Sex differences on the competitive place task in the water maze: The influence of peripheral pool time on spatial navigation performance in rats.

This study investigated sex differences on the competitive place version of the Morris water maze task to determine whether potential strategy differences would emerge during any phase of the study but in particular on the competitive place phase. Previous findings indicate that this version of the task is highly sensitive to measures that disrupt NMDA-dependent synaptic plasticity within the hippocampus during memory consolidation (McDonald et al., 2005). The present findings revealed significant sex differences during all phases of the study, including Phase I with standard place training to located a hidden platform/goal, Phase II mass training to a new place with the platform/goal relocated to the diagonally opposite quadrant and Phase III, competitive place probe test with the platform removed to measure spatial behaviour directed at either location. The findings showed no sex difference in escape latency and other standard performance measures during the first two phases, initial place acquisition and mass training to a new location. A very subtle male advantage in visiting both Old and New place locations during the third phase place competition test was observed, however, in the time spent swimming in the periphery of the pool, the pool wall (Zone C - outer third radial distance) was increased for females during all phases of the study, suggesting a general effect may have influenced place location search behaviour of the females. Increased peripheral pool time may represent a female preference for approaching the wall, a local cue. Alternatively, the possibility that increased peripheral swimming/thigmotaxis may represent hormonal influences interacting with strategic preferences were discussed, though no definitive conclusions about sex differences in cognitive-spatial performance or memory consolidation were inferred from the present findings. The findings suggest that mixed results reported in the literature by others may be due in part to an interaction with a persistent peripheral pool swimming response demonstrated in female rats.

Hippocampal development and the dissociation of cognitive-spatial mapping from motor performance.

The publication of a recent article in F1000Research has led to discussion of, and correspondence on a broader issue that has a long history in the fields of neuroscience and psychology.  Namely, is it possible to separate the cognitive components of performance, in this case spatial behavior, from the motoric demands of a task?  Early psychological experiments attempted such a dissociation by studying a form of spatial maze learning where initially rats were allowed to explore a complex maze, termed "latent learning," before reinforcement was introduced.  Those rats afforded the latent learning experience solved the task faster than those that were not, implying that cognitive map learning during exploration aided in the performance of the task once a motivational component was introduced.  This form of latent learning was interpreted as successfully demonstrating that an exploratory cognitive map component was acquired irrespective of performing a learned spatial response under deprivation/motivational conditions.  The neural substrate for cognitive learning was hypothesized to depend on place cells within the hippocampus.  Subsequent behavioral studies attempted to directly eliminate the motor component of spatial learning by allowing rats to passively view the distal environment before performing any motor response using a task that is widely considered to be hippocampal-dependent.  Latent learning in the water maze, using a passive placement procedure has met with mixed results.  One constraint on viewing cues before performing a learned swimming response to a hidden goal has been the act of dynamically viewing distal cues while moving through a part of the environment where an optimal learned spatial escape response would be observed.  We briefly review these past findings obtained with adult animals to the recent efforts of establishing a "behavioral topology" separating cognitive-spatial learning from tasks differing in motoric demands in an attempt to define when cognitive-spatial behavior emerges during development.

Phosphodiesterase inhibition facilitates cognitive restoration in rodent models of age-related memory decline.

BACKGROUND: Previous studies have shown that cyclic nucleotide phosphodiesterase type 5 (PDE5) inhibition with the drugs sildenafil and vardenafil can enhance spatial performance and object recognition in rodent models of learning and memory. OBJECTIVE: We review recent studies on PDE5 inhibition and report novel data that specifically tests the systemic effects of both pharmacological agents in aged rats using two different spatial learning/memory paradigms. METHODS: The 14-unit T-maze was used as a test of egocentric spatial processing that requires rats to learn a series of left/right turns to avoid mild footshock. The Morris water maze is a test of allocentric spatial learning that requires the acquisition of place information to localize a hidden platform relative to distal room cues. RESULTS: In both cases, acquisition (i.e., learning performance) was not improved, however after a one week drug washout period, aged animals demonstrated improved spatial memory retention compared to aged controls, ruling out simple performance effects. CONCLUSIONS: These findings are discussed in relation to recent reports on the use of PDE inhibitors to treat Alzheimer's disease (AD) dementia and age-related memory impairments. While some report promising pre-clinical results, others note that PDE5 may not be an appropriate target in AD due to a lack of localization within critical brain structures where therapeutic activity is needed. Despite these limitations, PDE5 inhibition may produce beneficial effects via several mechanisms that target predisposing risk factors leading to increased incidence of memory impairment in aged individuals and influence memory consolidation mechanisms that preserve long-term retention of cognitive information.

Parallel associative processing in the dorsal striatum: segregation of stimulus-response and cognitive control subregions.

Although evidence suggests that the dorsal striatum contributes to multiple learning and memory functions, there nevertheless remains considerable disagreement on the specific associative roles of different neuroanatomical subregions. We review evidence indicating that the dorsolateral striatum (DLS) is a substrate for stimulus-response habit formation - incremental strengthening of simple S-R bonds - via input from sensorimotor neocortex while the dorsomedial striatum (DMS) contributes to behavioral flexibility - the cognitive control of behavior - via prefrontal and limbic circuits engaged in relational and spatial information processing. The parallel circuits through dorsal striatum interact with incentive/affective motivational processing in the ventral striatum and portions of the prefrontal cortex leading to overt responding under specific testing conditions. Converging evidence obtained through a detailed task analysis and neurobehavioral assessment is beginning to illuminate striatal subregional interactions and relations to the rest of the mammalian brain.

Striatal lesions interfere with acquisition of a complex maze task in rats.

The 14-unit T-maze has proven to be a valuable tool for investigating age-associated memory impairment (AAMI). While another task widely used to evaluate AAMI, the water maze, is primarily used to evaluate allocentric hippocampal-dependent spatial memory, the 14-unit T-maze can assess egocentric procedural memory. Although several brain structures, e.g. hippocampus, parietal cortex, have been implicated in acquisition and retention performance in the 14-unit T-maze, there has been no evaluation of the involvement of the striatum, a brain region implicated in procedural learning and memory. The current study revealed that excitotoxic lesions of the medial or lateral striatum significantly impaired acquisition, as measured by errors and latency, on this task without disruption of motor function. These results indicate that the 14-unit T-maze most likely is requires a large egocentric procedural learning component, and previously observed AAMI may involve age-related dysfunction of the striatum.

A blueberry-enriched diet provides cellular protection against oxidative stress and reduces a kainate-induced learning impairment in rats.

Young male Fischer-344 rats were fed a diet containing 2% blueberry (BB) extract or control diet for at least 8 weeks and then received bilateral hippocampal injections of kainic acid (KA 200 ng/0.5 microl) or phosphate buffered saline (PBS). One week later rats were trained in one-way active footshock avoidance in a straight runway followed the next day by training in a footshock motivated 14-unit T-maze with documented sensitivity to hippocampal glutamatergic manipulations. Based on analyses of several performance variables, KA-treated rats exhibited clearly impaired learning performance; however, the BB diet significantly reduced this impairment. Supporting the behavioral findings, stereological assessment of CA1 pyramidal neurons documented greater neuronal loss in KA-treated controls compared to KA-treated rats on the BB diet. In an in vitro experiment, FaO cells grown in medium supplemented with serum from BB-fed rats had enhanced viability after exposure to hydrogen peroxide. These findings suggest that BB supplementation may protect against neurodegeneration and cognitive impairment mediated by excitotoxicity and oxidative stress.

Combined administration of subthreshold doses of the nitric oxide inhibitor, nitro-L-arginine, and muscarinic receptor antagonist, scopolamine, impairs complex maze learning in rats.

Traditionally, research into the neurobiological mechanisms of age-related memory impairments has focused on single neurotransmitter systems. As normal and abnormal age-related declines in memory function probably involve alterations in more than one system, a more effective approach for elucidating underlying neurobiological changes and resulting impairments may be to evaluate the roles of multiple systems simultaneously. This study evaluated the interaction of the cholinergic and nitric oxide systems in rats on acquisition in the 14-unit T-maze. This task requires learning a series of turns to avoid foot shock, and most likely reflects procedural learning. Administration of scopolamine (0.1 mg/kg) or N-nitro-L-arginine methyl ester (30 mg/kg) alone did not impair acquisition, whereas administration of the same doses in combination increased both the latency to complete the maze and number of errors committed. These data suggest that manipulation of learning and memory processes with multiple compounds potentially offers a clinically relevant paradigm for investigating cognitive function in normal and abnormal aging.

Sildenafil citrate attenuates a complex maze impairment induced by intracerebroventricular infusion of the NOS inhibitor Nomega-nitro-L-arginine methyl ester.

In a previous study, our laboratory reported that sildenafil citrate, a cyclic nucleotide phosphodiesterase type 5 inhibitor, reversed a learning impairment in rats induced by systemic inhibition of nitric oxide synthase (60 mg/kg, i.p., Nomega-nitro-L-arginine methyl ester; L-NAME). To limit the peripheral effects of L-NAME and further localize the site of action of sildenafil, L-NAME (48 microg, i.c.v.) was infused bilaterally into the lateral cerebral ventricles 30 min prior to maze training. Saline or sildenafil citrate (1.5 or 3.0 mg/kg, i.p.) was administered systemically 15 min before training. Drug injections occurred 24 h after pretraining rats to avoid foot shock on a one-way active avoidance straight runway. Following drug treatment, the rats received 15 training trials on a 14-unit T-maze task that requires learning a complex sequence of turns to avoid mild foot shock. This complex maze paradigm is sensitive to aging and blockade of cholinergic, N-methyl-D-aspartate and nitric oxide signaling systems. Behavioral measures of performance included deviations from the correct pathway (errors), runtime from start to goal (latency), shock frequency and shock duration. Statistical analysis revealed that central infusion of L-NAME impaired maze performance and that sildenafil (3.0 mg/kg) significantly attenuated the impairment. These results suggest that sildenafil citrate may serve as a cognitive enhancer by modulating central nitric oxide/cGMP signal transduction following N-methyl-D-aspartate receptor activation. This pathway has been implicated in age-related cognitive decline and may be a useful target for pharmacological intervention of neurodegenerative disease.

Phosphodiesterase inhibition by sildenafil citrate attenuates a maze learning impairment in rats induced by nitric oxide synthase inhibition.

RATIONALE: The nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signal transduction pathway has been implicated in some forms of learning and memory. Recent findings suggest that inhibition of phosphodiesterase (PDE) enzymes that degrade cGMP may have memory-enhancing effects. OBJECTIVES: We examined whether treatment with sildenafil citrate, a PDE type 5 inhibitor, would attenuate a learning impairment induced by inhibition of NO synthase [60 mg/kg N(omega)-nitro-L-arginine methyl ester (L-NAME), i.p.]. METHODS: Rats were pretrained in a one-way active avoidance of foot shock in a straight runway and, on the next day, received 15 training trials in a 14-unit T-maze, a task that has been shown to be sensitive to aging and impairment of central NO signaling systems. Combined treatments of L-NAME or saline and sildenafil (1.0, 1.5, 3.0, or 4.5 mg/kg, i.p.) or vehicle were given 30 and 15 min before training, respectively. Behavioral measures of performance included entries into incorrect maze sections (errors), run time from start to goal (latency), shock frequency, and shock duration. RESULTS: Statistical analysis revealed that L-NAME impaired maze performance and that sildenafil (1.5 mg/kg) significantly attenuated this impairment. Control experiments revealed that administration of L-NAME alone did not significantly increase latencies in a one-way active avoidance test and that different doses of sildenafil alone did not significantly alter complex maze performance. CONCLUSIONS: The results indicate that sildenafil may improve learning by modulating NO-cGMP signal transduction, a pathway implicated in age-related cognitive decline and neurodegenerative disease.

The cholinesterase inhibitor, phenserine, improves Morris water maze performance of scopolamine-treated rats.

Male Fischer-344 rats (n = 38) at 5 months old were tested in a Morris water maze to determine if treatment with the cholinesterase inhibitor, phenserine (PHEN), would overcome a learning impairment induced by scopolamine (SCOP), a muscarinic cholinergic receptor antagonist. Each rat was randomly assigned to one of five groups to receive two intraperitoneal injections 60 and 30 min, prior to testing, respectively, as follows: (1) saline-saline (SAL); (2) saline-1.0 mg/kg (SCOP); (3) 2 mg/kg PHEN- SCOP (PHEN2); (4) 4 mg/kg PHEN-SCOP (PHEN4); and (5) 1 mg/kg PHEN-SAL (PHEN1). Maze testing occurred across 5 days with 4 days of acquisition trials (4 trials per day) and a fifth day consisting of a single 120 sec probe trial. PHEN1 and SAL were combined into one control (CON) group for purposes of statistical analysis for both acquisition and probe trials as comparison of the two groups revealed that they did not significantly differ on any measure. SCOP-treated rats were significantly impaired compared to CON in learning the location of the submerged platform as measured by latency to locate the platform and the distance traversed to find the platform across days of testing. The PHEN4 group had significantly lower latencies and traveled a shorter distance to reach the submerged platform when compared to SCOP on the fourth day of trials while the PHEN2 group traveled more directly to the submerged platform but did not have shorter latencies than the SCOP group. For probe trials, CON rats swam closer to the target area (a measure of proximity to the removed platform) than did all other groups, and the PHEN4 group swam in an area more proximate to the target area than did the SCOP-treated group. These findings demonstrate the ability of this drug to improve learning when cholinergic function has been impaired in a spatial memory task.

Phosphodiesterase inhibition by sildenafil citrate attenuates the learning impairment induced by blockade of cholinergic muscarinic receptors in rats.

We examined whether treatment with sildenafil citrate (the active compound of Viagra), a cyclic nucleotide phosphodiesterase type 5 inhibitor (PDE5), would reverse the learning impairment induced by cholinergic muscarinic (mACh) receptor blockade [0.75 mg/kg scopolamine HCl, intraperitoneal (i.p.) injections]. Rats were pretrained in a one-way active avoidance of foot shock in a straight runway and the next day received 15 training trials in a 14-unit T-maze. Performance in this maze paradigm requires accurate responding to avoid mild foot shock and has been shown to be sensitive to aging and to impairment in central cholinergic systems. Intraperitoneal (i.p.) injections of scopolamine or saline and sildenafil or vehicle were given 30 and 15 min before training, respectively. The combined treatment conditions were as follows: saline+vehicle (control), scopolamine (0.75 mg/kg)+vehicle, and scopolamine (0.75 mg/kg)+sildenafil (1.5, 3.0, or 4.5 mg/kg). Behavioral measures of performance included deviations from the correct pathway (errors), run time from start to goal, shock frequency, and duration. Statistical analysis revealed that scopolamine impaired maze performance and that sildenafil (3.0 mg/kg) significantly attenuated this impairment in a dose-dependent manner. These results suggest that sildenafil citrate may serve as a cognitive enhancer for therapeutic treatment of cholinergic dysfunction in age-related cognitive decline and Alzheimer's dementia (AD).

The challenges of understanding mammalian cognition and memory-based behaviours: an interactive learning and memory systems approach.

Various research problems are presented to illustrate the utility of using the interactive multiple learning and memory systems view to better understand normal and abnormal manifestations of mammalian behaviour. Evidence for incidental learning and memory processes is presented and various implications of this work are discussed. Empirical and theoretical work directed at understanding the cognitive and non-cognitive processes associated with place learning in the water task and context conditioning during aversive events is also presented.

Multiple memory systems: the power of interactions.

Two relatively simple theories of brain function will be used to demonstrate the explanatory power of multiple memory systems in your brain interacting cooperatively or competitively to directly or indirectly influence cognition and behaviour. The view put forth in this mini-review is that interactions between memory systems produce normal and abnormal manifestations of behaviour, and by logical extension, an understanding of these complex interactions holds the key to understanding debilitating brain and psychiatric disorders.

Effect of D-serine on a delayed match-to-place task for the water maze.

The effect of the amino acid d-serine, a partial NMDA receptor agonist, on a delayed match-to-place task in the water maze was examined. Twenty-four male rats were first trained to attain baseline measurements, then administered D-serine or saline. Rats administered D-serine (100 mg/kg, i.p.) before swim trials did not show a decrease in escape latencies, but did show an increase in swim time spent within the previous days' escape platform location.

Partial reinforcement across trials impairs escape performance but spares place learning in the water maze.

We studied the effects of partial reinforcement on escape performance and place learning in the water maze. Rats given 50% reinforcement across trials (i.e. the escape platform was present only on odd trials) were compared to controls given 100% reinforcement (platform present on all trials). Control groups either received 8 or 4 trials per day, which was equal to either the total number of trials (100%-8) or reinforced escapes (100%-4) of the 50% group. Analysis of escape performance (latency) revealed that the 50% group was impaired relative to the 100%-8 group, but not the 100%-4 group, during the first 5 days of acquisition. The 50% group was impaired relative to both control groups on days 6-10 of overtraining. However, analyses of within-trial behavior (target annulus preference and thigmotaxis) on nonreinforced trials suggest that the 50% group did learn the location of the hidden platform (place information), in addition to a wall-based thigmotactic response. By dividing the 60s nonreinforced trials into three 20-s time bins, we were able to detect a significant preference for the target annulus early in the trial (bin 1 of trial 40 and bins 1-2 of trial 80). Further, there was a significant increase in time spent in the periphery of the pool, near the wall, in the last time bin of trial 40. Because the platform was in the middle zone, this behavior competed with a place response. We conclude that across-trial partial reinforcement procedures may promote response competition and mask evidence of place learning in addition to weakening escape performance late in training.

A room with a view and a polarizing cue: individual differences in the stimulus control of place navigation and passive latent learning in the water maze.

We investigated individual differences in the stimulus control of navigational behavior in the water maze by comparing measures of place learning in one environment to measures of latent learning (via passive placement on the goal platform) in a novel environment. In the first experiment, 12 rats were trained to find a slightly submerged hidden platform at a fixed location in room A for 10 days (4 trials/day). Fast and slow place learners were identified by their mean escape latency and cumulative distance to the goal during acquisition. The same animals were then given a 2-min passive placement on the submerged platform in room B. Latent learning was assessed by the animal's escape latency on a single swim trial immediately following the placement in room B. The results showed that the good latent learners in room B were not necessarily the fast place learners in room A. This weak correlation may be related to the fact that some rats swam near the area in room B that corresponded to the former goal location in room A relative to a common polarizing cue (i.e., the door/entrance to both rooms). When the view of the door was blocked in a second experiment a significant positive correlation between place acquisition and the latent learning test was obtained, although escape performance following passive placement was not improved. These findings suggest that while place navigation and latent learning via passive placement may involve some common cognitive-spatial function, other associative (S-S and/or S-R) processes that occur during place navigation/active movement may be required for animals to exhibit truly accurate navigational behavior characteristic of asymptotic escape performance in the water maze. Additional implications for neurobiological studies using a procedural pretraining design are discussed.