.

These experiments addressed the role of striatal N-methyl-{d}-aspartate (NMDA) receptors in spatial behavior in the radial arm maze. Rats treated with the NMDA antagonist D-2-amino-5-phosphonopentanoic acid (AP-5) in the nucleus accumbens core, medial caudate, and posterior caudate were all significantly impaired in acquiring the correct spatial responses. In contrast, rats infused with AP-5 in the nucleus accumbens shell showed little impairment. When rats in all groups had learned the maze and were performing at similar levels, AP-5 had relatively little effect except in the posterior caudate group, where errors and trial times were again increased. These findings demonstrate the importance of NMDA receptor-dependent activity within the accumbens and caudate in spatial learning and performance. The neural processes necessary for adaptive spatial learning in complex environments may recruit multiple cortical systems having specialized functions, which in turn are integrated in widespread striatal regions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of an amygdalo-nigrostriatal pathway in associative learning

The present study examined the role of an amygdalo-nigrostriatal pathway in associative learning. An asymmetrical lesion model was used to test whether a circuit from the amygdala central nucleus to the dorsolateral striatum, via the substantia nigra, is critical for mediating conditioned orienting responses. Rats with an asymmetrical lesion, consisting of neurotoxic removal of central nucleus neurons in one hemisphere and depletion of the dopamine innervation of the dorsolateral striatum in the contralateral hemisphere, failed to acquire conditioned orienting responses. In contrast, the asymmetrical lesion had no effect on spontaneous orienting or learning another response directed to the source of the food unconditioned stimulus in the same task. A second experiment tested the effect of reversible inactivation of the dorsolateral striatum contralateral to a neurotoxic central nucleus lesion on acquisition of the conditioned orienting response. Although inactivation did not affect spontaneous orienting, rats failed to acquire the conditioned orienting response during sessions in which inactivation occurred. Immediately after the inactivation procedure was terminated, however, a significant increase in orienting to the conditioned stimulus was evident. These data support the interpretation that the dorsolateral striatum provides a route for the expression of the conditioned orienting response but is not essential for acquisition of this learned behavior.     

Metabolism of 4,7,10,13,16,19-docosahexaenoic acid in isolated perfused adult and newborn pig eyes

In rats, hippocampal lesions result in impairment of spatial navigation, although other learning abilities remain unaltered. When learning a left/right discrimination task, rats can use a spatial strategy (with external maze landmarks-Situation 1) or are forced to use an egocentric strategy (without external or internal maze cues-Situation 2). Little is known about the extrahippocampal systems involved in the utilization of egocentric strategy. It is suggested that striatum could play an important role in the learning abilities that are spared after hippocampal lesion. The aim of our study was to investigate which strategy is used by rats bearing hippocampal or caudate-putamen lesions in the acquisition of a left/right discrimination task in an elevated T-maze in both Situations 1 and 2. We also investigated the effect of each lesion on the reversal of discrimination in both situations. Acquisition was not altered in any of the situations; however, a transfer test showed that hippocampal-lesioned rats used a different strategy (egocentric) from control animals (spatial) in Situation 1. In addition, reversal of the discrimination was impaired in Situation 2. Caudate-putamen lesion produced a transient effect on reversal of discrimination only in the egocentric task (Situation 2), but did not impair acquisition of the task in either situation, thus suggesting that the animals were able to use either strategy.     

The effect of rat anterior cingulate inactivation on cognitive flexibility.

The present experiment investigated the effects of muscimol injections into the rat dorsal anterior cingulate on the acquisition and reversal learning of a 4-choice odor discrimination. Long-Evans rats were trained to dig in cups that contained distinct odors. In the odor discrimination, one odor cup contained a cereal reinforcement in acquisition whereas a different odor cup contained a cereal reinforcement in reversal learning. The other 2 odor cups were never associated with reinforcement. Bilateral infusions of the gamma aminobutyric acid-A agonist muscimol did not impair acquisition of the odor discrimination but impaired reversal learning in a dose-dependent manner. During reversal learning, dorsal anterior cingulate inactivation did not lead to perseveration but selectively increased errors to the odor cups that were never reinforced. These findings suggest that the dorsal anterior cingulate supports learning when conditions require a shift in choice patterns and may enhance cognitive flexibility by decreasing interference of irrelevant stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The contribution of spatial cues to memory: Direction, but not cue, changes support response reversal learning.

In four experiments, rats were trained on a response problem followed by three reversals. Rats that changed rooms between acquisition and reversals learned the reversals in fewer trials than rats that remained in the same room, even when distal visual cues were limited. Changes in orientation, even in the same room, also facilitated response reversal learning. The advantage observed with changes in orientation across reversals does not appear to be due to differences in local views or to different start positions. Direction changes, but not cue changes, may support response reversal learning by taking advantage of the natural interaction between responses and direction when one map is used. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Triple dissociation of anterior cingulate, posterior cingulate, and medial frontal cortices on visual discrimination tasks using a touchscreen testing procedure for the rat.

Four experiments examined effects of quinolinic acid-induced lesions of the anterior cingulate, posterior cingulate, and medial frontal cortices on tests of visual discrimination learning, using a new "touchscreen" testing method for rats. Anterior cingulate cortex lesions impaired acquisition of an 8-pair concurrent discrimination task, whereas posterior cingulate cortex lesions facilitated learning but selectively impaired the late stages of acquisition of a visuospatial conditional discrimination. Medial frontal cortex lesions selectively impaired reversal learning when stimuli were difficult to discriminate; lesions of anterior and posterior cingulate cortex had no effect. These results suggest roles for the anterior cingulate, posterior cingulate, and medial frontal cortex in stimulus-reward learning, stimulus-response learning or response generation, and attention during learning, respectively. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Olfactory repeated discrimination reversal in rats: Effects of chlordiazepoxide, dizocilpine, and morphine.

Effects of a benzodiazepine (chlordiazepoxide), an N-methyl-D-aspartate receptor antagonist (dizocilpine), and an opiate agonist (morphine) were studied with a procedure designed to assess effects of drugs and other manipulations on nonspatial learning in rats. In each session, rats were exposed to 2 different 2-choice odor-discrimination problems with food reinforcement for correct responses. One problem (performance discrimination) remained the same throughout the study. That is, 1 odor was always correct (S+) and the other was never correct (S-). For the other problem (reversal discrimination), stimuli changed every session. Six different odors were used to program the reversal discrimination; on any given session, S+ was a stimulus that had served as S- the last time it had appeared, S- was a stimulus that had been S+ on its last appearance. Thus, in each session, learning a discrimination reversal could be studied along with the performance of a comparable, but previously learned, discrimination. Chlordiazepoxide interfered with reversal learning at doses that had no effect on the performance discrimination. Morphine and dizocilpine also impaired reversal learning but only at doses that also affected performance of the well-learned performance discrimination. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of the dorsomedial striatum in behavioral flexibility for response and visual cue discrimination learning.

These experiments examined the effects of dorsomedial striatal inactivation on the acquisition of a response and visual cue discrimination task, as well as a shift from a response to a visual cue discrimination, and vice versa. In Experiment 1, rats were tested on the response discrimination task followed by the visual cue discrimination task. In Experiment 2, the testing order was reversed. Infusions of 2% tetracaine did not impair acquisition of the response or visual cue discrimination but impaired performance when shifting from a response to a visual cue discrimination, and vice versa. Analysis of the errors revealed that the deficit was not due to perseveration of the previously learned strategy, but to an inability to maintain the new strategy. These results contrast with findings indicating that prelimbic inactivation impairs behavioral flexibility due to perseveration of a previously learned strategy. Thus, specific circuits in the prefrontal cortex and striatum may interact to enable behavioral flexibility, but each region may contribute to distinct processes that facilitate strategy switching. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pharmacological evidence of the role of dorsal striatum in spatial memory consolidation in mice.

This study investigated the role of dorsal striatum in spatial memory in mice. The mice were tested for their ability to detect a spatial displacement 24 hrs after training. In order to manipulate the dorsal striatum, focal administrations of the N-methyl-D-aspartate (NMDA) antagonist D-2-amino-5 phosphonopentanoic acid (AP-5) were performed immediately after training. AP-5 impaired the mice's ability to detect the spatial change only if their initial position was constant during training and testing. These findings demonstrate that NMDA receptor blockade within the dorsal striatum impairs spatial memory consolidation in a task in which no explicit reward or procedural learning is involved. The results are discussed with reference to a possible selective involvement of this structure in processing spatial information acquired through an egocentric, but not an allocentric, frame of reference. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Inactivation of Dorsolateral Striatum Impairs Acquisition of Response Learning in Cue-Deficient, but Not Cue-Available, Conditions.

Rats received bilateral injections of lidocaine or artificial cerebrospinal fluid (aCSF) into the doisolateral striatum 6 min prior to training in either a plus- or T-shaped maze under cue-poor or cue-available conditions. Lidocaine injections significantly impaired acquisition in the cue-poor environments, but not in the cue-available environments. In addition, aCSF control rats trained in a plus-maze in a cue-poor environment reached criterion much more rapidly than did rats trained in a cue-available environment. These findings suggest that cue availability can permit acquisition of response learning in a manner that is not dependent on activity of the striatum. However, in a cue-poor environment, alternate strategies may be less readily available, revealing more efficient striatal involvement in response learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impaired learning of a color reversal task after NMDA receptor blockade in the pigeon (Columbia livia) associative forebrain (Neostriatum Caudolaterale).

The neostriatum caudolaterale (NCL) in the pigeon (Columba livia) forebrain is a multisensory associative area and a functional equivalent to the mammalian prefrontal cortex (PFC). To investigate the role of N-methyl-{D}-aspartate (NMDA) receptors in the NCL for learning flexibility, the authors trained pigeons in a color reversal task while locally blocking NMDA receptors with {D},{L}-2-2-amino-5phosphorrovalerate (AP-5). Controls received saline injections. AP-5-treated pigeons made significantly more errors and showed significantly stronger perseveration in a learning strategy applied by both groups but were unimpaired in initial learning. Results indicate that NMDA receptors in the NCL are necessary for efficient performance in this PFC-sensitive task, and that they are involved in extinction of obsolete information rather than in acquiring new information. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The contribution of the rat prelimbic-infralimbic areas to different forms of task switching.

The experiments examined the effects of prelimbic-infralimbic inactivation in rats on the acquisition and reversal learning of different discrimination tasks: 2- or 4-choice odor discrimination in Experiments 1 and 2, the shift from 2-choice odor discrimination to 2-choice place discrimination in Experiment 3, and the shift from 2-choice place to 2-choice odor discrimination in Experiment 4. Infusions of 2% bupivacaine did not impair performance in the odor discrimination tests. Prelimbic-infralimbic inactivation did not impair acquisition but did impair the shift from an odor to a place discrimination and vice versa. Analysis of the errors revealed that the deficit was due to perseveration of the previously learned strategy. The selective deficits observed in the odor-place tests suggest that the prelimbic-infralimbic areas enable behavioral flexibility when conditions demand inhibiting the use of one type of attribute information and learning a new type of attribute information. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Visual discrimination and reversal learning in rough-necked monitor lizards (Varanus rudicollis).

Reptile learning has been studied with a variety of methods and has included numerous species. However, research on learning in lizards has generally focused on spatial memory and has been studied in only a few species. This study explored visual discrimination in two rough-necked monitors (Varanus rudicollis). Subjects were trained to discriminate between black and white stimuli. Both subjects learned an initial discrimination task as well as two reversals, with the second reversal requiring fewer sessions than the first. This reduction in trials required for reversal acquisition provides evidence for behavioral flexibility in the monitor lizard genus. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Effects of systemic, intracerebral, or intrathecal administration on an N-methyl-D-aspartate receptor antagonist on associative morphine analgesic tolerance and hyperalgesia in rats.

A flavor paired with morphine shifted to the right the function relating morphine dose to tail-flick latencies and provoked hyperalgesic responses when rats were tested in the absence of morphine. These learned increases in nociceptive sensitivity were not mediated by alterations in tail-skin temperature. Microinjection of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP-5) into the lateral ventricle reversed the hyperalgesic responses but spared the tolerance to morphine analgesia. By contrast, systemic administration of the noncompetitive NMDA receptor antagonist MK-801 or intrathecal infusion of AP-5 reversed the hyperalgesic responses as well as the tolerance to morphine analgesia. The results demonstrate that associatively mediated tolerance to morphine analgesia can co-occur with hyperalgesic responses and are discussed relative to learned activation of endogenous pronociceptive mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hippocampal lesions in rats alter learning about intramaze cues.

In these experiments, we used a new procedure to study cognitive mapping in normal rats and those with hippocampal lesions by observing their behavioral responses to a rearrangement of intramaze cues. Controls learned cognitive maps, and their goal-directed behavior was disrupted by a change in the cue sequence. A comparison of pre- and postoperatively trained rats with hippocampal lesions (HPLs) showed that hippocampal damage prevented the acquisition, but not retrieval, of cognitive maps. HPLs learned a discrimination between mazes as quickly as controls did, but learning did not facilitate the acquisition of maps. The rats with lesions were moderately impaired in a discrimination reversal, but their behavior suggested that they could sometimes interrupt and correct their errors. In summary, controls and HPLs were equally able to run the mazes, but additional testing revealed a dissociation between the learning and performance of the two groups. These data add to our understanding of how normal rats learn about their environment and how HPL damage affects this type of learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)