The effects of aging and dorsal hippocampal lesions: performance on spatial and nonspatial comparable versions of the water maze

Aged intact and young hippocampal-lesioned rats show similar deficits on the spatial water maze. However, this does not necessitate that the source of these deficits in the aged animals is due to hippocampal damage. These water maze deficits may arise from other aging factors such as changes in thermoregulation, muscle fatigue, swim ability, and response to stress. Consequently, it is imperative to examine the performance of aged rats on a comparable nonhippocampal version of this task. Past attempts to develop a hippocampus-independent version of the water maze were confounded because these tasks were easier (i.e., the rats spent much less time swimming in the water) than the spatial versions of the task. The current study examined performance on a hippocampus-independent task comparable in difficulty to the spatial water one. Middle-aged (16-m) and old (25-m) male F344 rats were given sham or dorsal hippocampus lesions and tested on both a spatial and a nonspatial water maze. The middle-aged rats with hippocampal lesions were impaired on the spatial task but not on the nonspatial task. Conversely, aged animals showed a similar impairment on both types of water maze tasks. Additionally, hippocampal lesions exacerbated the age-related impairment on both tasks. These findings indicate that caution must be used when interpreting the results of water maze tasks for aged animals.     

Lesions of the rat postsubiculum impair performance on spatial tasks.

Previous studies have identified a population of neurons in the postsubiculum that discharge as a function of the rat's head direction in the horizontal plane (Taube, Muller, & Ranck, 1990a). To assess the contribution of these cells in spatial learning, Long-Evans rats were tested in a variety of spatial and nonspatial tasks following bilateral electrolytic or neurotoxic lesions of the postsubiculum. Compared to unlesioned control animals, lesioned animals were impaired on two spatial tasks, a radial eight-arm maze task and a Morris water task, although the performance scores of both lesion groups improved over the course of behavioral testing. In contrast, lesioned animals were unimpaired on two nonspatial tasks, a cued version of the water maze task and a conditioned taste-aversion paradigm. In addition, lesioned animals showed transient hyperactivity in an open-field activity test. These results support the concept that neurons in the postsubiculum are part of a neural network involved in the processing of spatial information.     

GABA(A) receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress: possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders

Protracted social isolation in laboratory animals causes stress, which induces a variety of behavioral abnormalities including increased aggressiveness, anxiety-related behaviors, cognitive deficits and hyper locomotion. Many of these disorders are similar to the symptoms found in psychiatric disorders, such as depression, anxiety, premenstrual dysphoria and posttraumatic stress disorders (PTSD). Recent studies have demonstrated that male mice that have been socially isolated for more than 4 weeks show: (a) reduced responsiveness of GABA(A) receptors (GABA(A)-R) to the administrations of GABA mimetic drugs at GABA(A)-R; (b) downregulated biosynthesis of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP) (allopregnanolone: ALLO), a neurosteroid with a potent positive allosteric modulatory effect on the action of GABA on GABA(A)-R; and (c) alterations in the expression of GABA(A)-R subunits (i.e. a decrease of alpha1/alpha2 and gamma2 subunits and an increase of alpha4 and alpha5 subunits). The selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) and its congener norfluoxetine (Nor-FLX), when administered systemically at nmol/kg doses, normalize the reduced content of brain ALLO and the reduced responsiveness of GABA(A)-R to GABA mimetic drugs (i.e. pentobarbital) and also attenuate aggressive behavior in socially isolated mice in a stereospecific manner. Although these compounds inhibit ex vivo serotonin reuptake into brain tissue, their SSRI activities require high micromol/kg dose ranges and are not stereospecific. These studies suggest that in socially isolated mice, abnormalities of GABA(A)-R signal transduction are attributable to the downregulation of ALLO production and to a switch in heteropentameric GABA(A)-R subunit assembly composition. Hence, the normalization of ALLO biosynthesis may be a new target for the development of drugs effective for psychiatric disorders related to neurosteroid biosynthesis downregulation.     

Reversible disconnection of the hippocampal-prelimbic cortical circuit impairs spatial learning but not passive avoidance learning in rats

Wistar rats, treated with the GABA(A) receptor agonist muscimol, were used to investigate the role of the hippocampal-prelimbic cortical (Hip-PLC) circuit in spatial learning in the Morris water maze task, and in passive avoidance learning in the step-through task. In the water maze task, animals were trained for three consecutive days and tested 24 h after the end of training. In the step-through task, the animals were trained once and tested 24h after training. On the training days, daily infusion of muscimol (0.5 microg/0.25 microl) was given (1) bilaterally to the ventral hippocampus (vHip), (2) bilaterally to the prelimbic cortex (PLC), (3) to the unilateral vHip and the ipsilateral PLC, or (4) for disconnecting the Hip-PLC circuit, to both the unilateral vHip and the contralateral PLC 30 min before training. The results showed that inhibition of the vHip resulted in disruption of performance in both tasks. Inhibition of the PLC produced impaired water maze performance, but had no effect on the step-through task. Disconnection of the Hip-PLC circuit produced similar effects to PLC inhibition. However, simultaneous inhibition of the unilateral vHip and the ipsilateral PLC had little effect on performance of the water maze task. The results suggested that spatial learning depends on the Hip-PLC circuit, whereas passive avoidance learning is independent of this circuit.     

Hippocampal alpha 5 subunit-containing GABA A receptors are involved in the development of the latent inhibition effect

Hippocampal GABA(A) receptors containing the alpha 5 subunit have been implicated in the modulation of hippocampal-dependent learning, presumably via their tonic inhibitory influence on hippocampal glutamatergic activity. Here, we examined the expression of latent inhibition (LI)--a form of selective learning that is sensitive to a number of manipulations targeted at the hippocampal formation, in alpha 5(H105R) mutant mice with reduced levels of hippocampal alpha 5-containing GABA(A) receptors. A single pre-exposure to the taste conditioned stimulus (CS) prior to the pairing of the same CS with LiCl-induced nausea was effective in reducing the conditioned aversion against the taste CS in wild-type mice--thus constituting the LI effect. LI was however distinctly absent in male alpha 5(H105R) mutant mice. Hence, a partial loss of hippocampal alpha 5 GABA(A) receptors is sufficient to alter one major form of selective learning, albeit this was not seen in the female. This observed phenotype suggests that specific activation of these extrasynaptic GABA(A) receptors may confer therapeutic potential against the failure to show selectivity in learning by human psychotic patients.     

The role of spatial working memory in visual search efficiency

Many theories have proposed that visual working memory plays an important role in visual search. In contrast, by showing that a nonspatial working memory load did not interfere with search efficiency, Woodman, Vogel, and Luck (2001) recently proposed that the role of working memory in visual search is insignificant. However, the visual search process may interfere with spatial working memory. In the present study, a visual search task was performed concurrently with either a spatial working memory task (Experiment 1) or a nonspatial working memory task (Experiment 2). We found that the visual search process interfered with a spatial working memory load, but not with a nonspatial working memory load. These results suggest that there is a distinction between spatial and nonspatial working memory in terms of interactions with visual search tasks. These results imply that the visual search process and spatial working memory storage require the same limited-capacity mechanisms.     

Sequential training in separate paradigms impairs second task consolidation and learning-associated modulations of hippocampal NCAM polysialylation.

As transient and time-dependent modulations of neural cell adhesion molecule polysialylation (NCAM PSA) are associated with morphofunctional change and required for the consolidation of spatial and nonspatial forms of learning, we determined the demands imposed on this system by sequential training in the Morris water maze followed by the passive avoidance paradigm. Animals trained in this manner had recall of the water maze but not the passive avoidance response as judged by their escape and avoidance latencies, respectively. Activation of NCAM PSA on dentate neurons at the 12-h post-training time suggested information processing; however, this was significantly less than that predicted for coincident acquisition of both tasks. When sequential training was separated by an interparadigm period of 2 h, an enduring NCAM PSA activation was observed which was indistinguishable from the sum of the expected activations for each individual task. These observations suggest that the NCAM PSA response may become saturated when alternate tasks are presented without an intervening period.     

Spatial and nonspatial escape strategies in the Barnes maze

The Barnes maze is a spatial memory task that requires subjects to learn the position of a hole that can be used to escape the brightly lit, open surface of the maze. Two experiments assessed the relative importance of spatial (extra-maze) versus proximal visible cues in solving the maze. In Experiment 1, four groups of mice were trained either with or without a discrete visible cue marking the location of the escape hole, which was either in a fixed or variable location across trials. In Experiment 2, all mice were trained with the discrete visible cue marking the target hole location. Two groups were identical to the cued-target groups from Experiment 1, with either fixed or variable escape locations. For these mice, the discrete cue either was the sole predictor of the target location or was perfectly confounded with the spatial extra-maze cues. The third group also used a cued variable target, but a curtain was drawn around the maze to prevent the use of spatial cues to guide navigation. Probe trials with all escape holes blocked were conducted to dissociate the use of spatial and discrete proximal cues. We conclude that the Barnes maze can be solved efficiently using spatial, visual cue, or serial-search strategies. However, mice showed a strong preference for using the distal room cues, even when a discrete visible cue clearly marked the escape location. Importantly, these data show that the cued-target control version of the Barnes maze as typically conducted does not dissociate spatial from nonspatial abilities.     

Kv4.2 knockout mice have hippocampal-dependent learning and memory deficits

Kv4.2 channels contribute to the transient, outward K(+) current (A-type current) in hippocampal dendrites, and modulation of this current substantially alters dendritic excitability. Using Kv4.2 knockout (KO) mice, we examined the role of Kv4.2 in hippocampal-dependent learning and memory. We found that Kv4.2 KO mice showed a deficit in the learning phase of the Morris water maze (MWM) and significant impairment in the probe trial compared with wild type (WT). Kv4.2 KO mice also demonstrated a specific deficit in contextual learning in the fear-conditioning test, without impairment in the conditioned stimulus or new context condition. Kv4.2 KO mice had normal activity, anxiety levels, and prepulse inhibition compared with WT mice. A compensatory increase in tonic inhibition has been previously described in hippocampal slice recordings from Kv4.2 KO mice. In an attempt to decipher whether increased tonic inhibition contributed to the learning and memory deficits in Kv4.2 KO mice, we administered picrotoxin to block GABA(A) receptors (GABA(A)R), and thereby tonic inhibition. This manipulation had no effect on behavior in the WT or KO mice. Furthermore, total protein levels of the α5 or δ GABA(A)R subunits, which contribute to tonic inhibition, were unchanged in hippocampus. Overall, our findings add to the growing body of evidence, suggesting an important role for Kv4.2 channels in hippocampal-dependent learning and memory.     

Spatial working memory load affects counting but not subitizing in enumeration

The present study investigated whether subitizing reflects capacity limitations associated with two types of working memory tasks. Under a dual-task situation, participants performed an enumeration task in conjunction with either a spatial (Experiment 1) or a nonspatial visual (Experiment 2) working memory task. Experiment 1 showed that spatial working memory load affected the slope of a counting function but did not affect subitizing performance or subitizing range. Experiment 2 showed that nonspatial visual working memory load affected neither enumeration efficiency nor subitizing range. Furthermore, in both spatial and nonspatial memory tasks, neither subitizing efficiency nor subitizing range was affected by amount of imposed memory load. In all the experiments, working memory load failed to influence slope, subitizing range, or overall reaction time. These findings suggest that subitizing is performed without either spatial or nonspatial working memory. A possible mechanism of subitizing with independent capacity of working memory is discussed.     

Visuospatial working memory and mental representation of spatial descriptions

The purpose of the present research is to investigate whether different components of working memory (WM) are involved in processing spatial and nonspatial texts. The interference effects of two concurrent tasks on comprehension and recall of two kinds of text were investigated in two experiments. Each participant listened to a spatial and a nonspatial text, with one of two concurrent tasks: articulatory suppression or spatial tapping. The dependent variables in Experiment 1 were accuracy of recall and verification of information inferred from the texts. In Experiment 2 response times in the verification task were also considered. Results support the hypothesis that verbal and spatial components of working memory are differentially involved in the comprehension and memory of spatial and nonspatial texts, with a selective interference effect of the spatial concurrent task on the spatial text and an interference effect of the verbal concurrent task on both the spatial and nonspatial texts. These effects emerged for recall, sentence verification, and response times. Our findings confirm previous results showing that the verbal component of working memory is involved in the process of text comprehension and memory. In addition, they show that visuospatial working memory is involved, in so far as the text conveys visuospatial information.     

Brain interleukin-1 is involved in spatial memory and passive avoidance conditioning

Within the brain, the inflammatory cytokine interleukin-1 (IL-1) mediates illness-associated neural, neuroendocrine, and behavioral responses; however, its role in normal neurobehavioral processes is not clear. To examine the role of IL-1 signaling in memory, we infused Long-Evans rats intracerebroventricularly with IL-1beta (10 ng/rat), IL-1 receptor antagonist (IL-1ra, 100 microg/rat), or saline immediately following a learning task and tested memory functioning 1-8 days later. In the Morris water maze (MWM), IL-1ra caused memory impairment in the hippocampus-dependent, spatial version, whereas IL-1beta had no effect. Neither IL-1beta nor IL-1ra influenced the hippocampus-independent, nonspatial version of the MWM. In the passive avoidance response, which also depends on hippocampal functioning, IL-1ra caused memory impairment, and IL-1beta caused memory improvement. These results suggest that IL-1 signaling within the hippocampus plays a critical role in learning and memory processes.     

Cognitive spatial processing and the regulation of posture

Subjects performed the Brooks (1967) spatial and nonspatial memory tasks either while sitting or while maintaining a difficult standing balance position. The balance task disrupted spatial but not nonspatial memory performance. Balance steadiness during spatial and nonspatial memory conditions did not differ. These results suggest that cognitive spatial processing may rely on neural mechanisms that are also required for the regulation of posture.     

Effects of intraseptal zolpidem and chlordiazepoxide on spatial working memory and high-affinity choline uptake in the hippocampus

Injection of GABA(A)/benzodiazepine receptor ligands into the medial septum (MS) alters the activity of cholinergic neurons that innervate the hippocampus and can produce bidirectional modulation of spatial memory. Recent evidence suggests that two subtypes of the GABA(A) receptor are differentially localized to either GABAergic (alpha(1)/beta(2)/gamma(2)) or cholinergic (alpha(3)/beta(3)/gamma(2)) neurons within the MS. The present studies characterized the dose-related behavioral and neurochemical effects of intraseptal infusions of two benzodiazepine (BDZ) agonists that appear to exhibit different profiles of pharmacological specificity for these receptor subtypes. Male Sprague-Dawley rats were cannulated and then artificial CSF, chlordiazepoxide (CDP: 8 or 12 microg), or zolpidem (4, 8, or 12 microg) was injected into the MS. Spatial working memory was assessed in a delay radial-arm maze task and the activity of cholinergic neurons in the MS was evaluated by high-affinity choline uptake (HA-ChU) in the hippocampus. Intraseptal injection of either CDP or zolpidem produced dose-related impairments in spatial working memory and decreases in hippocampal HAChU. Both BDZ agonists were found to produce retrograde memory deficits and a decrease in HAChU following the highest dose tested (12 microg). However, intraseptal injection of 8 microg of zolpidem produced a behavioral deficit comparable to the high dose of CDP, but did not alter HAChU within the HPC. Although the cholinergic component of the septohippocampal pathway has been shown to be important in modulating hippocampal physiology and spatial memory processes, data from the present experiments suggest that the GABAergic component may also play an important role in the behavioral functions of the septohippocampal pathway.     

Effects of Unilateral Entorhinal Cortex Lesion and Ganglioside GM1 Treatment on Performance in a Novel Water Maze Task

Transient deficits have been reported after unilateral entorhinal cortex (EC) lesion. To determine whether there is a more persistent deficit, adult male Sprague–Dawley rats with electrolytic or sham lesions of the left entorhinal cortex were examined on acquisition of a modified working memory task in the Morris water maze. This delayed matching-to-sample task, with a 1-h intertrial interval, reveals a significant deficit in total distance to platform in both presentation (Trial 1) and matching (Trial 2) in the rats with entorhinal lesions. We have also found that this test can be used to assess significant deficits in perseveration (repeated nonproductive movement) in rats with entorhinal lesions. The deficits can be seen up to 16 days postinjury. Administration of ganglioside GM1 resulted in a moderate improvement in performance in both water maze measures analyzed. All groups (sham operated, lesion with saline treatment, and lesion with ganglioside GM1 treatment) were given three other tests, which were used to evaluate possible contributing factors to deficient water maze performance. A one-trial test for exploration of novel objects revealed no significant, simple working memory deficit in any group. Plus maze testing, to assess possible differences in levels of anxiety or increased activity as a component of water maze performance, also revealed no differences in the three groups. All groups were also similar in motor activity, shown by monitoring of activity levels. The worsened water maze performance observed in rats with EC lesion may be related to deficits in working memory ability within the framework of acquisition of a more complex spatial learning task.     

Spatial training and high-frequency stimulation engage a common pathway to enhance glutamate release in the hippocampus

We have measured depolarization-induced release of endogenous glutamate in synaptosomes prepared from the dentate gyrus after the induction of LTP by high-frequency stimulation in anesthetized rats, and after training in the water maze. Both spatial training and LTP in untrained rats were accompanied by an increase in glutamate release from dentate synaptosomes. The enhancement of synaptosomal glutamate release induced by high-frequency stimulation was abolished in well-trained rats, and was reduced in partially trained rats and in rats trained in a nonspatial task. However, the magnitude of LTP was similar in well-trained and untrained groups. These results indicate that spatial training activates a glutamate release pathway that converges with that activated in LTP, and demonstrate an unexpected dissociation between increased glutamate release and LTP.     

Fimbria/fornix lesions facilitate the learning of a nonspatial response task

The spatial cognitive map theory of O’Keefe and Nadel (1978) predicts that lesions of the hippocampal system should impair learning on spatial tasks but not learning on nonspatial tasks. However, there is evidence that such lesions can facilitate learning on certain nonspatial tasks. Their theory does not predict such facilitation. Nevertheless, it is reasonable to expect that animals possessing a spatial cognitive map would have an inherent bias to engage a mapping strategy and thus be at a disadvantage on certain nonspatial tasks in comparison with animals without the mapping capacity and bias. In the present study, fimbria/fornix lesions impaired learning on a spatial task, but actually facilitated learning on a nonspatial task of equal difficulty. Thus, brain lesions that interfere with map functioning can facilitate learning on tasks for which a mapping strategy interferes with task solution. The results require a modification of the spatial cognitive map theory.     

Pre-training to find a hidden platform in the Morris water maze can compensate for a deficit to find a cued platform in a rat model of Parkinson's disease

The bilateral intranigral infusion of 1 micromol 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in adult male Wistar rats caused a specific and partial loss of substantia nigra pars compacta (SNc) dopamine neurons, a partial depletion of striatal dopamine, and a deficit to learn the intra-maze cued version of the Morris water maze. Pre-training the SNc rats in the spatial version of the water maze or simply maintaining the animals on the water maze platform reversed this deficit. This improvement was even observed when the order of the extra-maze cues presented to the rats during pre-training of the spatial version was changed during training of the intra-maze cued version. However, this deficit was not reversed either by maintaining the animals on the platform if the spatial cues were surrounded and covered with a curtain or by swimming sessions in the maze without the escape platform and the curtain. These findings suggest that none of the following elements alone, learned during the spatial task pre-training, could help SNc rats learn the intra-maze cued task: improvement of swimming skills or knowledge of the existence of the escape platform; distance between the platform and the border of the pool; location of a particular extra-maze cue; relations among extra-maze cues. However, the simultaneous presence of the escape platform and extra-maze cues (irrespective of their relational configuration) during the pre-training sessions proved to be necessary for this improving effect to occur.     

Differential Effects of Global Ischemia on Delayed Matching- and Non-Matching-to-Position Tasks in the Water Maze and Skinner Box

In order to assess effects of global ischemia in tasks of spatial learning and working memory, male Wistar rats were subjected to four vessel occlusion (4 VO) for periods of 5, 10, and 20 min and compared with sham-operated controls over four test phases, from 6 to 54 weeks after surgery. Rats were assessed on acquisition in the water maze, a task that is sensitive to ischemic impairments, before testing in Skinner box and water maze working memory tasks, which both require the short-term storage of information, but make different demands on spatial information processing. Phases 1 and 3 assessed spatial learning in a standard water maze procedure (12 and 10 training days, 2 trials/day with a 10-min intertrial interval: ITI). Phase 2 involved training and testing in delayed non-matching-to-position task in the Skinner box, with delays of 2–10 s between the information and choice stages. Phase 4 examined working memory in a water maze delayed matching-to-position task with 4 trials/day, an ITI of 30 s, and a novel platform position on each day. Ischemic rats showed duration-related impairments in water maze acquisition and working memory, but not in the less spatially demanding Skinner box task. Since water maze acquisition deficits were seen both before and after testing in the Skinner box the lack of effect cannot be attributed to time or to prior training. Ischemic deficits were more marked in Phase 3 than in Phase 1 of acquisition, suggesting that impairment may be progressive. Histological assessment showed that cell loss was largely confined to the hippocampal CA1 field and was linearly related to duration of occlusion. At the maximal level of loss (5.7 mm before the interaural line) the 20-min group showed 90% loss, the 10-min group 60% loss, and the 5-min group, which did not differ from controls, less than 10% loss. Only the 20-min group showed significant damage beyond the CA1 field, ranging from 30–40% loss in the CA3 field to 5% loss in one striatal area. No cortical damage was seen. The extent of CA1 cell loss correlated modestly with water maze acquisition (Phase 3) and working memory scores, but not with trials to criterion in the Skinner box task. There were significant correlations between different measures both within and between water maze tasks, but not Skinner box tasks, suggesting that the two types of procedure engaged different cognitive processes. The results indicate that the intrahippocampal damage induced by 4 VO impaired tasks which required processing of allocentric spatial information, but did not impair the storage of limited spatial information in working memory.