Spatial Working Memory In Rats Research Articles

Ventral hippocampal dopamine D 1 and D 2 systems and spatial working memory in rats

The hippocampus has long been known to be important for memory function. However, the involvement of hippocampal dopamine systems with memory has received little attention. In the current study, dopamine D 1 and D 2 hippocampal receptor system involvement with memory was assessed in female Sprague–Dawley rats by local infusion of D 1 and D 2 agonists and antagonists into the ventral hippocampus. Working memory performance was assessed on the radial-arm maze. Neither the D 1 agonist dihydrexidine (1.1–10 μg/side) nor the D 1 antagonist SCH 23390 (0.19–1.67 μg/side) was effective in significantly altering radial-arm maze choice accuracy. In contrast, there were significant and opposite effects of D 2 agonist and antagonist treatments. The D 2 agonist quinpirole caused a significant ( P<0.05) dose-related improvement in choice accuracy over a dose range of 1.1–10 μg/side. In a complementary fashion, the D 2 antagonist raclopride caused a significant ( P<0.05) dose-related choice accuracy deficit over a range of 0.19–1.67 μg/side. This study provides clear evidence that hippocampal D 2 activity is positively related to working memory performance, while evidence for D 1 systems is less compelling. Dopamine D 2 receptors in the ventral hippocampus were shown to have important influences on spatial working memory. In a consistent pattern of effects ventral hippocampal infusion of the D 2 agonist quinpirole improved working memory performance in the radial-arm maze, while ventral hippocampal infusion of the D 2 antagonist raclopride impaired performance.

Blockade of NMDA receptors located at the dorsomedial prefrontal cortex impairs spatial working memory in rats.

We investigated the effects of NMDA and muscarinic acetylcholine receptor blockade in the rostral part of dorsomedial (dmPFC) and dorsolateral prefrontal cortex (dlPFC) on spatial working memory (SWM) (delayed non-matching to position task (DNMTP)). The NMDA antagonist, CPP (0.01, 0.03, 0.1 and 0.3 microg/hemisphere) and the muscarinic antagonist, scopolamine (10 microg/hemisphere) were locally infused into the brain of male Wistar rats. In the mPFC CPP 0.1 microg disrupted SWM delay-dependently and CPP 0.3 microg caused a delay-independent performance deficit. Scopolamine disrupted non-cognitive performance, but did not affect SWM accuracy. In the dlPFC, scopolamine or lower doses of CPP did not affect SWM accuracy, but CPP 0.3 microg disrupted non-cognitive performance. We concluded that the NMDA receptors in the dmPFC regulate SWM processes, whereas the muscarinic receptors in the dmPFC mediate non-cognitive performance in the DNMTP task.

Effects of piracetam on the performance of rats in a delayed match-to-position task

1. 1. The influence of acute and chronic treatment with piracetam on spatial working memory of rats was examined. A new version of an operant chamber “delayed match-to-position task” was used, in which the animals had to visit one randomly baited box out of three boxes (“choice boxes”) in a front panel. Hereafter a delay period began, in which the subjects had to visit an alcove in the back panel (“reference box”). At the end of the delay the animals should return to the front panel and choose the same choice box that was baited before the delay, thereby obtaining a reward. 2. 2. Rats were trained to a stable level of performance, measured as per cent correct responses during sessions of 20 trials. Additionally, the time spent between leaving the choice box and entering the reference box was recorded. Results were obtained from a single group of rats tested repeatedly under different experimental conditions. 3. 3. Injections of scopolamine (0.6 mg/kg) significantly reduced the percentage of correct choices and increased the time spent to reach the reference box. The impairment of correct choices was reversed after chronic treatment with piracetam (250 mg/kg). However, the same treatment did not reverse the effect of scopolamine on the time performance. 4. 4. Scopolamine also induced an increase of repetitive errors (a measure of perseverance), and the chronic treatment with piracetam caused full reversal of this increase. These results represent the first observation of a piracetam induced reversal of scopolamine impairments in a working memory test. 5. 5. In normal animals not treated with scopolamine, acute injection of piracetam had no effect compared to saline injected controls, but chronic treatment with the nootropic significantly enhanced working memory performance. The drug did not affect the time used to reach the reference box. 6. 6. The resulting data suggest that piracetam has distinct effects on working memory depending on the mode of treatment (acute versus chronic).

Nicotinic antagonist administration into the ventral hippocampus and spatial working memory in rats

Nicotinic acetylcholine receptors are important for maintaining optimal memory performance. In order to more fully characterize the involvement of nicotinic systems in memory, the contributions of nicotinic acetylcholine receptor subtypes were investigated. This study targeted the α7 and α4 β2 nicotinic receptors in the ventral hippocampus, an area known to be important for spatial working memory. Antagonists of α7 and α4 β2 receptors were locally infused into the ventral hippocampus of rats and the effects on memory were examined with the radial-arm maze. The subtype-specific competitive antagonists infused into separate groups of rats were methyllycaconitine citrate (an α7 antagonist) and dihydro- β-erythroidine hydrobromide (an α4 β2 antagonist). Their effects on radial-arm maze performance were contrasted with the non-specific competitive antagonist, d-tubocurarine chloride. Significant deficits in radial-arm maze choice accuracy performance were found at 78.7 μg/side for methyllycaconitine and at 106.9 μg/side for dihydro- β-erythroidine. Increased response latency was also seen at these doses. Tubocurarine induced seizures at doses previously reported to have no effect. Wet dog shakes were seen in most rats at 0.1 μg/side with tubocurarine, 26.3 μg/side with methyllycaconitine and 106.9 μg/side with dihydro- β-erythroidine. This study suggests that both α7 and α4 β2 nicotinic acetylcholine receptor subtypes are involved in working memory formation and that the hippocampus is a critical site for nicotinic cholinergic involvement in memory function, though the high doses of antagonists needed to produce the memory impairment may have had less than completely specific effects.

Clozapine reverses the spatial working memory deficits induced by FG7142 in monkeys

The atypical neuroleptic, clozapine, has been shown to have encouraging, but mixed, effects on prefrontal cortical (PFC) cognitive deficits in schizophrenia, a stress-exacerbated disorder involving dopamine (DA) dysregulation. The current study examined the effects of acute clozapine pretreatment on the spatial working memory deficits induced by the pharmacological stressor, FG7142, in monkeys. Previous research has shown that FG7142 impairs spatial working memory in rats and monkeys through excessive DA receptor stimulation in the PFC (Murphy et al. 1996). Lower clozapine doses (1-3 mg/kg p.o.) reversed the FG7142-induced spatial working memory deficits, whereas doses in the clinical range (e.g., 6 mg/kg, p.o.) did not improve cognitive function in most animals. Clozapine alone produced a dose-related impairment in delayed response performance. These results from nonhuman primates suggest that the clozapine doses commonly used to treat schizophrenia may not be optimal for treating the PFC cognitive deficits associated with this illness.

Cognitive enhancers in theory and practice: studies of the cholinergic hypothesis of cognitive deficits in Alzheimer's disease

The current status of the cholinergic hypothesis of cognitive dysfunction in Alzheimer's disease is reviewed in the context of recent attempts to alleviate specific cognitive impairments produced in rats by excitotoxic lesions of basal forebrain neurons by treatment with cholinergic agents. AMPA-induced lesions of the nucleus basalis region in rats produce profound and relatively specific reductions in neocortical markers of cholinergic function but fail to affect performance in many tests of memory and learning in rats. However, such lesions produce specific deficits in responding accurately in a test of visual attentional performance, which are reversed dose-dependently by treatment with systemic physostigmine or nicotine. Analogous improvements have been reported in a clinical trial of the anticholinesterase tacrine in patients with Alzheimer's disease. By contrast, AMPA-induced lesions of the medial septum produce profound reductions in hippocampal acetylcholine and accompanying delay-dependent deficits in a delayed non-matching-to-position procedure which measures spatial working memory in rats. This impairment is shown to be reversed to some extent by treatment with low doses of physostigmine.The results are discussed in terms of the multivariate nature of the neurochemical pathology of Alzheimer's disease and attendant limitations in the use of the cholinergic strategy. The cognitive costs, as well as benefits, of cognitive enhancers are discussed, as well as the need to broaden our therapeutic approach to other neurotransmitter systems and other neurodegenerative disorders.

Candidates for cognitive enhancer extracted from medicinal plants: paeoniflorin and tetramethylpyrazine

A traditional Chinese medicine, Shimotsu-to, consisting of four herbs: Japanese angelica root, cnidium rhizome, peony root and rehmannia root, has been reported to improve spatial working memory in rats. The present results indicate that Paeoniflorin and tetramethylpyrazine (TMP) extracted from peony root and cnidium rhizome, respectively, are candidates for cognitive enhancer.

Spatial working memory is preserved in rats treated with anabolic-androgenic steroids

The effects of anabolic-androgenic steroid (AAS) compounds on spatial working memory were evaluated in male rats. Thirty days of administration of a high dose of three individual AAS compounds (17α-methyltestosterone, methandrostenolone, or testosterone cypionate) had no effects on spatial memory or motivation as tested on a delayed non-match-to-sample radial arm maze task. Administration of these AAS compounds at doses within the human abuse range does not impair spatial working memory in rats.

Nicotinic, muscarinic and dopaminergic actions in the ventral hippocampus and the nucleus accumbens: effects on spatial working memory in rats

Acetylcholine (ACh) systems have been widely shown to be important for memory. In particular, ACh hippocampal neurons are critical for memory formation, though ACh innervation of other areas such as the nucleus accumbens may also be important. There has also been increasing interest in ACh and dopaminergic (DA) interactions with regard to short-term spatial memory. In a series of studies, we have found that ACh and DA agonists and antagonists given systemically interact to influence memory. The critical neural loci of these interactions are not currently known. In the present study, we used local infusion techniques to examine the role of ACh and DA transmitter systems in the nucleus accumbens and the ventral hippocampus on radial-arm maze (RAM) working memory performance. Into the nucleus accumbens of rats, we infused the nicotinic ACh agonist nicotine, the nicotinic ACh antagonist mecamylamine, the DA agonist apomorphine, or the DA antagonist haloperidol. Into the ventral hippocampus, we infused nicotine, mecamylamine, the muscarinic ACh agonist pilocarpine, or the muscarinic ACh antagonist, scopolamine. The nicotinic ACh and DA interaction was tested by a hippocampal infusion of mecamylamine alone or together with the DA D 2 agonist quinpirole given via subcutaneous injection. The results confirmed that both nicotinic and muscarinic ACh receptors in the ventral hippocampus play a significant role in spatial working memory. Blockade of either nicotinic or muscarinic ACh receptors caused significant impairments in RAM choice accuracy. However, infusion of either nicotinic or muscarinic agonists failed to improve choice accuracy. The interaction of DA D 2 systems is different with hippocampal nicotinic blockade than with general nicotinic blockade. Systemic administration of quinpirole potentiated the amnestic effect of mecamylamine infused into the ventral hippocampus, whereas it was previously found to reverse the amnestic effect of systemically administered mecamylamine. In contrast to the significant effects of mecamylamine in the hippocampus, no effects were found after infusion into the nucleus accumbens. Nicotine also was not found to have a significant effect on memory after intra-accumbens infusion. Neither the DA agonist apomorphine nor the DA antagonist haloperidol had a significant effect on memory after infusion into the nucleus accumbens. This study provides support for the involvement of nicotinic and muscarinic receptors in the ventral hippocampus in memory function. Ventral hippocampal nicotinic systems have significant interactions with D 2 systems, but these differ from their systemic interactions. In contrast, nicotinic ACh and DA systems in the nucleus accumbens were not found in the current study to be important for working memory performance in the RAM.

Nicotinic, muscarinic and dopaminergic actions in the ventral hippocampus and the nucleus accumbens: effects on spatial working memory in rats

Acetylcholine (ACh) systems have been widely shown to be important for memory. In particular, ACh hippocampal neurons are critical for memory formation, though ACh innervation of other areas such as the nucleus accumbens may also be important. There has also been increasing interest in ACh and dopaminergic (DA) interactions with regard to short-term spatial memory. In a series of studies, we have found that ACh and DA agonists and antagonists given systemically interact to influence memory. The critical neural loci of these interactions are not currently known. In the present study, we used local infusion techniques to examine the role of ACh and DA transmitter systems in the nucleus accumbens and the ventral hippocampus on radial-arm maze (RAM) working memory performance. Into the nucleus accumbens of rats, we infused the nicotinic ACh agonist nicotine, the nicotinic ACh antagonist mecamylamine, the DA agonist apomorphine, or the DA antagonist haloperidol. Into the ventral hippocampus, we infused nicotine, mecamylamine, the muscarinic ACh agonist pilocarpine, or the muscarinic ACh antagonist, scopolamine. The nicotinic ACh and DA interaction was tested by a hippocampal infusion of mecamylamine alone or together with the DA D2 agonist quinpirole given via subcutaneous injection. The results confirmed that both nicotinic and muscarinic ACh receptors in the ventral hippocampus play a significant role in spatial working memory. Blockade of either nicotinic or muscarinic ACh receptors caused significant impairments in RAM choice accuracy. However, infusion of either nicotinic or muscarinic agonists failed to improve choice accuracy. The interaction of DA D2 systems is different with hippocampal nicotinic blockade than with general nicotinic blockade. Systemic administration of quinpirole potentiated the amnestic effect of mecamylamine infused into the ventral hippocampus, whereas it was previously found to reverse the amnestic effect of systemically administered mecamylamine. In contrast to the significant effects of mecamylamine in the hippocampus, no effects were found after infusion into the nucleus accumbens. Nicotine also was not found to have a significant effect on memory after intra-accumbens infusion. Neither the DA agonist apomorphine nor the DA antagonist haloperidol had a significant effect on memory after infusion into the nucleus accumbens. This study provides support for the involvement of nicotinic and muscarinic receptors in the ventral hippocampus in memory function. Ventral hippocampal nicotinic systems have significant interactions with D2 systems, but these differ from their systemic interactions. In contrast, nicotinic ACh and DA systems in the nucleus accumbens were not found in the current study to be important for working memory performance in the RAM.

Hippocampal and amygdaloid involvement in nonspatial and spatial working memory in rats: effects of delay and interference.

Parametric manipulations of the task demand were used to examine the role of the hippocampus and amygdala in nonspatial and spatial working memory in rats. Hippocampal lesions produced an immediate and long-lasting impairment of nonspatial working memory in an operant task. The memory deficits increased as the delay interval and the amount of proactive interference increased. Hippocampal lesions severely impaired spatial working memory in spatial alternation. Extensive postoperative testing reduced the magnitude of impairment of nonspatial but not spatial working memory. Amygdaloid lesions did not impair any aspect of performance in 2 tasks. The results suggest that the hippocampus, but not the amygdala, is involved in working memory and the task demand is a critical determinant for observing impairments of nonspatial working memory following hippocampal lesions.

Hippocampal and amygdaloid involvement in nonspatial and spatial working memory in rats: Effects of delay and interference.

Hippocampal and amygdaloid involvement in nonspatial and spatial working memory in rats: Effects of delay and interference.

Peony and its major constituent, paeoniflorin, improved radial maze performance impaired by scopolamine in rats

A traditional Chinese medicine, Shimotsu-to has been shown to improve spatial working memory in rats. Shimotsu-to consists of four herbs, Japanese angelica root, cnidium rhizome, peony root, and rehmannia root. In the present study, the effects of aqueous extracts of each component herb on scopolamine (0.3 mg/kg)-induced spatial working memory disruption were examined using an eight-arm radial maze task in rats. Among the four component herbs, peony root extract (0.25 and 1 g dried herb/kg, PO) exhibited the most potent antagonizing effect on the scopolamine disruption of the choice accuracy. Japanese angelica root extract ( 1 g dried herb/kg, PO) also significantly attenuated the scopolamine disruption, whereas neither cnidium rhizome nor rehmannia root affected it. Paeniflorin (0.01–1 mg/kg, PO), a major constitutent of peony root, dose-dependently attenuated the scopolamine-induced impairment in the choice accuracy. Scopolamine (0.3 mg/kg, IP) significantly decreased the acetylcholine contents in the hippocampus, cortex, and striatum. Although paeoniflorin alone did not affect the acetylcholine content decrease in the acetylcholine content in the striatum, but not in the hippocampus or cortex. These data suggest that peony root mainly contributes to the cognitive enhancing effect of Shimotsu-to and that paeoniflorin may be one of the active constituents of peony root.

Panax ginseng extract improves scopolamine‐induced deficits in working memory performance in the T‐maze delayed alternation task in rats

AbstractThe effects of Panax ginseng water extract on spatial working memory disruption induced by scopolamine were examined using a T‐maze delayed alternation task in rats. Scopolamine (0.025–0.1 mg/kg, i.p.) dose‐dependently impaired the maze performance, and physostigmine (0.4 mg/kg) significantly reversed the scopolamine (0.1 mg/kg)‐induced performance deficits. Ginseng extract (0.5–4.0 g dried root/kg) orally administered 60 min before testing dose‐dependently improved the maze performance disrupted by scopolamine (0.1 mg/kg). Ginseng extract given for 7 days in drinking water (2.0 and 4.0 g/kg/day) also exhibited dose‐dependent reversal of the scopolamine‐induced performance deficits. These data indicate the beneficial effects of ginseng extract on spatial working memory in rats.

The competitive NMDA antagonist AP5, but not the non-competitive antagonist MK801, induces a delay-related impairment in spatial working memory in rats

Rats were trained to alternate responses on a discrete trial working memory task on a T-maze. In Experiment 1, the rats were then matched for choice accuracy and allocated to three treatment groups. These were: implantation of osmotic minipumps for intraventricular infusion of either (a) 15 mM D-2-amino-5-phosphonopentanoic acid (AP5) or (b) artificial cerebrospinal fluid (VEH); and an unoperated control group (UNOP). In Phase 1 we assessed alternation performance with a minimal delay between responses: the UNOP and VEH rats continued to choose accurately; the AP5 rats showed an impairment of choice accuracy, but recovered over days. In Phase 2 a 20-s delay between responses was enforced, and choice accuracy was assessed following injections either of saline or of Milacemide HCl (10 mg/kg). There was now a severe and enduring impairment of choice accuracy in the AP5 group, but Milacemide injections did not affect performance in any of the treatment groups. In Experiment 2 rats were trained in a similar way, and then given intraperitoneal injections of MK801 or of physiological saline in a within-subjects design and tested for T-maze performance with a minimal or a 20-s delay between responses. In the first Phase, MK801 was given 10-min before behavioural testing commenced; in the second Phase, it was given 28-40 min before behavioural testing commenced. The outcome depended critically on the time between drug injection and testing. There was a significant drug-induced impairment of choice accuracy in both Phases; but in Phase 1 there was no impairment in testing with a minimal retention interval and an impairment with a 20-s retention both retention intervals. We conclude that AP5, but not MK801, interferes with temporary memory storage in a delay-dependent manner.

Opiate antagonists enhance the working memory of rats in the radial maze

Two experiments tested the influence of the opiate antagonists naloxone and naltrexone on the spatial working memory of rats in a 12-arm radial maze. In Experiment 1, ten rats were serially forced to visit six randomly selected arms, then were removed from the maze for delays of either 30, 60, or 240 minutes, and then returned to the maze for a free-choice memory test with all 12 arms available. Five minutes into the delay, rats were injected intraperitoneally (IP) with either physiological saline or naloxone (1 mg/kg). When injected with naloxone the rats revisited forced-choice arms less often than when injected with saline during a subsequent free-choice test. In Experiment 2, twelve rats showed a similar facilitation of working memory when injected with the opiate antagonists naltrexone (0.3 mg/kg) and naloxone (1 mg/kg) in comparison to a saline control condition. These findings demonstrate the beneficial effects that opiate antagonists exert on working memory-based performance in the radial maze. They may also resolve conflicting reports about the influence of opiate antagonists on radial maze performance, by suggesting that the choice of measurement and testing conditions are crucial for detecting these effects in working memory procedures.

Effects of amygdaloid and amygdaloid-hippocampal lesions on object recognition and spatial working memory in rats.

Neurotoxic lesions of the amygdala did not affect the postoperative acquisition of a nonspatial test of object recognition (delayed nonmatching to sample) even when retention delays were increased from 0 s to 20 or 60 s, or when test stimuli were deliberately repeated within a session. Although these amygdaloid lesions did not alter forced-choice spatial alternation, they slightly increased neophobic responses to novel foods and environments. In contrast, combined amygdalohippocampal (A + H) lesions impaired performance on the object recognition task when the retention intervals were increased beyond 0 s and when test stimuli were repeated within a session. The A + H rats were also severely impaired on the spatial alternation task, and they showed reduced neophobia. Comparisons with a previous study show that damage to the amygdala or hippocampus does not affect object recognition, whereas A + H damage produces clear deficits.

Effects of amygdaloid and amygdaloid-hippocampal lesions on object recognition and spatial working memory in rats.

Effects of amygdaloid and amygdaloid-hippocampal lesions on object recognition and spatial working memory in rats.

Spatial working memory in rats: Effects of monoaminergic antagonists

To assess the possible involvement of the monoaminergic neurotransmitters norepinephrine, dopamine and serotonin in the maintenance of spatial working memory rats were treated with antagonists 0 or 2 hr after completing the first 4 choices in an 8 arm maze. Haloperidol (0.25–1 mg/kg), when administered 2 hr after Choice 4, produced a small but consistent impairment in performance on retention tests given 5 hr after the first 4 choices. This deficit closely resembled natural forgetting in terms of the type of errors committed. By contrast, haloperidol in the same doses given 0 hr after Choice 4 or 3 hr before the first 4 choices did not affect retention. Likewise treatment with propranolol (10–20 mg/kg), phentolamine (5–20 mg/kg) or methysergide (5–15 mg/kg) did not impair spatial memory, regardless of when these drugs were injected within the session. Evidently dopaminergic neuronal systems are important in the maintenance of normal spatial working memory.

A multiple choice apparatus for electrophysiological investigations of spatial working memory in rats

A multiple choice apparatus, minimizing the rat's movements and thus simplifying brain stimulation and/or recording in working memory experiments, consists of a dodecagonal enclosure (30 cm diameter, 100 cm high) with a horizontal platform assuming either an upper or a lower position, 43 or 65 cm below the top of the wall, respectively. The platform is moved between these two levels by a pneumatic system controlled by solid-state programming circuits. Each wall segment contains a choice window, 7 cm above the upper floor level, providing access to a recessed feeder. When the platform with a food-deprived rat moves into the upper position, the animal opens the hinged shutter of one window and gets the pellet. Five seconds later, a self-locking relay marks the visited window and the floor descends to the low position where it remains for a predetermined interval (e.g. 20 s), until it is raised again. The above cycle repeats as a long as different windows are chosen. When a choice is directed to an already visited window (error), the floor returns to the low position at once. During one trial, the animal is allowed 12 choices and the number of errors (i.e. choices directed to already entered windows) is recorded. In spite of the great reduction of kinaesthetic and vestibular signals and the almost complete elimination of visual extramaze cues, the working memory performance is similar to that in analogous radial maze.