Standard Morris Water Maze Research Articles

Exercise Improves Spatial Learning and Memory Performance through the Central GLP-1 Receptors.

The glucagon-like peptide 1 (GLP-1) is a hormone which is produced in the enteroendocrine L-cells in the ileum and the neurons of nucleus tractus solitarius (NTS) in the brain which has numerous metabolic effects. The central GLP-1R's role in cognitive functioning is well known. On the contrary, it has been shown that exercise has positive effects on brain function. So, we decided to elucidate whether the central GLP-1 has a role in memory and learning. Thirty-two rats were used in this experiment in 4 groups. After anesthetizing the rats, the right lateral ventricle was detected, and a cannula was directed to the ventricle. Ten micrograms of exendin-3 or sterile saline, according to the group, was injected via ICV once daily for seven days. The rats in the exercise group considered an exercise period of one hour each day (17 meters per minute) for seven consecutive days. To evaluate the performance of memory and learning, a standard Morris water maze (MWM) tank was utilized. According to the results, the TE-exendin group showed a statistically significant difference from the TE-SAL group in both parameters of latency and time in the zone. In summary, memory and learning were improved by GLP-1R in the exercise group, but not in the sedentary group, which we can hypothesize that exercise can affect memory and learning through this pathway.

Indexes for flotation and circling, two non-search behaviors in the water maze, sensitive to d-galactose–induced accelerated aging and Alzheimer’s disease

The study of behavioral and psychological symptoms of dementia (BPSD) has been largely neglected in most experimental research on Alzheimer’s disease (AD) classically focused on cognitive symptoms. The aquatic environment of the Morris water maze (MWM) implies a stressful condition for mice leading to cognitive performances with presence of other behaviors related to emotionality. This can be critical in models such as the 3xTg-AD mice that exhibit a noticeable BPSD-like profile. The present work is aimed to provide a quantitative (number of episodes and duration) and qualitative (prevalence) analysis of flotation and circling, the most common ‘non-searching behaviors’ elicited in the MWM. We studied the expression of these behaviors in 6-month-old gold-standard wildtype C57BL/6 mice (genetic background) and 3xTg-AD mice (onset of disease) and when both genotypes were submitted to chronic d-galactose induced accelerated aging. Elicitation of floating and circling was recorded during three standard MWM paradigms: visual perceptual learning, place task for spatial reference memory and a final probe trial for short-term memory. In view of the results, we demonstrate that the index of ‘flotation’, characteristic of non-transgenic performance, is sensitive (reduction) to accelerated aging and AD. Conversely, circling behavior, characteristic of 3xTg-AD mice, can be an additional tool for evaluating BPSD-like symptoms in AD-models while its index unveils bizarre behavior induced by d-galactose induced aging. These results can be useful in relation to preventive and/or therapeutical interventions targeting AD but they may also be suitable in the evaluation of the potential risk factors in animals with normal aging.

Riboflavin may ameliorate neurological motor disability but not spatial learning and memory impairments in murine model of multiple sclerosis

Summary Background & aims Riboflavin has an important role in myelin formation. This experimental study assesses the interactions between the effects of riboflavin and interferon beta-1a (INF-β1a) on motor disability, spatial learning and memory, and brain-derived neurotrophic factor (BDNF) in experimental autoimmune encephalomyelitis (EAE). Methods In the present research C57BL/6 mice (n = 56) were divided into sham and treatment groups. Riboflavin was administrated (10 mg/kg/day) orally for two weeks alone and/or combined with INF-β1a at 150 IU/g of body weight. After the induction of EAE, the animals were investigated for the clinical signs. Spatial learning and memory were assessed through the standard Morris water maze (MWM). The brain and spinal cord levels of BDNF were studied using real-time polymerase chain reactions and enzyme-linked immunosorbent assay. The data were analyzed using one-way ANOVA, repeated measures, and generalized estimating equations model. Results The results in the brain revealed that BDNF mRNA expression (P Conclusion The data highlighted the synergistic role of riboflavin and INF-β1a in improving the disability but not spatial learning and memory mediated by BDNF in EAE.

Enhanced extinction of aversive memories in mice lacking SPARC-related protein containing immunoglobulin domains 1 (SPIG1/FSTL4).

Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity related to learning and memory. We previously reported that SPARC-related protein containing immunoglobulin domains 1 (SPIG1, also known as Follistatin-like protein 4, FSTL4) binds to pro-BDNF and negatively regulates BDNF maturation; however, its neurological functions, particularly in learning and memory, have not yet been elucidated. We herein examined the electrophysiological and behavioral phenotypes of Spig1-knockout (Spig1-KO) mice. Adult Spig1-KO mice exhibited greater excitability and facilitated long-term potentiation (LTP) in the CA1 region of hippocampal slices than age- and sex-matched wild-type (WT) mice. Facilitated LTP was reduced to the level of WT by the bath application of an anti-BDNF antibody to hippocampal slices. A step-through inhibitory avoidance learning paradigm revealed that the extinction of aversive memories was significantly enhanced in adult Spig1-KO mice, while they showed the normal acquisition of aversive memories; besides, spatial reference memory formation was also normal in the standard Morris water maze task. An intracerebroventricular (icv) injection of anti-BDNF in the process of extinction learning transiently induced the recurrence of aversive memories in Spig1-KO mice, but exerted no effects in WT mice. These results indicate a critical role for SPIG1 in BDNF-mediated synaptic plasticity in extinction of inhibitory avoidance memory.

Cognitive performance of male and female C57BL/6J mice after repetitive concussive brain injuries

In contact sports, repetitive concussive brain injury (rCBI) is the prevalent form of head injury seen in athletes. The need for effective treatment is urgent as rCBI has been associated with a host of cognitive, behavioral and neurological complaints. There has been a growing trend in the use of female animals in pre-clinical research, but few studies have investigated possible sex differences following rCBI. The goal of the current study was to determine any differences between male and female C57BL/6J mice on assessments of learning and memory after repetitive concussive injury. Following rCBI by impact to the scalp, male mice exhibited longer righting reflexes during acute recovery. In both sexes, there were no evident histopathological changes observed in the underlying cerebral cortex or hippocampus. Reactive astrogliosis was elevated in the corpus callosum and optic tract, and astrogliosis was slightly less in the optic tract of female mice. rCBI mice exhibited impairment during the learning phase of the Morris water maze (MWM), but female mice, in comparison to male mice, were observed to have superior spatial memory during standard MWM probe trials. Female mice were overall more active, evidenced by greater distances traveled in the y-maze and greater swim speeds in the MWM. The results of this study demonstrate sex differences in cognitive performance following rCBI and support previous research suggesting the neuroprotective role of sex in brain injury.

Deletion of the Mouse Homolog of CACNA1C Disrupts Discrete Forms of Hippocampal-Dependent Memory and Neurogenesis within the Dentate Gyrus.

L-type voltage-gated calcium channels (LVGCCs) have been implicated in various forms of learning, memory, and synaptic plasticity. Within the hippocampus, the LVGCC subtype, CaV1.2 is prominently expressed throughout the dentate gyrus. Despite the apparent high levels of CaV1.2 expression in the dentate gyrus, the role of CaV1.2 in hippocampal- and dentate gyrus-associated forms of learning remain unknown. To address this question, we examined alternate forms of hippocampal-dependent associative and spatial memory in mice lacking the mouse ortholog of CACNA1C (Cacna1c), which encodes CaV1.2, with dentate gyrus function implicated in difficult forms of each task. We found that while the deletion of CaV1.2 did not impair the acquisition of fear of a conditioned context, mice lacking CaV1.2 exhibited deficits in the ability to discriminate between two contexts, one in which the mice were conditioned and one in which they were not. Similarly, CaV1.2 knock-out mice exhibited normal acquisition and recall of the location of the hidden platform in a standard Morris water maze, but were unable to form a memory of the platform location when the task was made more difficult by restricting the number of available spatial cues. Within the dentate gyrus, pan-neuronal deletion of CaV1.2 resulted in decreased cell proliferation and the numbers of doublecortin-positive adult-born neurons, implicating CaV1.2 in adult neurogenesis. These results suggest that CaV1.2 is important for dentate gyrus-associated tasks and may mediate these forms of learning via a role in adult neurogenesis and cell proliferation within the dentate gyrus.

Supramammillary serotonin reduction alters place learning and concomitant hippocampal, septal, and supramammillar theta activity in a Morris water maze

Hippocampal theta activity is related to spatial information processing, and high-frequency theta activity, in particular, has been linked to efficient spatial memory performance. Theta activity is regulated by the synchronizing ascending system (SAS), which includes mesencephalic and diencephalic relays. The supramamillary nucleus (SUMn) is located between the reticularis pontis oralis and the medial septum (MS), in close relation with the posterior hypothalamic nucleus (PHn), all of which are part of this ascending system. It has been proposed that the SUMn plays a role in the modulation of hippocampal theta-frequency; this could occur through direct connections between the SUMn and the hippocampus or through the influence of the SUMn on the MS. Serotonergic raphe neurons prominently innervate the hippocampus and several components of the SAS, including the SUMn. Serotonin desynchronizes hippocampal theta activity, and it has been proposed that serotonin may regulate learning through the modulation of hippocampal synchrony. In agreement with this hypothesis, serotonin depletion in the SUMn/PHn results in deficient spatial learning and alterations in CA1 theta activity-related learning in a Morris water maze. Because it has been reported that SUMn inactivation with lidocaine impairs the consolidation of reference memory, we asked whether changes in hippocampal theta activity related to learning would occur through serotonin depletion in the SUMn, together with deficiencies in memory. We infused 5,7-DHT bilaterally into the SUMn in rats and evaluated place learning in the standard Morris water maze task. Hippocampal (CA1 and dentate gyrus), septal and SUMn EEG were recorded during training of the test. The EEG power in each region and the coherence between the different regions were evaluated. Serotonin depletion in the SUMn induced deficient spatial learning and altered the expression of hippocampal high-frequency theta activity. These results provide evidence in support of a role for serotonin as a modulator of hippocampal learning, acting through changes in the synchronicity evoked in several relays of the SAS.

Specific downregulation of hippocampal ATF4 reveals a necessary role in synaptic plasticity and memory.

Prior studies suggested that the transcription factor ATF4 negatively regulates synaptic plastic and memory. By contrast, we provide evidence from direct in vitro and in vivo knockdown of ATF4 in rodent hippocampal neurons and from ATF4-null mice that implicate ATF4 as essential for normal synaptic plasticity and memory. In particular, hippocampal ATF4 downregulation produces deficits in long-term spatial memory and behavioral flexibility without affecting associative memory or anxiety-like behavior. ATF4 knockdown or loss also causes profound impairment of both long-term potentiation (LTP) and long-term depression (LTD) as well as decreased glutamatergic function. We conclude that ATF4 is a key regulator of the physiological state necessary for neuronal plasticity and memory.

The Peroxisomal Proliferator-Activated Receptor (PPAR) α Agonist, Fenofibrate, Prevents Fractionated Whole-Brain Irradiation-Induced Cognitive Impairment

We hypothesized that dietary administration of the peroxisomal proliferator-activated receptor α agonist, fenofibrate, to young adult male rats would prevent the fractionated whole-brain irradiation (fWBI)-induced reduction in cognitive function and neurogenesis and prevent the fWBI-induced increase in the total number of activated microglia. Eighty 12-14-week-old young adult male Fischer 344 × Brown Norway rats received either: (1) sham irradiation, (2) 40 Gy of fWBI delivered as two 5 Gy fractions/week for 4 weeks, (3) sham irradiation + dietary fenofibrate (0.2% w/w) starting 7 days prior to irradiation, or (4) fWBI + fenofibrate. Cognitive function was measured 26-29 weeks after irradiation using: (1) the perirhinal cortex (PRh)-dependent novel object recognition task; (2) the hippocampal-dependent standard Morris water maze (MWM) task; (3) the hippocampal-dependent delayed match-to-place version of the MWM task; and (4) a cue strategy preference version of the MWM to distinguish hippocampal from striatal task performance. Neurogenesis was assessed 29 weeks after fWBI in the granular cell layer and subgranular zone of the dentate gyrus using a doublecortin antibody. Microglial activation was assessed using an ED1 antibody in the dentate gyrus and hilus of the hippocampus. A significant impairment in perirhinal cortex-dependent cognitive function was measured after fWBI. In contrast, fWBI failed to alter hippocampal-dependent cognitive function, despite a significant reduction in hippocampal neurogenesis. Continuous administration of fenofibrate prevented the fWBI-induced reduction in perirhinal cortex-dependent cognitive function, but did not prevent the radiation-induced reduction in neurogenesis or the radiation-induced increase in activated microglia. These data suggest that fenofibrate may be a promising therapeutic for the prevention of some modalities of radiation-induced cognitive impairment in brain cancer patients.

MDMA enhances hippocampal-dependent learning and memory under restrictive conditions, and modifies hippocampal spine density

Addictive drugs produce forms of structural plasticity in the nucleus accumbens and prefrontal cortex. The aim of this study was to investigate the impact of chronic MDMA exposure on pyramidal neurons in the CA1 region of hippocampus and drug-related spatial learning and memory changes. Adolescent rats were exposed to saline or MDMA in a regime that mimicked chronic administration. One week later, when acquisition or reference memory was evaluated in a standard Morris water maze (MWM), no differences were obtained between groups. However, MDMA-exposed animals performed better when the MWM was implemented under more difficult conditions. Animals of MDMA group were less anxious and were more prepared to take risks, as in the open field test they ventured more frequently into the central area. We have demonstrated that MDMA caused an increase in brain-derived neurotrophic factor (BDNF) expression. When spine density was evaluated, MDMA-treated rats presented a reduced density when compared with saline, but overall, training increased the total number of spines, concluding that in MDMA-group, training prevented a reduction in spine density or induced its recovery. This study provides support for the conclusion that binge administration of MDMA, known to be associated to neurotoxic damage of hippocampal serotonergic terminals, increases BDNF expression and stimulates synaptic plasticity when associated with training. In these conditions, adolescent rats perform better in a more difficult water maze task under restricted conditions of learning and memory. The effect on this task could be modulated by other behavioural changes provoked by MDMA.

Comparing the Predictive Value of Multiple Cognitive, Affective, and Motor Tasks after Rodent Traumatic Brain Injury

Controlled cortical impact injury (CCI) is a widely-used, clinically-relevant model of traumatic brain injury (TBI). Although functional outcomes have been used for years in this model, little work has been done to compare the predictive value of various cognitive and sensorimotor assessment tests, singly or in combination. Such information would be particularly useful for assessing mechanisms of injury or therapeutic interventions. Following isoflurane anesthesia, C57BL/6 mice were subjected to sham, mild (5.0 m/sec), moderate (6.0 m/sec), or severe (7.5 m/sec) CCI. A battery of behavioral tests were evaluated and compared, including the standard Morris water maze (sMWM), reversal Morris water maze (rMWM), novel object recognition (NOR), passive avoidance (PA), tail-suspension (TS), beam walk (BW), and open-field locomotor activity. The BW task, performed at post-injury days (PID) 0, 1, 3, 7, 14, 21, and 28, showed good discrimination as a function of injury severity. The sMWM and rMWM tests (PID 14-23), as well as NOR (PID 24 and 25), effectively discriminated spatial and novel object learning and memory across injury severity levels. Notably, the rMWM showed the greatest separation between mild and moderate/severe injury. PA (PID 27 and 28) and TS (PID 24) also reflected differences across injury levels, but to a lesser degree. We also compared individual functional measures with histological outcomes such as lesion volume and neuronal cell loss across anatomical regions. In addition, we created a novel composite behavioral score index from individual complementary behavioral scores, and it provided superior discrimination across injury severities compared to individual tests. In summary, this study demonstrates the feasibility of using a larger number of complementary functional outcome behavioral tests than those traditionally employed to follow post-traumatic recovery after TBI, and suggests that the composite score may be a helpful tool for screening new neuroprotective agents or for addressing injury mechanisms.

Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: Relationships to β-amyloid deposition and neurotransmitter abnormalities

Transgenic mice made by crossing animals expressing mutant amyloid precursor protein (APPswe) to mutant presenilin 1 (PS1dE9) allow for incremental increases in Abeta42 production and provide a model of Alzheimer-type amyloidosis. Here, we examine cognition in 6- and 18-month old transgenic mice expressing APPswe and PS1dE9, alone and in combination. Spatial reference memory was assessed in a standard Morris Water Maze task followed by assessment of episodic-like memory in Repeated Reversal and Radial Water maze tasks. We then used factor analysis to relate changes in performance in these tasks with cholinergic markers, somatostatin levels, and amyloid burden. At 6 months of age, APPswe/PS1dE9 double-transgenic mice showed visible plaque deposition; however, all genotypes, including double-transgenic mice, were indistinguishable from nontransgenic animals in all cognitive measures. In the 18-month-old cohorts, amyloid burdens were much higher in APPswe/PS1dE9 mice with statistically significant but mild decreases in cholinergic markers (cortex and hippocampus) and somatostatin levels (cortex). APPswe/PS1dE9 mice performed all cognitive tasks less well than mice from all other genotypes. Factor and correlation analyses defined the strongest correlation as between deficits in episodic-like memory tasks and total Abeta loads in the brain. Collectively, we find that, in the APPswe/PS1dE9 mouse model, some form of Abeta associated with amyloid deposition can disrupt cognitive circuits when the cholinergic and somatostatinergic systems remain relatively intact; and that episodic-like memory seems to be more sensitive to the toxic effects of Abeta.

Developmental Iron Deficiency Impairs Rat Watermaze Performance.

Top of pageAbstract Background: Iron deficiency (ID), a common nutritional disorder during development, has been associated with cognitive and behavioral impairments. Previous studies suggest developmental ID in rats affects hippocampal dendritic morphology and alters performance in the Morris Water Maze (MWM). Objective: To explore the nature of MWM deficits in rats that had ID during development. Design/Methods: 8-week old dams were randomized to iron sufficient (IS) or iron deficient (ID) groups. IS or ID diets were given during gestation and lactation. All pups received the IS diet after postnatal day (P)20. At P35, 8 to 9 IS and ID group males began one of two MWM assessments. 1st: Place learning (standard MWM) and memory (platform removed at 24 hours – probe) were assessed. Rats continued with trials to enhance learning to search the target quadrant then had a second probe trial. 2nd: IS and ID rats had thigmotaxis training before standard MWM assessment and probe. Data (days to criteria, latency, quadrant preference and thigmotaxis) were analyzed using one-way and repeated measures ANOVA (RPM). Results: 1st: ID group rats had longer latencies on place learning (RPM p<0.001). Two ID rats reached criteria (ID+) but six did not (ID-). ID- rats had significantly more thigmotaxis in place learning trials than IS rats (RPM p<0.002) but ID+ and IS rats did not differ. In the probe, IS rats had greater quadrant preference (30.94 ± 9.03) than ID- rats (-19.62 ± 8.84) and less thigmotaxis. After additional trials, latency was similar for IS and all ID rats. However, IS vs ID- remained different on probe quadrant preference (25.49 ± 5.83 vs -20.46 ± 10.32, p<0.05). 2nd: After thigmotaxis training, IS rats still had shorter latencies than ID rats in the standard MWM (RPM, p<0.001) and greater quadrant preference than ID- rats on the probe (10.29 ± 11.31 vs -33.30 ± 0.01). Conclusions: Previously ID rats demonstrate poorer MWM performance that appears related to persistent thigmotaxis behavior. Although learning improved for ID rats with additional training, memory for platform location did not. Thigmotaxis training did not impair learning measures for IS rats. The results suggest that developmental ID is associated with poorer ability to leave thigmotaxis and switch-strategies in spatial learning and memory tasks.

Beta-sheet breaker peptide prevents Abeta-induced spatial memory impairments with partial reduction of amyloid deposits.

Current evidence supports the notion that beta-amyloid deposits or Abeta intermediates may be responsible for the pathogenesis in Alzheimer's disease (AD) patients. In the present work, we have assessed the neuroprotective effect of the chronic intraperitoneal administration of a five-amino-acid beta-sheet breaker peptide (iAbeta5p) on the rat behavioral deficit induced by the intrahippocampal Abeta-fibrils injection. At 1 month after the injection, animals showed a partial reduction of the amyloid deposits formed and a decreased astrocytic response around the injection site. More importantly, we report that following the iAbeta5p treatment, hippocampal-dependent spatial learning paradigms, including the standard Morris water maze and a working memory analysis, showed a significant prevention from impairments induced by Abeta deposits in the dorsal hippocampus. Thus, it is possible that a noninvasive treatment such as the one presented here with beta-sheet breaker peptides may be used as a potential therapy for AD patients.

Estradiol enhances neurogenesis in the dentate gyri of adult male meadow voles by increasing the survival of young granule neurons

This study investigated whether estradiol influenced the survival of new granule neurons, independent of altering cell proliferation, in the adult rodent dentate gyrus and whether estradiol-induced changes in new neuron number relate to any observed changes in hippocampus-dependent behavior. To test whether estradiol specifically promotes the survival of new neurons we injected castrated adult male meadow voles with the cell synthesis marker bromodeoxyuridine (BrdU; 50 mg/kg) twice on day 0 and then injected either estradiol (10 μg) or vehicle for 5 consecutive days either over days 1–5, days 6–10 or days 11–15 and perfused them on day 16. Estradiol doubled the number of hippocampal BrdU-labeled neurons but only when administered during a discrete period (days 6–10; P≤0.01) when most new neurons extend their axons [J Comp Neurol 413 (1999) 146]. To test whether the estradiol-induced increase in new neuron number was related to hippocampus-dependent behavior, males were injected with BrdU twice on day 0 and with estradiol or vehicle over days 6–10 before standard Morris water maze training commenced on day 16, 5 days after the final hormone injection. As in the first study, estradiol-treated males had more BrdU-labeled cells than vehicle-treated males. On a probe trial, estradiol-treated males spent significantly more time in the training quadrant than vehicle-treated males despite similar performance between groups during acquisition and reversal training trials. Thus estradiol enhanced the survival of young neurons but only when administered during their ‘axon extension’ phase and this effect was related to better spatial memory in male voles.

Task solving by procedural strategies in the Morris water maze

The aim of the present work was to assess the importance of the “general procedural” components, when for rats it was impossible to employ extramaze allothetic information to reach the goal in the Morris water maze (MWM). Groups of Long–Evans rats (males, 70 days old) were trained (10 trials per day, over five consecutive days) following seven paradigms. Four paradigms differed in context (extramaze cues available; extramaze cues not available) and in platform location (constantly at the center of one quadrant of the water maze; at random at the center of any one of the quadrants). In the fifth paradigm, there were no extramaze cues available, and the platform was located at random distances from the maze wall. In the sixth paradigm, rats underwent the standard MWM training (extramaze cues available, invisible platform constantly placed in the center of one quadrant) but they were administered with scopolamine before the daily trials. In a seventh paradigm, the platform was visible. In all paradigms, the starting point was randomized with respect to the goal. When platform distance from the wall was random, there was no significative better performance after the trials. In all the six paradigms in which platform location was at a constant distance from the wall the times spent before reaching the platform decreased progressively, to become constant on Days 4 and 5. The groups which could not employ the allothetic extramaze component (extramaze cues not available; changing of the quadrant of platform location; scopolamine administration) showed a progressively better performance even though their delays on the last 2 days were longer than those of the “standard MWM” and “visible platform” groups. The slightly less efficient performance is attributable to the rat's search strategy, a “subcircular” swimming pattern within the geometric limits of the central areas of the quadrants, where the platform was constantly placed. That no extramaze allothetic information was employed is shown by the finding that on Day 6 (probe test: 90 s in the tank without platform) no animals exhibited preference for any quadrant, while the “standard MWM” group did show such a preference. It can be concluded that rats under conditions of constant relationship of the goal to the contours of the pool employ search strategies based on general procedural components.

Impaired acquisition of a Morris water maze task following selective destruction of cerebellar purkinje cells with OX7-saporin

Spatial learning in the Morris water maze task is believed to be dependent on an intact hippocampal system. However, evidence from human studies and animal experiments suggests a potential cerebellar involvement in spatial processing, place learning, and other types of ‘higher-order’ cognition. In order to investigate this possibility, intraventricular injections (ICV) of the anti-neuronal immunotoxin OX7-saporin were used to selectively destroy cerebellar Purkinje cells, without affecting other brain areas believed to be critically involved in spatial learning and memory. Bilateral ICV injections of 2 μg OX7-saporin (4 μg total) in adult male rats produced substantial loss of Purkinje cells (56%) throughout the cerebellum without affecting hippocampal morphology or biochemical indices of cholinergic, serotonergic, or catecholaminergic function in the hippocampus, frontal cortex, or striatum. ICV OX7-saporin significantly impaired acquisition and performance of the standard Morris water maze task (though the impairment was less severe than reported in earlier studies that used alternate lesion methods or mutant mice species), but did not alter performance on the cued version of the task, or locomotor activity. In addition, lesioned animals spent significantly less time in the target quadrant on probe trial days 4 and 7 and the average distance to target scores (ADT) were significantly greater than controls on those days. Swim speed was not affected. Based on the specificity of the behavioral and neurobiological alterations, these data support the hypothesis that the cerebellum is involved in spatial processing and place learning.

The influence of Cerebrolysin and E021 on spatial navigation of 24-month-old rats.

In the present study the behavioural effects of Cerebrolysin (Cere), a peptidergic nootropic drug, and E021, the concentrated peptide fraction of Cere, were investigated in 24-month-old rats. Rats passing a pretest to exclude motor- and eye-deficits were treated with either drugs or saline as control (2.5 ml/kg, intraperitoneally i.p.) for 19 days. Animals were tested in a standard Morris water maze on day 16 after pretest for 4 consecutive days (test days 1-4), eight trials per day. No significant differences of escape latency between males and females were found, therefore, results were pooled. Both Cere and E021 treated rats showed significant lower escape latencies than saline treated controls on all four test days (p < 0.01). More pronounced effects of both drugs were found for female rats. Female rats showed no significant differences in motor activity whereas drug treated males swam quicker on test day 1 (Cere p < 0.01: E021 p < 0.05) and day 2 (Cere p < 0.01). In the present experiments it was demonstrated that i.p. administration of both Cere and E021 improves the spatial learning and memory of 24 month-old male and female rats.

Comparison of effects of global cerebral ischaemia on spatial learning in the standard and radial water maze: relationship of hippocampal damage to performance

Groups of rats which had undergone global ischaemia for 10, 15 or 20 min using the four-vessel occlusion technique were compared with sham-operated controls on learning to locate a submerged platform in both acquisition and working memory tasks in a standard Morris water maze, and in a working memory task in an eight-channel water radial maze. Ischaemic rats showed duration-related impairments in all three tasks. The water radial maze task was learned more slowly than standard water maze tasks, but deficits were long-lasting. In the first phase of training in the radial water maze controls were more reluctant than ischaemic rats to visit all arms of the maze, and were subsequently found to spend less time on the open arms of an elevated plusmaze. However, differences in anxiety are not likely to account for differences in working memory performance in the radial water maze, as groups showed similar error rates before and after habituation to the maze. Histological examination showed that cell loss occurred chiefly in the CAI field of the hippocampus and was linearly related to duration of occlusion. Cell loss was significantly correlated with the extent of impairment, but the pattern of relationships varied across the different tasks. For water maze acquisition, deficits in latency, heading angle and time spent in the training quadrant related more strongly to CAI than CA3 cell loss, but radial water maze impairments showed the reverse tendency. In all cases correlations were substantially reduced following exclusion of rats with maximal CAI cell loss, although a modest relationship with CAI damage remained for latency in acquisition and working memory tasks, and heading angle on the probe trial. These results suggested that relationships between water maze impairments and cell loss are robust only after near total destruction of the dorsal CAI field.

Selective immunolesions of hippocampal cholinergic input fail to impair spatial working memory

The septo-hippocampal cholinergic pathway has traditionally been thought of as essential for spatial memory. Recent studies have demonstrated intact spatial learning following removal of this pathway with an immunotoxin selective for cholinergic neurons. In the present experiment, rats with selective removal of hippocampal cholinergic input were tested in a delayed nonmatching-to-position task in a water version of the radial arm maze. This allowed us to increase and parametrically vary the memory load compared with the standard Morris water maze (by varying the delay between the initial four choices and the final four choices) to determine if this would reveal a deficit in rats with lesions of septo-hippocampal cholinergic projections. Male Long-Evans rats were given injections of 192 lgG-saporin, a selective immunotoxin for cholinergic neurons, into the medial septum/vertical limb of the diagonal band (MS/VDB) to remove cholinergic projections to the hippocampus, or a control surgery. The rats were trained on the radial maze task following surgery. An escape platform was located at the end of each arm of the maze and was removed after an arm was utilized for escape. After initial training, a delay was interposed between the first four trials and the second four trials. Errors during the second four-trial component were scored in two categories: retroactive (reentering an arm chosen before the delay) and proactive (reentering an arm chosen after the delay). Retroactive errors increased as delay increased (from 60 s to 6 h) but were equivalent in control and MS/VDB-lesion groups. Proactive errors did not vary with delay and were also unaffected by the lesion. Radioenzymatic assays for choline acetyltransferase activity in the hippocampus of lesioned rats confirmed a significant loss of cholinergic input from the MS/VDB. These results indicate that normal spatial working memory is possible after substantial loss of septo-hippocampal cholinergic projections. Hippocampus 7:130–136, 1997. © 1997 Wiley-Liss, Inc.