Spatial Reference Memory Task Research Articles

Reversal Of Cognitive Impairment By Pharmacologic Neuroregeneration: A Novel Therapeutic Approach

In addition to neurofibrillary tangles and Aβ plaques, the two histopathological hallmarks, neurogenesis and neuronal plasticity are markedly altered in Alzheimer's disease. While one therapeutic approach, toward which most of the current efforts in the field are being made, is to inhibit neurodegeneration, another is to shift the balance from neurodegeneration to neurogenesis and neuronal plasticity by employing the regenerative capacity of the brain. We have recently shown that an 11-mer peptide, Peptide 6, corresponding to an active region of CNTF, can enhance the dentate gyrus neurogenesis and neuronal plasticity (Chohan et al. 2009).To assess whether treatment with Peptide 6 can reverse cognitive impairment by enhancing neurogenesis and neuronal plasticity before the formation of Aβ plaques and neurofibrillary tangles in 3xTgAD mice. We administered peripherally Peptide 6 or vehicle control for six weeks (daily i.p. 50 nmol/injection) to 7-8 months 3xTgAD mice and WT control animals. At this age the transgenic mice were cognitively impaired but had no Aβ plaques or tangles. After four weeks of treatment, general behavior and learning and memory function were evaluated. At the end of behavioral studies, animals were sacrificed, and the effects of treatment with Peptide 6 on Aβ and tau pathologies and neurogenesis and neuronal plasticity were studied. Treatment with Peptide 6 did not induce weight loss or other side effects known to be caused by CNTF. Instead the Peptide 6 reversed impairments in object discrimination task as well as in spatial reference memory task in transgenic mice. While this treatment had no detectable effect on Aβ and tau pathologies, it enhanced neurogenesis in dentate gyrus, reduced ectopic birth in the granular cell layer, and increased neuronal plasticity in the hippocampus and in the cerebral cortex. These findings, for the first time, demonstrate that pharmacological enhancement of neurogenesis and neuronal plasticity can be sufficient to reverse cognitive impairment in transgenic mouse model of AD pathology.

A novel etiopathogenic mechanism and a disease-relevant non-transgenic rat model of Alzheimer's disease

Alzheimer's disease (AD) is pathologically characterized by the presence of numerous intracellular neurofibrillary tangles and extracellular β-amyloid plaques. Development of rational therapeutical treatments of AD requires the elucidation of the mechanisms that lead to tau protein pathology and β-amyloidosis. We employed an adeno-associated virus serotype 1 (AAV1)-induced expression of the C-terminal fragment (I2CTF) of I2PP2A/SET and infected newborn Wistar rat pups by bilateral intracerebroventricular (ICV) injection with the AAV1- I2CTF. I2CTF, tau phosphorylation and neurodegeneration were studied immunohistochemically and by Western blot. The reference memory of the animals was evaluated by a spatial reference memory task in the water maze. The AAV1- I2CTF induced a decrease in brain protein phosphatase 2A (PP2A) activity, abnormal hyperphosphorylation of tau and neurodegeneration. Furthermore, there was an increase in the level of activated glycogen synthase kinase-3β and enhanced expression of intraneuronal Aβ in AAV1-I2CTF animals. Morris Water Maze behavioral test revealed that infection with AAV1-I2CTF induced a spatial reference memory and memory consolidation deficit. Finally, this cognitive impairment was associated with a decrease in the brain level of pSer133-CREB. This findings of this study suggest (1) a novel etiopathogenic mechanism of AD which is initiated by the cleavage of I2PP2A, producing I2CTF and (2) provide a practical, non-transgenic animal model which is based on an etiopathogenic mechanism of AD.

Chronic treatment with a CNTF peptide enhances neuronal plasticity and alleviates cognitive impairment in 3xTgAD mice

In addition to neurofibrillary tangles and β-amyloid plaques, the two histopathological hallmarks in Alzheimer disease, neurogenesis and neuronal plasticity are markedly altered. While one therapeutic approach, toward which most of the current effort in the field is being made, is to inhibit neurodegeneration, another is to shift the balance from neurodegeneration to neurogenesis and neuronal plasticity by employing the regenerative capacity of the brain. We have recently shown that an 11-mer peptide, Peptide 6, corresponding to an active region of CNTF, can enhance the dentate gyrus neurogenesis and neuronal plasticity and associated cognition in C57Bl6 mice (Chohan et al. 2009). To assess whether Peptide 6 can enhance neurogenesis and neuronal plasticity, and improve cognitive function in a mouse model of AD. We administered peripherally Peptide 6 or saline as a placebo for six weeks (daily i.p. 50 nmol/injection) to 7-8 months 3xTgAD mice and WT control animals. After four weeks of treatment, general behavior and learning and memory function were evaluated. At the end of the treatment, animals were sacrificed, brains dissected, and the effects of treatment with Peptide 6 on neurogenesis and neuronal plasticity studied by immunohistochemistry. Treatment with Peptide 6 did not induce weight loss or other side effects observed previously with CNTF. Instead it restored 3xTgAD mice impairments in object discrimination task as well as in spatial reference memory task. This treatment also restored neurogenesis alterations in 3xTgAD mice dentate gyrus, reduced ectopic birth in the granular cell layer, and increased neuronal plasticity in the hippocampus and in the cerebral cortex. These findings demonstrate that it might be possible to improve cognition of AD patients with a CNTF peptide that has a neurogenic- and neurotrophic-enhancing property.

Methylphenidate affects memory, brain-derived neurotrophic factor immunocontent and brain acetylcholinesterase activity in the rat

Methylphenidate, a psychostimulant that affects both dopaminergic and noradrenergic systems, is one of the most frequently prescribed treatments for attention-deficit hyperactivity disorder. The present study investigated the effects of chronic administration of methylphenidate to juvenile rats on spatial memory, brain-derived neurotrophic factor immunocontent and acetylcholinesterase activity in hippocampus and prefrontal cortex. Rats received intraperitoneal injections of methylphenidate (2.0 mg/kg) once a day, from the 15th to the 45th day of age or an equivalent volume of 0.9% saline solution (controls). Twenty-four hours after the last injection, animals were subjected to testing in the Morris water maze. After that, animals were sacrificed and hippocampus and prefrontal cortex were dissected out for determination of brain-derived neurotrophic factor immunocontent and acetylcholinesterase activity. Chronic administration of methylphenidate provoked cognitive impairments on spatial reference and working memory tasks. A reduction on brain-derived neurotrophic factor immunocontent and increased acetylcholinesterase activity in prefrontal cortex, but not in hippocampus, of rats treated with methylphenidate were also observed. These results suggest that the deficit in spatial memory may be associated to decreased brain-derived neurotrophic factor immunocontent and increased acetylcholinesterase in prefrontal cortex of juvenile rats subjected to methylphenidate administration.

Spatial working memory deficits in GluA1 AMPA receptor subunit knockout mice reflect impaired short-term habituation: Evidence for Wagner's dual-process memory model

Genetically modified mice, lacking the GluA1 AMPA receptor subunit, are impaired on spatial working memory tasks, but display normal acquisition of spatial reference memory tasks. One explanation for this dissociation is that working memory, win-shift performance engages a GluA1-dependent, non-associative, short-term memory process through which animals choose relatively novel arms in preference to relatively familiar options. In contrast, spatial reference memory, as exemplified by the Morris water maze task, reflects a GluA1-independent, associative, long-term memory mechanism. These results can be accommodated by Wagner's dual-process model of memory in which short and long-term memory mechanisms exist in parallel and, under certain circumstances, compete with each other. According to our analysis, GluA1−/− mice lack short-term memory for recently experienced spatial stimuli. One consequence of this impairment is that these stimuli should remain surprising and thus be better able to form long-term associative representations. Consistent with this hypothesis, we have recently shown that long-term spatial memory for recently visited locations is enhanced in GluA1−/− mice, despite impairments in hippocampal synaptic plasticity. Taken together, these results support a role for GluA1-containing AMPA receptors in short-term habituation, and in modulating the intensity or perceived salience of stimuli.

Portal hypertension in 18-month-old rats: Memory deficits and brain metabolic activity

Portal hypertension is a major complication of cirrhosis that frequently leads to a neuropsychiatric disorder that affects cognition. We compared the performance of 18-month-old prehepatic portal hypertensive rats (PH) and 18-month-old normal rats (CO) in spatial short-term and reference memory tasks in the Morris water maze and in active avoidance task. The PH group showed worse spatial short-term memory than the CO group. Also, the PH group tended to perform worse than the CO group in the reference memory task, but it presented a correct acquisition of the active avoidance task. We assessed the brain metabolic activity of the animals by means of cytochrome c-oxidase (COx) histochemistry. We found that the PH group developed prefrontal dysfunction characterized by increased COx activity in this region compared to the CO group. Similar results were found in the medial mammillary nucleus and dentate gyrus, whereas the CA1 area, bed nucleus of the stria terminalis, and supramammillary nucleus showed lower COx activity in the PH group as compared to the CO group. We conclude that the 18-month-old portal hypertensive rats present spatial memory impairment without alteration of implicit learning. This deficit could be related to the alteration of the metabolic activity of the brain regions involved in the processing of spatial memories.

WIN55,212-2 induced deficits in spatial learning are mediated by cholinergic hypofunction

Cannabinoids acting on CB 1 receptors induce learning and memory impairments. However, the identification of novel non-CB 1 receptors which are insensitive to the psychoactive ingredient of marijuana, Δ 9-tetrahydrocannabinol (Δ 9-THC) but sensitive to synthetic cannabinoids such as WIN55,212-2 (WIN-2) or endocannabinoids like anandamide lead us to question whether WIN-2 induced learning and memory deficits are indeed mediated by CB 1 receptor activation. Given the relative paucity of receptor subtype specific antagonists, a way forward would be to determine the transmitter systems, which are modulated by the respective cannabinoids. This study set out to evaluate this proposition by determination of the effects of WIN-2 on acquisition of spatial reference memory using the water maze in rats. Particular weight was given to performance in trial 1 of each daily session as an index of between-session long-term memory, and in trial 4 as an index of within-session short-term memory. Intraperitoneal (i.p.) administration of WIN-2 (1 mg/kg and 3 mg/kg) prior to training impaired long-term, but not short-term memory. This deficit was not reversed by the CB 1 antagonists/inverse agonists Rimonabant (3 mg/kg i.p.) and AM281 (0.5 mg/kg i.p.), but recovered in the presence of the cholinesterase inhibitor rivastigmine (1 mg/kg). Reversal by rivastigmine was specific to WIN-2, as it failed to reverse MK801 (0.08 mg/kg) induced learning impairments. Collectively, these data suggest that in this spatial reference memory task WIN-2 causes a reduction in cholinergic activation, possibly through a non-CB 1-like mechanism, which affects long-term but not short-term spatial memory.

Fractionating spatial memory with glutamate receptor subunit-knockout mice

In recent years, the contribution that different glutamate receptor subtypes and subunits make to spatial learning and memory has been studied extensively using genetically modified mice in which key proteins are knocked out. This has revealed dissociations between different aspects of spatial memory that were not previously apparent from lesion studies. For example, studies with GluA1 AMPAR [AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor] subunit-knockout mice have revealed the presence of a GluA1-dependent, non-associative short-term memory mechanism that is important for performance on spatial working memory tasks, and a GluA1-independent, long-term associative memory mechanism which underlies performance on spatial reference memory tasks. Within this framework we have also studied the contributions of different GluN2-containing NMDARs [NMDA (N-methyl-D-aspartate) receptors] to spatial memory. Studies with GluN2 NMDAR mutants have revealed different contributions from GluN2A- and GluN2B-containing NMDARs to spatial learning. Furthermore, comparison of forebrain- and hippocampus-specific GluN2B-knockout mice has demonstrated that both hippocampal and extra-hippocampal NMDARs make important contributions to spatial memory performance.

Remote spatial memory and the hippocampus: Effect of early and extensive training in the radial maze

In a previous study we showed a temporally graded retrograde amnesia after hippocampal lesions when rats learned a spatial reference memory task in which two types of signals simultaneously indicated the goal arm (shape of the experimental room and extramaze landmarks). To investigate the effect that the navigational demands of the task have on remote memory expression, the same task was used in the present study as in our previous report, but on this occasion the shape of the surroundings was not predictive, which resulted in a highly demanding spatial task. Additionally, animals received extensive training in an early phase to ensure that the task was well learned. Results indicated a profound retrograde amnesia when dorsal hippocampal lesions were made 1 or 70 d after the end of the training (experiments 1 and 2). Using a long period of retraining, however, lesioned animals in the 70-d groups showed progressively more spared memory than the lesioned rats of the 1-d group. Experiments 3 and 4 showed that rats did not learn the above spatial task through an S-R association. Specifically, when animals acquired the task using a single cue (intra- or extramaze), hippocampal lesions did not produce retrograde amnesia. These findings support the possibility that in a highly demanding spatial task, hippocampal lesions produce a performance/navigational impairment that could interfere with the expression of spared remote spatial memory. The long period of retraining, however, seems to partially compensate for this deficit, but only when a long learning-surgery interval is employed.

Role of dentate gyrus in aligning internal spatial map to external landmark

Humans and animals form internal representations of external space based on their own body movement (dead reckoning) as well as external landmarks. It is poorly understood, however, how different types of information are integrated to form a unified representation of external space. To examine the role of dentate gyrus (DG) in this process, we conducted physiological and behavioral experiments using Bax knockout (Bax-KO) mice in which newly generated granule cells continue to accumulate disrupting neural circuitry specifically in the DG. Unlike in wild-type (WT) littermates, spatial firing of hippocampal neurons was completely dissociated from a distinct visual cue and instead, tended to stay constant relative to the recording room in Bax-KO mice. Behaviorally, whereas spatial learning was intact in conventional spatial reference memory tasks, Bax-KO mice were impaired in finding a target location based on visual landmarks when target locations predicted by dead reckoning and visual landmarks were made incongruent. These results provide converging evidence for the role of DG in binding animal's internal spatial map with the sensory information on external landmarks in building a distinct spatial representation for each environment.

Neuroprotective Effect of PACAP on Translational Control Alteration and Cognitive Decline in MPTP Parkinsonian Mice

Parkinson's disease (PD) is characterized by a triade of motor symptoms due to the degeneration of nigrostriatal pathway. In addition to these motor impairments, cognitive disturbances have been reported to occur in PD patients in the early stage of the disease. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin widely used to produce experimental models of PD. In a previous work, we showed that MPTP altered the expression of proteins involved in mTOR antiapoptotic and PKR apoptotic pathways of translational control (TC) in neuroblastoma cells. In the present study, the results indicated that a subchronic MPTP intoxication in mice decreased the dopaminergic neuron number, produced an activation of PKR way and an inhibition of mTOR way of TC especially in striatum and frontal cortex associated with a great activation of PKR in hippocampus. Moreover, in parallel to biochemical analysis, the mnesic disturbances induced by MPTP were characterized in C57Bl/6 mice, by testing their performance in three versions of the Morris Water Maze task. Behavioral results showed that the MPTP lesion altered mice learning of a spatial working memory, of a cued version and of a spatial reference memory task in the water maze. Furthermore, we previously demonstrated that the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) could counteract the MPTP toxicity on TC factors in neuroblastoma cells. Thus, the second objective of our study was to assess the PACAP effect on MPTP-induced TC impairment and cognitive deficit in mice. The pretreatment with PACAP27 by intravenous injections partially protected TH-positive neuron loss induced by MPTP, prevented the MPTP-induced protein synthesis control dysregulation and mnesic impairment of mice. Therefore, our results could indicate that PACAP may be a promising therapeutic agent in Parkinson's disease.

Experimental sleep fragmentation impairs spatial reference but not working memory in Fischer/Brown Norway rats

Sleep fragmentation is a common symptom in sleep disorders and other medical complaints resulting in excessive daytime sleepiness. The present study seeks to explore the effects of sleep fragmentation on learning and memory in a spatial reference memory task and a spatial working memory (WM) task. Fischer/Brown Norway rats lived in custom treadmills designed to induce locomotor activity every 2 min throughout a 24-h period. Separate rats were either on a treadmill schedule that allowed for consolidated sleep or experienced no locomotor activation. Rats were tested in one of two water maze-based tests of learning and memory immediately following 24 h of sleep interruption. Rats tested in a spatial reference memory task (eight massed acquisition trials) with a 24-h follow-up probe trial to assess memory retention showed no differences in acquisition performance but were impaired on the 24 h retention of the platform location. In contrast, the performance of rats tested in a spatial WM task (delayed matching to position task) was not impaired. Therefore, sleep fragmentation prior to testing impairs the ability to retain spatial reference memories but does not impair spatial reference memory acquisition or spatial WM in Fischer-Norway rats.

Short-term effects of an acute exposure to predatory cues on the spatial working and reference memory performance in a subterranean rodent

Spatial memory is important for animals to achieve successful foraging, reproduction, territorial defence and predator avoidance in structurally complex habitats. This cognitive function has been shown to be affected under stress conditions in surface-dwelling rodents. Here we used the Tala's tuco-tuco, Ctenomys talarum , a subterranean rodent that inhabits complex burrow systems, as a study model. This species has a highly developed spatial ability and individuals are regularly exposed to predatory stress while foraging on the surface. We examined the consequences of a single and brief exposure to predatory cues on the spatial working and reference memory performance. We trained wild-caught individuals (32 males, 36 females) in a six-arm radial maze (spatial working memory task) or a longitudinal maze (spatial reference memory task). Once the animals reached a memory performance criterion, they were exposed to a direct predatory cue (immobilization), an indirect predatory cue (cat urine odour) or both cues combined, and their memory performance was evaluated. Exposure to direct and combined predatory cues impaired spatial reference memory, increasing both the latency to achieve the goal and the number of errors during the test. Combined presentation of both predatory cues also negatively affected spatial working memory, but only for latency to achieve the goal. Our results suggest that use of spatial working memory during a predatory attack on the surface allows C. talarum to relocate burrow entries rapidly and hence increases survival probabilities.

Selective Suppression of Hippocampal Ripples Perturbs Learning in a Spatial Reference Memory Task

Selective Suppression of Hippocampal Ripples Perturbs Learning in a Spatial Reference Memory Task

Premarin improves memory, prevents scopolamine-induced amnesia and increases number of basal forebrain choline acetyltransferase positive cells in middle-aged surgically menopausal rats

Conjugated equine estrogen (CEE) is the most commonly prescribed estrogen therapy, and is the estrogen used in the Women's Health Initiative study. While in-vitro studies suggest that CEE is neuroprotective, no study has evaluated CEE's effects on a cognitive battery and brain immunohistochemistry in an animal model. The current experiment tested whether CEE impacted: I) spatial learning, reference memory, working memory and long-term retention, as well as ability to handle mnemonic delay and interference challenges; and, II) the cholinergic system, via pharmacological challenge during memory testing and ChAT-immunoreactive cell counts in the basal forebrain. Middle-aged ovariectomized (Ovx) rats received chronic cyclic injections of either Oil (vehicle), CEE-Low (10 μg), CEE-Medium (20 μg) or CEE-High (30 μg) treatment. Relative to the Oil group, all three CEE groups showed less overnight forgetting on the spatial reference memory task, and the CEE-High group had enhanced platform localization during the probe trial. All CEE groups exhibited enhanced learning on the spatial working memory task, and CEE dose-dependently protected against scopolamine-induced amnesia with every rat receiving the highest CEE dose maintaining zero errors after scopolamine challenge. CEE also increased number of ChAT-immunoreactive neurons in the vertical diagonal band of the basal forebrain. Neither the ability to remember after a delay nor interference, nor long-term retention, was influenced by the CEE regimen used in this study. These findings are similar to those reported previously for 17 β-estradiol, and suggest that CEE can provide cognitive benefits on spatial learning, reference and working memory, possibly through cholinergic mechanisms.

Spatial memory in the Morris water maze and activation of cyclic AMP response element-binding (CREB) protein within the mouse hippocampus

We investigated the spatio-temporal dynamics of learning-induced cAMP response element-binding protein activation/phosphorylation (pCREB) in mice trained in a spatial reference memory task in the water maze. Using immunohistochemistry, we examined pCREB immunoreactivity (pCREB-ir) in hippocampal CA1 and CA3 and related brain structures. During the course of spatial learning over Days 1-9, pCREB-ir progressively increased in hippocampal neurons whereas its level in the dorsal striatum decreased. No significant changes were observed in the prelimbic cortex and lateral amygdala. Mice killed at various time points after the last training session demonstrated two waves of pCREB-ir in CA1 and an early transient CREB phosphorylation in area CA3, lateral amygdala, and prelimbic cortex. We show that CREB phosphorylation and downstream gene Zif268 activation remained sustained in CA1 and CA3 for at least 24 h after extended training (Days 8-9) but not during early training (Day 3). The present results indicate that the strong CA1 CREB phosphorylation observed immediately after training was not related strictly to learning or to memory. In contrast, at 15 min after training, the changes in CA1 CREB phosphorylation state were specifically related to individual learning capability. We suggest that hippocampal-learning specificity of CREB is reflected best by duration, rather than magnitude, of CREB phosphorylation.

Faster forgetting contributes to impaired spatial memory in the PDAPP mouse: Deficit in memory retrieval associated with increased sensitivity to interference?

Two experiments were conducted to investigate the possibility of faster forgetting by PDAPP mice (a well-established model of Alzheimer's disease as reported by Games and colleagues in an earlier paper). Experiment 1, using mice aged 13-16 mo, confirmed the presence of a deficit in a spatial reference memory task in the water maze by hemizygous PDAPP mice relative to littermate controls. However, after overtraining to a criterion of equivalent navigational performance, a series of memory retention tests revealed faster forgetting in the PDAPP group. Very limited retraining was sufficient to reinstate good memory in both groups, indicating that their faster forgetting may be due to retrieval failure rather than trace decay. In Experiment 2, 6-mo-old PDAPP and controls were required to learn each of a series of spatial locations to criterion with their memory assessed 10 min after learning each location. No memory deficit was apparent in the PDAPP mice initially, but a deficit built up through the series of locations suggestive of increased sensitivity to interference. Faster forgetting and increased interference may each reflect a difficulty in accessing memory traces. This interpretation of one aspect of the cognitive deficit in human mutant APP mice has parallels to deficits observed in patients with Alzheimer's disease, further supporting the validity of transgenic models of the disease.

Temporary inactivation of the supramammillary area impairs spatial working memory and spatial reference memory retrieval

The aim of our study was to examine the supramammillary (SuM) area involvement in spatial memory. Sprague–Dawley rats with chronically implanted cannula in the supramammillary area were trained in two spatial memory tasks with different memory demands: reference and working memory. In the spatial reference memory task, the rats received microinjections in the SuM area of tetrodotoxin (TTX) (0.5 ng diluted in 0.5 µL of saline) or saline (0.5 µL). The microinjections were administered 30 min before the spatial training (day 4) (to assess the effect on acquisition) and on the following two days (days 5 and 6) the training was conducted without microinjections (to study the effect on consolidation). On the last training day (day 7), in order to assess the retrieval of spatial information, the rats received the microinjections 30 min before the spatial training. The spatial working memory used was a delayed-matching-to-position (DMTP) task. Spatial training was performed for seven days. During the first three days of the spatial training, the rats achieved a good spatial knowledge and learnt the working memory rule necessary to solve the spatial task. On days 4 and 6, the rats received microinjections to study involvement of the SuM area in working memory. The results showed that temporary inactivation of SuM area impairs both the rat's ability to solve a spatial working memory task with DMTP demands and the recovery of spatial information in a spatial reference memory task. We suggest that SuM area is involved in the rearrangement of spatial information during spatial working memory tasks with DMTP memory demands.

Sex differences in spatial cognition are not caused by isolation housing

Summary In mammals, males typically have better spatial ability than do females. However, most of the data come from laboratory tests and it is possible that factors impacting on the captive animal cause the observed sex differences in spatial cognition. A common influence on cognitive ability is stress, which may have its effect acutely, in the testing situation, or chronically, due to the housing conditions. We used a spatial working and reference memory task (the Morris water maze) to investigate if isolation housing had a differential impact on spatial cognition in male and female rats. Either as juveniles or as adults, rats were housed in pairs or in isolation. We also manipulated the duration of isolation housing. Regardless of housing condition, we found a sex difference in spatial ability only in the youngest rats. However, we found no evidence that isolated rats were spatially impaired relative to pair-housed rats. We also found no difference in body weight, food intake or bar biting behaviour (indicators of welfare in rodents) between pair and isolated rats. We conclude that isolation housing causes insufficient stress to cause sex differences in spatial cognition.

The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates

The scopolamine-reversal model is enjoying a resurgence of interest in clinical studies as a reversible pharmacological model for Alzheimer's disease (AD). The cognitive impairment associated with scopolamine is similar to that in AD. The scopolamine model is not simply a cholinergic model, as it can be reversed by drugs that are noncholinergic cognition-enhancing agents. The objective of the study was to determine relevance of computer-assisted operant-conditioning tasks in the scopolamine-reversal model in rats and monkeys. Rats were evaluated for their acquisition of a spatial reference memory task in the Morris water maze. A separate cohort was proficient in performance of an automated delayed stimulus discrimination task (DSDT). Rhesus monkeys were proficient in the performance of an automated delayed matching-to-sample task (DMTS). The AD drug donepezil was evaluated for its ability to reverse the decrements in accuracy induced by scopolamine administration in all three tasks. In the DSDT and DMTS tasks, the effects of donepezil were delay (retention interval)-dependent, affecting primarily short delay trials. Donepezil produced significant but partial reversals of the scopolamine-induced impairment in task accuracies after 2 mg/kg in the water maze, after 1 mg/kg in the DSDT, and after 50 microg/kg in the DMTS task. The two operant-conditioning tasks (DSDT and DMTS) provided data most in keeping with those reported in clinical studies with these drugs. The model applied to nonhuman primates provides an excellent transitional model for new cognition-enhancing drugs before clinical trials.