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)     

Failure to down regulate NMDA receptors in the striatum and nucleus accumbens associated with neuroleptic-induced dyskinesia

The syndrome of vacuous chewing movements (VCMs) in rats is similar in many respects to tardive dyskinesia (TD) in humans. Both syndromes are characterized by delayed onset of persistent orofacial dyskinesias in a sub-group of subjects chronically treated with neuroleptics. Using the rat model, we examined the role of NMDA receptor-mediated corticostriatal neurotransmission in the expression of VCMs. Rats were treated for 36 weeks with haloperidol decanoate or vehicle and then withdrawn for an additional 28 weeks. Chronic persistent VCMs were induced in one subgroup of treated animals (+VCM), but not in another group (-VCM). Rats from +VCM, -VCM groups and vehicle-treated controls were selected for post mortem studies (n = 12 to 14 per group). NMDA receptor levels were assessed using [3H]-MK-801 binding in sections from the mid-striatum and nucleus accumbens. Chronic haloperidol treatment produced a marked reduction of NMDA receptor binding levels throughout the striatum and nucleus accumbens. Post hoc comparisons demonstrated that -VCM rats had lower NMDA receptor binding levels than +VCM and vehicle-treated controls. Ventromedial striatum and nucleus accumbens core were the most affected areas. These findings suggest that down-regulation of striatal NMDA receptor binding levels may protect against the expression of neuroleptic-induced dyskinesia.     

Involvement of mechanisms dependent on NMDA receptors, nitric oxide and protein kinase A in the hippocampus but not in the caudate nucleus in memory

The effects of the NMDA receptor antagonist AP5, the nitric oxide synthase (NO) inhibitor NO-arg or the protein kinase A (PKA) inhibitor KT5720 on memory were evaluated. Rats bilaterally implanted in the CA1 region of the dorsal hippocampus were trained and tested in a step-down inhibitory avoidance task, and rats unilaterally implanted in the left posteroventral region of the caudate nucleus were trained and tested in a cued water maze task. Previous findings from this and other laboratories had found that lesions or pharmacological treatments of these sites significantly altered memory of these two tasks. Immediately after training, animals received intrahippocampal or intracaudate 0.5 microliter microinfusions of saline, AP5, NO-arg or KT5720. All three drugs impaired retention of inhibitory avoidance, but did not affect retention of the cued water maze. The findings suggest that NMDA receptor-, NO- and PKA-mediated processes in the dorsal hippocampus, but not in the caudate nucleus, are involved in memory.     

Muscarinic receptor antagonism of the nucleus accumbens core causes avoidance to flavor and spatial cues.

Pharmacological blockade of muscarinic receptors in the nucleus accumbens reduces food intake and instrumental behaviors that are reinforced by food delivery. Nucleus accumbens muscarinic antagonism may specifically suppress the hedonic or reinforcing effects of food, thus blocking its capacity to direct behavior. Alternatively, muscarinic receptor blockade may cause a negative hedonic state that interferes with appetitive learning and food intake. In these experiments, rats received infusions of scopolamine methyl bromide (10 μg/0.5 μl) into the nucleus accumbens core, following exposure to a novel flavor of liquid diet (Experiment 1) or prior to being placed into a place preference apparatus (Experiment 2). In both experiments, nucleus accumbens muscarinic receptor antagonism caused subsequent avoidance of the paired cue (flavor or spatial location). This effect was specific to cholinergic manipulation; no conditioned taste avoidance was observed after pairing the novel flavor with nucleus accumbens core antagonism of N-methyl-D-aspartate, dopamine D?, or opioid receptors (Experiment 3). These experiments confirm previous reports of a critical role for striatal acetylcholine in modulating goal-directed behaviors, but suggest caution when interpreting behavioral effects of pharmacological manipulation of striatal acetylcholine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Microinfusions of neurotensin antagonist SR 48692 within the nucleus accumbens core impair spatial learning in rats.

The involvement of neurotensin (NT) within the nucleus accumbens core (NAC) in behavior has been sparsely investigated. Moreover, little is known of what role NT within the ventral striatum has on spatial learning. The present study investigated whether NT receptors in the NAC are implicated in learning of spatial information. Male Long-Evans rats were trained on a food search spatial learning task. Rats were microinfused with either NT antagonist SR 48692 (50 nM/0.5 =L) or saline in the NAC before each training session. Rats treated with SR 48692 made more reference and working memory errors during the acquisition of spatial learning than did rats infused with saline. These results suggest that NT receptors contribute to NAC-mediated spatial learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pretraining does not ameliorate spatial learning deficits induced by intrahippocampal infusion of AP5.

Previous studies show discrepancies concerning the effects of pretraining on spatial learning deficits induced by blockade of the N-methyl-d-aspartate (NMDA) receptor. These inconsistencies might be attributed to the differences in the nature of the pretraining tasks and the method of blocking NMDA receptors. In the present study, the authors pretrained rats in a spatial water maze task. The authors then trained them with a novel spatial task in a novel environment under chronic blockade of hippocampal NMDA receptors by intrahippocampal infusion of 2-amino-5-phosphonopentanoic acid (AP5) using osmotic pumps. Although the rats had acquired the basic techniques needed to solve a water-maze spatial task during pretraining, those given high or low doses of AP5 showed acquisition deficits. As the spatial pretraining failed to ameliorate the acquisition deficits of a new task in a novel environment, it was suggested that NMDA receptors were necessary in forming spatial representations. Because neither dose of AP5 affected the performance of a spatial task in the retention phase, sensory motor disturbances could not have caused these deficits. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The contribution of NMDA receptors in the dorsolateral striatum to egocentric response learning.

The present study examined the effects of the N-methyl-D-aspartate (NMDA) competitive antagonist, 2-amino-5-phosphonopentanoic acid (AP-5), injected into the dorsolateral striatum on the acquisition and reversal learning of a response discrimination. Male Long-Evans rats were tested across 2 consecutive days in a modified cross-maze. An infusion of either saline or AP-5 (5 or 25 nM) occurred 5 min prior to testing. In acquisition rats learned to turn left or right. In reversal learning rats learned to turn in the opposite direction. An AP-5 infusion at 25 nmol, but not 5 nmol, impaired response acquisition. Neither AP-5 dose impaired response reversal learning. The results suggest that NMDA receptors in the dorsolateral striatum are critical for the initial learning of an egocentric response discrimination. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Selective memory impairments produced by transient lidocaine-induced lesions of the nucleus accumbens in rats.

Reversible lidocaine-induced lesions of the nucleus accumbens (NAC) impaired performance on the spatial win-stay, but not on the cued win-stay, radial arm maze task. Pretraining lesions on the former task did not affect foraging for 4 pellets during either the training or test phases. In contrast, lesions given prior to the test phase significantly disrupted retrieval of 4 pellets on the 8-arm maze. Comparable deficits also were observed in rats trained to forage for 4 pellets on an 8-arm maze without prior win-shift experience. State-dependent drug effects were ruled out by replicating the disruptive effects of lidocaine infusions into the NAC on spatial win-shift performance in rats receiving this treatment prior to both training and test phases. These results suggest that the NAC may interact with the hippocampus to guide foraging behavior requiring memory of previous spatial locations on a maze. (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)     

A differential involvement of the shell and core subterritories of the nucleus accumbens of the rats in memory processes.

The role of the core and the shell subterritories of the nucleus accumbens in conditioned freezing and spatial learning was investigated by means of selective N-methyl-D-aspartate lesions. Shell-lesioned rats showed reduced conditioned freezing to context and a tendency toward reduced freezing to the discrete stimulus compared with controls. However, lesions of the core did not modify the freezing response either to the context or to the discrete stimuli. Although spatial memory, as assessed by a water-maze paradigm, was not disrupted by the lesions, in a 4-arm baited, 4-arm unbaited radial-arm maze paradigm, the shell-lesioned rats showed selective deficits in working memory, but not in reference memory. In contrast, core-lesioned rats showed no memory deficits. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cytogenetics and molecular genetics in multiple myeloma

The striatum of the human brain has a highly differentiated neurochemical architecture visible in stains for many of the neurotransmitter-related molecules present in the striatum. The distributions for these chemical markers have never been analyzed comprehensively. We compared the distributions of multiple neurochemical markers in a serial-section analysis of the caudate nucleus, the putamen, and the ventral striatum in normal human brains. The cholinergic system was identified with choline acetyltransferase (ChAT). The organization of the cholinergic fiber system was compared with that of striatal systems expressing immunoreactivity for calbindin D28k, met-enkephalin, substance P, tyrosine hydroxylase, and parvalbumin. Each striatal region analyzed displayed a unique neurochemical organization. In the dorsal caudate nucleus, the distribution of all markers followed the classical striosome/matrix organization as previously reported. In the dorsal putamen, ChAT-staining was less intense, and striosomes were delineated primarily by unstained fiber bundles. In the ventral caudate nucleus/nucleus accumbens region, the boundaries of ChAT-stained regions were not always visible with stains for calbindin, enkephalin, and substance P. The ventral putamen displayed a similar organization, except in its lateral part, where ChAT-poor regions were often found adjacent to, rather than in register with, regions expressing low levels of the other markers (calbindin, enkephalin, substance P, and tyrosine hydroxylase). Our findings suggest that, in addition to the classical striosome-matrix organization visible in the dorsal caudate nucleus and putamen, there is further neurochemical differentiation in a large ventral part of the caudate nucleus and putamen and in the ventral striatum-nucleus accumbens proper. The more complex relationships among the different neurochemical systems in the ventral striatum may reflect the increase in size in the primate of striatal regions associated with association and limbic cortex.     

Spatial localization in the Morris water maze in rats: Acquisition is affected by intra-accumbens injections of the dopaminergic antagonist haloperidol.

Previous studies (e.g., G. E. Ploeger et al; see record 1993-20962-001) showed that low doses of systemically injected haloperidol affected spatial learning in the Morris water maze. This study investigated effects of intra-accumbens injections of haloperidol on spatial learning. To control for motivation and sensorimotor coordination, the researchers trained rats to escape onto a visible platform. Low doses (50–200 ng) of haloperidol impaired spatial learning, whereas escaping on a visible platform was undisturbed. The 500-ng dose of haloperidol completely blocked acquisition because of combined learning and motor impairments. Retrieval of an acquired escape response was unaffected by 500 ng haloperidol. The data show that mesolimbic dopaminergic activity is involved in the acquisition of spatial localization. The results are related to studies demonstrating the involvement of the nucleus accumbens in cue-directed behaviors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of Hippocampus and Medial Caudate Nucleus Lesions on Memory for Direction Information in Rats.

A delayed matching-to-sample task was designed to assess memory for direction information in rats. During the study phase, rats traversed a maze arm oriented in 1 of 3 directions. After a delay period, a test phase was presented that required a choice between the study phase direction and a foil direction. Once rats reached a learning criterion, probe trials suggested that normal rats favor the use of direction, rather than turning response, information and use vestibular feedback. Rats were then given hippocampus, medial caudate nucleus (MCN), or cortical control lesions. Unlike control rats, those with hippocampus and MCN lesions exhibited marked impairments when retested. However, all rats were able to learn a direction discrimination task. These results suggest that the hippocampus and MCN support processes associated with short-term memory for direction information. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Functional dissociation within the caudate nucleus of rats.

Reports results of 3 experiments with a total of 134 male albino rats. Ss with posteroventral caudate nucleus lesions were impaired, relative to controls, on 1-way, 2-way, and passive avoidance conditioning; anterodorsal caudate lesions interfered only with 2-way and passive avoidance learning. The anterodorsal group was significantly more impaired than the posteroventral group on the 2-way task, and there were also important differences in passive avoidance learning. Enhancement of positive and negative cues in a 2-way avoidance task selectively benefited the anterodorsal group. It is concluded that the caudate nucleus was functionally dissociated with respect to avoidance conditioning. The importance of the caudate nucleus in motor control and spatial orientation is discussed. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Posttraining paradoxical sleep in rats is increased after spatial learning in the Morris water maze.

The role of posttraining paradoxical sleep (PS) in spatial or nonspatial learning in the Morris water maze was evaluated. Sprague-Dawley rats were given a 12-trial training session in either the hidden or the visible platform versions of the task. Subgroups then underwent paradoxical sleep deprivation (PSD) beginning at different times after training. Rats with PSD imposed from 14 hr after spatial training had poorer retest scores than any other group. Other rats, implanted with electrodes to permit continuous recording of sleep electroencephalography, were found to undergo a prolonged period of elevated PS after spatial training. By contrast, rats trained in the nonspatial version of the water maze task did not show retention deficits after PSD or elevated PS after training. These results support a role for PS in spatial, but not nonspatial, learning in the Morris water maze. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

What do comparative studies of inbred mice add to current investigations on the neural basis of spatial behaviors?

In the present article a number of comparative lesion studies in two inbred strains of mice (C57BL/6 and DBA/2) with different levels of radial maze performance are reviewed. The effects of lesions in several brain areas on maze learning were investigated, thus revealing strain differences in the neural circuitry subserving spatial cognition. Results showed that the hippocampus and parietal cortex appear to be involved in the control of radial maze learning in both C57 and DBA mice, although in a strain-dependent fashion. Lesions in other structures such as the medial frontal cortex and the amygdala only affected spatial learning in the C57 strain. Lastly, the results showed some improvement in radial maze performance in DBA mice with nucleus accumbens lesions. The data highlight the variability in the neural mechanisms subserving well-differentiated levels of spatial performance. The contribution of inbred mice to our general understanding of the neural basis of spatial cognition is discussed.     

Detailed behavioral analysis of water maze acquisition under systemic NMDA or muscarinic antagonism: Nonspatial pretraining eliminates spatial learning deficits.

A detailed behavioral analysis of water-maze acquisition showed that the N-methyl-{d}-aspartate (NMDA) antagonist NPC17742 and the muscarinic antagonist scopolamine caused sensorimotor disturbances in behaviors required for maze performance and that these correlated with acquisition impairments in both hidden and visible platform versions of the maze in male rats. Behavioral disturbances included thigmotaxic swimming, swimming over and deflecting off the platform, abnormal swim behavior, and hyperactivity. Rats familiar with the behavioral strategies involved in the task performed normally under NPC17742 or scopolamine. The results indicated that drug-induced sensorimotor disturbances contributed to poor acquisition scores in naive rats. NMDA or muscarinic activity may contribute to but do not appear to be essential for spatial learning in the water maze. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Double dissociation of fornix and caudate nucleus lesions on acquisition of two water maze tasks: Further evidence for multiple memory systems.

Examined the effect of lesions of the caudate nucleus or fimbria-fornix on the acquisition of 2 water maze tasks. In both tasks, 2 rubber balls with different visual patterns were used as cues. The correct cue was attached to a submerged rectangular platform and could be mounted by an animal to escape the water. The incorrect cue was attached to a thin round pedestal and could not be mounted. In a spatial version of the task, the correct cue was located in the same quadrant of the maze on all trials, whereas the visual pattern on the cue was varied from trial to trial. Lesions of the fornix, but not the caudate nucleus, impaired acquisition of this spatial task in relation to control animals. In a simultaneous visual discrimination version of the task, the correct cue on all trials was one with a specific visual pattern, and the spatial location of the correct cue was varied from trial to trial. Lesions of the caudate nucleus, but not the fornix, impaired acquisition of this visual discrimination task in relation to control animals. The double dissociation observed supports the hypothesis that the hippocampus and caudate nucleus are parts of systems that differ in the type of memory they mediate. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Selective immunotoxic lesions of basal forebrain cholinergic cells: Effects on learning and memory in rats.

Male Long-Evans rats were given injections of either 192 IgG-saporin, an apparently selective toxin for basal forebrain cholinergic neurons (LES), or vehicle (CON) into either the medial septum and vertical limb of the diagonal band (MS/VDB) or bilaterally into the nucleus basalis magnocellularis and substantia innominata (nBM/SI). Place discrimination in the Morris water maze assessed spatial learning, and a trial-unique matching-to-place task in the water maze assessed memory for place information over varying delays. MS/VDB-LES and nBM/SI-LES rats were not impaired relative to CON rats in acquisition of the place discrimination, but were mildly impaired relative to CON rats in performance of the memory task even at the shortest delay, suggesting a nonmnemonic deficit. These results contrast with effects of less selective lesions, which have been taken to support a role for basal forebrain cholinergic neurons in learning and memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Unilateral striatal grafts induce behavioral and electrophysiological asymmetry in rats with bilateral kainate lesions of the caudate nucleus.

Rats (n?=?11) with bilateral kainate lesions of the caudate nucleus and subsequent unilateral transplantation of embryonic striatal tissue into the damaged area preferred 4 months later to reach for food with the forepaw contralateral to the graft. No such asymmetry was observed in lesioned, nontransplanted (n?=?8) or unoperated (n?=?5) control rats. Good integration of the graft with the host brain was indicated by the finding that cortical spreading depression did not enter the lesioned caudate nucleus but did penetrate into the lesioned caudate with the graft almost as regularly as in intact rats. Behavioral asymmetry produced by unilateral grafts in bilaterally lesioned animals reveals the effects of transplantation with more sensitivity than the graft-induced compensation of the asymmetries caused by unilateral lesions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)