Task-dependent role for dorsal striatum metabotropic glutamate receptors in memory

The effect of post-training intradorsal striatal infusion of metabotropic glutamate receptor (mGluR) drugs on memory consolidation processes in an inhibitory avoidance (IA) task and visible/hidden platform water maze tasks was examined. In the IA task, adult male Long-Evans rats received post-training intracaudate infusions of the broad spectrum mGluR antagonist α-methyl-4-carboxyphenylglycine (MCPG; 1.0, 2.0 mM/0.5 μL), the group I/II mGluR agonist 1-aminocyclopentane-1,3-carboxylic acid (ACPD; 0.5 or 1.0 μM/0.5 μL), or saline immediately following footshock training, and retention was tested 24 h later. In the visible- and hidden-platform water maze tasks, rats received post-training intracaudate infusions of ACPD (1.0 μM), MCPG (2.0 mM), or saline immediately following an eight-trial training session, followed by a retention test 24 h later. In the IA task, post-training infusion of ACPD (0.5 and 1.0 μM) or MCPG (1.0 and 2.0 mM) impaired retention. In the IA and visible-platform water maze tasks, post-training infusion of ACPD (1.0 μM), or MCPG (2.0 mM) impaired retention. In contrast, neither drug affected retention when administered post-training in the hidden-platform task, consistent with the hypothesized role of the dorsal striatum in stimulus-response habit formation. When intradorsal striatal injections were delayed 2 h post-training in the visible-platform water maze task, neither drug affected retention, indicating a time-dependent effect of the immediate post-training injections on memory consolidation. It is hypothesized that MCPG impaired memory via a blockade of postsynaptic dorsal striatal mGluR's, while the impairing effect of ACPD may have been caused by an influence of this agonist on presynaptic “autoreceptor” striatal mGluR populations.     

Norepinephrine infused into the basolateral amygdala posttraining enhances retention in a spatial water maze task

Recent evidence indicates that the amygdala plays a role in modulating memory processes in other brain regions. For example, posttraining intra-amygdala infusions of amphetamine enhanced memory in both spatial and cued training water maze tasks; these tasks are known to depend on the integrity of the hippocampus and caudate nucleus, respectively. To determine whether this modulation is dependent on noradrenergic activation within a subregion of the amygdala (the basolateral nucleus), the present study examined the effects of posttraining microinfusions (0.2 microl) of norepinephrine or propranolol into the basolateral amygdala immediately following training in a spatial version of the water maze task. Rats received a four-trial training session on each of 2 consecutive days. On the third day, rats were given a 60-s probe test in the absence of a platform. Retention latencies obtained on the second training day revealed that norepinephrine dose-dependently enhanced retention for the location of the hidden platform. In contrast, propranolol significantly impaired retention. Probe trial analysis revealed that rats treated with 0.25 microg norepinephrine demonstrated a selective spatial bias for the training platform location relative to all other groups. These findings are consistent with others and support the view that the basolateral amygdala has a role in modulating memory storage by interacting with other brain regions.     

Post-training cyclooxygenase-2 (COX-2) inhibition impairs memory consolidation

Evidence indicates that prostanoids, such as prostaglandins, play a regulatory role in several forms of neural plasticity, including long-term potentiation, a cellular model for certain forms of learning and memory. In these experiments, the significance of the COX isoforms cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in post-training memory processes was assessed. Adult male Long-Evans rats underwent an eight-trial (30-sec intertrial interval) training session on a hippocampus-dependent (hidden platform) or dorsal striatal–dependent (visible platform) tasks in a water maze. After the completion of training, rats received an intraperitoneal injection of the nonselective COX inhibitor indomethacin, the COX-1–specific inhibitor piroxicam, the COX-2–specific inhibitor N-[2-cyclohexyloxy-4-nitrophenyl]-methanesulfonamide (NS-398), vehicle (45% 2-hydroxypropyl-β-cyclodextrin in distilled water), or saline. On a two-trial retention test session 24 h later, latency to mount the escape platform was used as a measure of memory. In the hidden platform task, the retention test escape latencies of rats administered indomethacin (5 and 10 mg/kg) or NS-398 (2 and 5 mg/kg) were significantly higher than those of vehicle-treated rats, indicating an impairment in retention. Injections of indomethacin or NS-398 that were delayed 2 h post-training had no effect on retention. Post-training indomethacin or NS-398 had no influence on retention of the visible platform version of the water maze at any of the doses administered. Furthermore, selective inhibition of COX-1 via post-training piroxicam administration had no effect on retention of either task. These findings indicate that COX-2 is a required biochemical component mediating the consolidation of hippocampal-dependent memory.     

D2 dopamine receptor blockade immediately post-training enhances retention in hidden and visible platform versions of the water maze

Considerable evidence shows that post-training administration of dopamine agonists can enhance memory through actions on consolidation processes, but relatively little is known regarding the effects of dopamine antagonists on consolidation. These experiments investigated the effects of post-training systemic administration of the D2 receptor antagonist sulpiride on consolidation of memory for two versions of the Morris water maze task. Rats trained in either the hidden (spatial) or visible (cued) platform version received a subcutaneous injection of sulpiride or vehicle immediately following training. Retention testing 48 hr later revealed that relative to vehicle controls, sulpiride reduced platform latencies in both task versions, suggesting that like dopamine agonists, sulpiride can also have memory-enhancing effects.     

Differential interaction of platelet-activating factor and NMDA receptor function in hippocampal and dorsal striatal memory processes

The interaction between platelet activating factor (PAF) and NMDA receptor function in hippocampal and dorsal striatal memory processes was examined. In both a hidden and a visible platform water maze task, peripheral post-training injection of MK-801 (0.05 mg/kg) impaired memory. Post-training intrahippocampal infusions of PAF (1.0 microg/0.5 microl) enhanced memory in the hidden platform task, while intradorsal striatal infusion of PAF (1.0 microg/0.5 microl) enhanced memory in the visible platform task. The memory impairing effects of post-training injection of MK-801 was blocked by concurrent intrahippocampal infusion of PAF. In contrast, post-training injection of MK-801 blocked the memory enhancing effects of concurrent intradorsal striatal infusion of PAF. The results suggest that (1) the memory enhancing effects of intracerebral PAF infusion involve an interaction with NMDA receptor function, and (2) the nature of this interaction may represent a differential mechanism mediating the distinct roles of the hippocampus and dorsal striatum in cognitive memory and stimulus-response habit formation, respectively.     

Effects of Posttraining Intrahippocampal Injections of Platelet-Activating Factor and PAF Antagonists on Memory

The present experiments examined the effects of posttraining intrahippocampal injections of the degradative enzyme-resistant methylcarbamyl analog of the bioactive phospholipid platelet-activating factor (mc-PAF) and the platelet-activating factor (PAF) receptor antagonists BN52021 and BN 50730 on memory in male Long-Evans rats trained in a hidden platform version of the Morris water maze. Following an eight-trial training session, rats received a unilateral intrahippocampal injection of mc-PAF (0.5, 1.0, or 2.0 μg/0.5 μl), lyso-PAF (1.0 μg/0.5 μl), the cell surface PAF receptor antagonist BN 52021 (0.25, 0.5, or 1.0 μg/0.5 μl), the intracellular PAF receptor antagonist BN 50730 (2.0, 5.0, or 10.0 μg/0.5 μl), or vehicle (50% DMSO in 0.9% saline; 0.5 μl). On a retention test conducted 24 h after training, the escape latencies of rats administered mc-PAF (1.0 or 2.0 μg) were significantly lower than those of the vehicle-injected controls, demonstrating a memory-enhancing effect of mc-PAF. Injections of lyso-PAF, a structurally similar metabolite of PAF, had no influence on memory, indicating that the memory-enhancing effect of mc-PAF is not caused by membrane perturbation by the phospholipid. The retention test escape latencies of rats administered BN 52021 (0.5 μg) and BN 50730 (5.0 or 10 μg) were significantly higher than those of the controls, indicating a memory impairing effect of both PAF antagonists. When mc-PAF, BN 52021, or BN 50730 was administered 2 h posttraining, no effect on retention was observed, indicating a time-dependent effect of the neuroactive substances on memory storage. The findings suggest a role for endogenous PAF in hippocampal-dependent memory processes.     

Acute exposure to a 50 Hz magnetic field impairs consolidation of spatial memory in rats

This study was planned to evaluate the effect of an exposure to magnetic fields on consolidation and retrieval of hippocampus dependent spatial memory using a water maze. In Experiments 1 and 2, rats were trained in a hidden version (spatial) of water maze task with two blocks of four trials. The retention of spatial memory was evaluated 48 h later. Exposure to a 50 Hz 8 mT, but not 2 mT magnetic fields for 20 min immediately after training impaired retention performance. The same time exposure shortly before retention testing had no effect. In Experiment 3, rats were trained in a cued version of water maze with two blocks of four trials. Exposure to magnetic field at 8 mT for 20 min immediately after training did not impair retention performance. These findings indicate that acute exposure to a 50 Hz magnetic field at 8 mT for short time can impair consolidation of spatial memory.     

Post-training infusion of glutamate into the bed nucleus of the stria terminalis enhanced inhibitory avoidance memory: An effect involving norepinephrine

This study examined an interaction between glutamate and norepinephrine in the bed nucleus of the stria terminalis (BNST) in modulating affective memory formation. Male Wistar rats with indwelling cannulae in the BNST were trained on a one-trial step-through inhibitory avoidance task and received pre- or post-training intra-BNST infusion of glutamate, norepinephrine or their antagonists. Results of the 1-day test indicated that post-training intra-BNST infusion of dl-2-amino-5-phosphonovaleric acid (APV) impaired retention in a dose- and time-dependent manner, while infusion of glutamate had an opposite effect. Co-infusion of 0.2 μg glutamate and 0.02 μg norepinephrine resulted in marked retention enhancement by summating non-apparent effects of the two drugs given at a sub-enhancing dose. The amnesic effect of 5.0 μg APV was ameliorated by 0.02 μg norepinephrine, while the memory enhancing effect of 1.0 μg glutamate was attenuated by 5.0 μg propranolol. These findings suggest that training on an inhibitory avoidance task may alter glutamate neurotransmission, which by activating NMDA receptors releases norepinephrine to modulate memory formation via β adrenoceptors in the BNST.     

MK-801 improves retention in aged rats: implications for altered neural plasticity in age-related memory deficits

Alterations in N-methyl-d-aspartate receptor (NMDAR)-dependent synaptic plasticity, characteristic of aged rodents, may contribute to impaired memory with advanced age. The purpose of the current research was to examine whether NMDARs contribute to rapid forgetting on a spatial memory task. Aged (22-24 months) and adult (3-6 months) male Fischer 344 rats received 18 training trials, over a period of 3 to 4 h, on the spatial version of the Morris water maze. Immediately after training, a standard free-swim probe trial was administered to assess the acquisition of spatial bias, which was determined by the percent of time spent in the goal quadrant and the number of platform crossings. Rats then received injections of the noncompetitive NMDAR antagonist, (+)-10, 11-dihydro-5methyl-5H-dibenzo(a,b)cycloheptene-5,10 imine (MK-801, 0. 05 mg/kg, i.p.), or a vehicle injection of equal volume. Approximately 24 h later, rats were administered a second free-swim probe trial to assess retention of spatial bias. All age/drug groups exhibited a spatial bias on the acquisition probe, with adults generally outperforming the aged rats. On the retention probe, this spatial bias continued to be shown by adult rats, regardless of treatment. For the aged group, in contrast, only MK-801-injected rats maintained a spatial bias on the retention probe, suggesting that NMDAR activity may be involved in rapid forgetting during aging. Because blockade of NMDARs also may impair new learning, which may, in turn, protect previously stored information from retroactive interference, rats in a second experiment received post-training injections of scopolamine (0.05 mg/kg), a compound known to inhibit learning. However, scopolamine did not enhance retention in the aged group, consistent with the hypothesis that MK-801 influenced memory in aged rats through its actions on NMDAR-dependent synaptic plasticity.     

Involvement of the posteroventral caudate-putamen in memory consolidation in the Morris water maze

Male Sprague-Dawley rats implanted with bilateral intracerebral guide cannulae were trained in the standard hidden platform version of the Morris water maze and given immediate posttraining infusions of the D2 dopamine receptor antagonist sulpiride (10.0 or 100.0 ng/side) or saline vehicle into the posteroventral caudate-putamen. Retention was tested 2 days later with a probe trial. Sulpiride-treated rats spent less time swimming near the trained platform location and more time in the periphery of the maze than controls, although their latency to reach the trained platform location was not significantly affected. The pattern of results suggests that whereas the posteroventral caudate-putamen seems to be involved in consolidation of memory in the Morris water maze, it may be involved in memory for procedural aspects of the task in a manner distinct from that of other brain regions such as the hippocampus.     

Enhancement of the Post-training Cholinergic Tone Antagonizes the Impairment of Retention Induced by a Nitric Oxide Synthase Inhibitor in Mice

The present experiments examined the role of the central cholinergic system in the memory impairment induced by post-training administration of a nitric oxide synthase (NOS) inhibitor in mice. Male Swiss mice received a one-trial inhibitory avoidance training (0.8 mA, 50 Hz, 1-s footshock) followed immediately by an ip injection of the NOS inhibitor -N^G-nitroarginine methyl ester ( -NAME; 100 mg/kg). Retention (cut-off time, 300 s) was tested 48 h after training. The administration of -NAME results in memory impairment for the inhibitory avoidance task. The effects of -NAME (100 mg/kg, ip) on retention were reversed in a dose-related manner by the centrally acting anticholinesterase physostigmine (35, 70, or 150 μg/kg, sc) administered 30 min after the NOS inhibitor. Further, -NAME (100 mg/kg, ip)-induced memory impairment was completely antagonized by the centrally acting muscarinic cholinergic agonist oxotremorine (OTM; 25, 50, or 100 μg/kg, sc) when given 30 min after -NAME. The peripherally acting anticholinesterase neostigmine (150 μg/kg, sc) did not modify the memory-impairing effects of -NAME. These findings suggest that the memory impairment following post-training administration of a NOS inhibitor is mediated, at least in part, by a reduction of the activity of central muscarinic cholinergic mechanisms and are consistent with our previous view that nitric oxide may be involved in post-training neural processes underlying the storage of newly acquired information.     

D1/D5 dopamine receptors modulate spatial memory formation

We investigated the effect of the intra-CA1 administration of the D1/D5 receptor antagonist SCH23390 and the D1/D5 receptor agonist SKF38393 on spatial memory in the water maze. When given immediately, but not 3h after training, SCH23390 hindered long-term spatial memory formation without affecting non-spatial memory or the normal functionality of the hippocampus. On the contrary, post-training infusion of SKF38393 enhanced retention and facilitated the spontaneous recovery of the original spatial preference after reversal learning. Our findings demonstrate that hippocampal D1/D5 receptors play an essential role in spatial memory processing.     

Testosterone fails to reverse spatial memory decline in aged rats and impairs retention in young and middle-aged animals

Recently, the vasopressin (AVP) innervation in the rat brain was shown to be restored in senescent rats following long-term testosterone administration. In order to investigate whether this restoration is accompanied by an improvement in learning and memory, both sham- and testosterone-treated young (4.5 months), middle-aged (20 months), and aged (31 months) male Brown-Norway rats were tested in a Morris water maze. All animals learned to localize a cued platform equally well, indicating that the ability to learn this task was not affected by sensory, motoric, or motivational changes with aging or testosterone treatment. There were no significant differences in retention following cue training. Subsequent training with a hidden platform in the opposite quadrant of the pool (place training) revealed impaired spatial learning in middle-aged and aged animals. Retention following place training was significantly impaired in the sham-treated aged rats as compared with sham-treated young rats. Testosterone treatment did not improve spatial learning nor retention of spatial information, but, on the contrary, impaired retention in young and middle-aged animals. The present results confirm earlier reports on an impairment of spatial learning and memory in senescent rats but fail to support a role of decreased plasma testosterone levels and central AVP innervation in this respect.     

Effects of opiate antagonists on spatial memory in young and aged rats

The effects of post-training opiate antagonist administration on spatial memory were assessed in young and aged male Long Evans rats. In Experiment I rats were trained to visit each arm of an eight-arm radial maze once in a session to obtain a food reward placed at the end of each arm. During training aged rats required significantly more trials to achieve criterion performance when compared to young mature rats. However, administration of the opiate antagonist naloxone (2.0 mg/kg) immediately after each training trial did not significantly alter the rate of achieving accurate performance in either age group. In Experiment II young and aged rats that were previously trained to a comparable criterion on the radial maze were tested on the same maze apparatus in novel spatial environments. When animals were exposed to novel spatial information, the effects of post-trial opiate antagonists were examined using a within-subjects counter-balanced design. In Experiment IIa naloxone (2 mg/kg) enhanced the performance of both young and aged rats. In Experiment IIB naltrexone (1.0 mg/kg) was found to have a comparable effect of enhancing the performance of both age groups. In addition, in Experiment IIb a significant age-related deficit was found in rats tested in novel spatial environments. These results indicate that opiate antagonists are capable of improving memory for new spatial information in both young and aged rats on a task that is sensitive to behavioral deficits during normal aging.     

A Necessity for MAP Kinase Activation in Mammalian Spatial Learning

Although the biochemical mechanisms underlying learning and memory have not yet been fully elucidated, mounting evidence suggests that activation of protein kinases and phosphorylation of their downstream effectors plays a major role. Recent findings in our laboratory have shown a requirement for the mitogen-activated protein kinase (MAPK) cascade in hippocampal synaptic plasticity. Therefore, we used an inhibitor of MAPK activation, SL327, to test the role of the MAPK cascade in hippocampus-dependent learning in mice. SL327, which crosses the blood-brain barrier, was administered intraperitoneally at several concentrations to animals prior to cue and contextual fear conditioning. Administration of SL327 completely blocked contextual fear conditioning and significantly attenuated cue learning when measured 24 hr after training. To determine whether MAPK activation is required for spatial learning, we administered SL327 to mice prior to training in the Morris water maze. Animals treated with SL327 exhibited significant attenuation of water maze learning; they took significantly longer to find a hidden platform compared with vehicle-treated controls and also failed to use a selective search strategy during subsequent probe trials in which the platform was removed. These impairments cannot be attributed to nonspecific effects of the drug during the training phase; no deficit was seen in the visible platform task, and injection of SL327 following training produced no effect on the performance of these mice in the hidden platform task. These findings indicate that the MAPK cascade is required for spatial and contextual learning in mice.     

Spatial information processing consequences of DAMGO injections into the dorsal striatum

The purpose of the present study was to examine the role of the dorsal striatum, and more specifically, the patch region of the dorsal striatum, in mediating spatial learning and memory. To this end, male, Long Evans rats were bilaterally implanted with cannula aimed at the dorsal striatum. Rats were injected with different doses (0, 0.05, 0.5 or 5 microg/0.5 microl) of [3H]-[D-Ala2,MePhe4,Gly-ol5]-enkephalin (DAMGO) into the dorsal striatum daily (Exp. 1) before training on a hidden platform version of the water maze task or during a reversal water maze spatial task (Exp. 2). In both experiments, probe retention tests were given drug free. Results from Exp. 1 showed that intra-striatal injection of the low DAMGO dose (0.05) resulted in enhanced spatial acquisition while the high dose (5.0) produced impairments compared to controls. During the probe test, the low dose group showed better retention of the platform location than controls as well as an enhanced ability to alter their search strategy. In Exp. 2, pretraining alleviated the high dose impairment found in Exp. 1 suggesting a motoric impairment in this group. The low dose group continued to show an enhanced ability to alter their search strategy during the probe test compared to all other groups. The data suggest that the low dose of DAMGO, when injected into the dorsal striatum, eliminates competition with the hippocampus thereby leading to enhanced spatial processing. Alternatively, inhibition of patch-striatal neurons may attenuate a memory decay process. Both alternatives are discussed.     

Involvement of basolateral amygdala alpha2-adrenoceptors in modulating consolidation of inhibitory avoidance memory

These experiments investigated the role of the alpha(2)-adrenoceptors of the basolateral nucleus of the amygdala (BLA) in modulating the retention of inhibitory avoidance (IA). In Experiment 1, male Sprague Dawley rats implanted with bilateral cannulae in the BLA received microinfusions of a selective alpha(2)-adrenoceptor antagonist idazoxan 20 min either before or immediately after training. Retention was tested 48 h later. Idazoxan induced a dose-dependent enhancement of retention performance and was more effective when administered post-training. In Experiment 2, animals received pre- or post-training intra-BLA infusions of a selective alpha(2)-adrenoceptor agonist UK 14,304. The agonist induced a dose-dependent impairment of retention performance and, as with the antagonist treatments, post-training infusions were more effective. These results provide additional evidence that consolidation of inhibitory avoidance memory depends critically on prolonged activation of the noradrenergic system in the BLA and indicate that this modulatory influence is mediated, in part, by pre-synaptic alpha(2)-adrenoceptors.     

Temporary inactivation of the dorsal entorhinal cortex impairs acquisition and retrieval of spatial information

We tested the effects of temporary inactivation of the dorsal entorhinal cortex on spatial discrimination using a conditioned cue preference (CCP) paradigm. The three phases of the procedure were: pre-exposure: unreinforced exploration of the center platform and two adjacent arms of an eight-arm radial maze; training: rats were confined to the ends of the two arms on alternate days – one arm always contained food and the other never contained food; testing: unreinforced exploration of the center platform and the two arms. Rats that received bilateral infusions of saline into the dorsal entorhinal cortex before the training trials or before the test trial spent significantly more time in the arm that previously contained food than in the arm that never contained food, demonstrating that they had acquired and were able to express information that discriminated between the two adjacent maze arms. In contrast, rats that received bilateral, intra-entorhinal infusions of muscimol, a gamma-aminobutyric acid_a (GABA_a) agonist, before either training or testing spent equal amounts of time in the two arms, indicating that they failed to acquire and were unable to express this information. Interactions between the entorhinal cortex and hippocampus in the acquisition and expression of the information required for this discrimination are discussed.     

Long-term effects of prior cocaine exposure on Morris water maze performance

Cocaine addiction is associated with long-term cognitive alterations including deficits on tests of declarative/spatial learning and memory. To determine the extent to which cocaine exposure plays a causative role in these deficits, adult male Long-Evans rats were given daily injections of cocaine (30 mg/kg/day x 14 days) or saline vehicle. Three months later, rats were trained for 6 sessions on a Morris water maze protocol adapted from Gallagher, Burwell, and Burchinal [Gallagher, M., Burwell, R., & Burchinal, M. (1993). Severity of spatial learning impairment in aging: development of a learning index for performance in the Morris water maze. Behavioral Neuroscience, 107, 618-626]. Rats given prior cocaine exposure performed similarly to controls on training trials, but searched farther from the platform location on probe trials interpolated throughout the training sessions and showed increased thigmotaxis. The results demonstrate that a regimen of cocaine exposure can impair Morris water maze performance as long as 3 months after exposure. Although the impairments were not consistent with major deficits in spatial learning and memory, they may have resulted from cocaine-induced increases in stress responsiveness and/or anxiety. Increased stress and anxiety would be expected to increase thigmotaxis as well as cause impairments in searching for the platform location, possibly through actions on ventral striatal dopamine signaling.     

Is the unilateral lesion of the left substantia nigra pars compacta sufficient to induce working memory impairment in rats?

Adult male Wistar rats with a substantia nigra pars compacta (SNc) lesion induced by intranigral administration of 1 micromol 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were used as a model of early phase Parkinson's disease (PD). This lesion caused a partial depletion of striatal dopamine (DA). The animals were submitted to a spatial working memory version of the water maze task in which they had to find a hidden (submersed) platform using online-maintained information that the platform remains in the same place during four consecutive trials, but that it is moved to another place every training day. Left, but not right SNc-lesioned rats were impaired in finding the platform in the second trial. This result suggests that the left SNc plays a key role in spatial working memory. Control experiments ruled out the possibility that motor impairment, sensory neglect, and/or impairment in the mental representation of the contralateral spatial environment had affected performance of the SNc-lesioned rats.