Differential induction of c-Jun and Fos-like proteins in rat hippocampus and dorsal striatum after training in two water maze tasks

Research examining the neuroanatomical bases of memory in mammals suggests that the hippocampus and dorsal striatum are parts of independent memory systems that mediate "cognitive" and stimulus-response "habit" memory, respectively. At the molecular level, increasing evidence indicates a role for immediate early gene (IEG) expression in memory formation. The present experiment examined whether acquisition of cognitive and habit memory result in differential patterns of IEG protein product expression in these two brain structures. Adult male Long-Evans rats were trained in either a hippocampal-dependent spatial water maze task, or a dorsal striatal-dependent cued water maze task. Ninety minutes after task acquisition, brains were removed and processed for immunocytochemical procedures, and the number of cells expressing Fos-like immunoreactivity (Fos-like-IR) and c-Jun-IR in sections from the dorsal hippocampus and the dorsal striatum were counted. In the dorsal hippocampus of rats trained in the spatial task, there were significantly more c-Jun-IR pyramidal cells in the CA1 and CA3 regions, relative to rats that had acquired the cued task, yoked controls (free-swim), or na?ve (home cage) rats. Relative to rats receiving cued task training and control conditions, increases in Fos-like IR were also observed in the CA1 region of rats trained in the spatial task. In rats that had acquired the cued task, patches of c-Jun-IR were observed in the posteroventral striatum; no such patches were evident in rats trained in the spatial task, yoked-control rats, or na?ve rats. The results demonstrate that IEG protein product expression is up-regulated in a task-dependent and brain structure-specific manner shortly after acquisition of cognitive and habit memory tasks.     

Neurotoxic dorsal CA1 lesions versus 4 VO ischaemic lesions: behavioural comparisons

Anterograde amnesia, a common consequence of transient cerebral ischaemia, has been attributed to cell loss in the hippocampal CA1 subfield. However, variable, widespread damage outside hippocampal CA1 can also occur following ischaemia. We compared the functional consequences of ischaemia and ibotenate acid CA1 lesions on 2 spatial memory tasks (water maze 'place' and 'matching-to-position') to address the possibility that extra-CA1 loss contributes to ischaemia-induced memory deficits in the rat. During place task acquisition, ischaemic rats showed deficits on more measures than ibotenic rats, and during a 1 min probe trial, only ischaemic rats were impaired. On the matching-to-position task, ibotenic rats showed greater impairment than ischaemic rats in terms of one-trial learning, whereas ischaemic rats were more impaired after Trial 2. Ischaemia and ibotenic acid lesions resulted in equivalent CA1 loss, but silver impregnation revealed additional extra-CA1 cell loss in ischaemic rats. Together with the greater behavioural deficits of ischaemic rats, these data indicate a role for extra-CA1 cell loss in ischaemia-induced memory impairments in both animals and humans.     

Anterior but not intralaminar thalamic nuclei support allocentric spatial memory

Medial thalamic damage is a common cause of severe memory disruption in humans. Both the anterior thalamic nuclei (ATN) and the intralaminar thalamic nuclei (ILN) have been suggested as primary sites of diencephalic injury underlying learning and memory deficits, but their respective roles have yet to be resolved. The present study explicitly compared two spatial memory tasks in male PVGc hooded rats with selective neurotoxic lesions to either (1) the ATN or (2) the rostral ILN (and adjacent lateral mediodorsal thalamic nuclei; ILN/LT lesions). As predicted, the ATN group, but not the ILN/LT group, exhibited clear deficits in the Morris water maze task for the initial acquisition of a fixed hidden platform and its reversal to a new position. The second task examined acquisition of egocentric spatial reference memory for a left or right body turn, using any three arms in an 8-arm water maze on any given trial; contrary to predictions, both lesion groups performed as well as the Sham group. The lack of deficits in ILN/LT rats on this second task contrasted with previous findings reporting a detrimental effect of ILN/LT lesions on egocentric working memory. The clear dissociation between the influence of ATN and ILN/LT lesions with respect to allocentric spatial reference memory in the Morris maze emphasizes that caution is required when interpreting the effects of non-ATN thalamic lesions on spatial memory when the lesions encroach substantial areas of the adjacent ATN region.     

Vitamins E and C pretreatment prevents ovariectomy-induced memory deficits in water maze

We investigated whether the pretreatment with vitamins E (alpha-tocopherol) and C (ascorbic acid) would act on ovariectomy-induced memory deficits in Morris water maze tasks. Adult female Wistar rats were divided into three groups: (1) naive (control), (2) sham (submitted to surgery without removal of ovaries) and (3) ovariectomized. Thirty days after surgery, they were trained in the Morris water maze in order to verify ovariectomy effects both on reference and working memory tasks. Results show that ovariectomized rats presented impairment in spatial navigation in the acquisition phase, as well as in the time spent in target quadrant and in the latency to cross over the location of the platform in test session, when compared to naive and sham groups (controls), in the reference memory task. Ovariectomy did not affect performance in the working memory task. Confirming our hypothesis, ovariectomized rats pretreated for 30 days with vitamins E and C had those impairments prevented. We conclude that ovariectomy significantly impairs spatial reference learning/memory and that pretreatment with vitamins E and C prevents such effect. Assuming this experimental memory impairment might mimic, at least in part, the cognitive deficit sometimes present in the human condition of lack of reproductive hormones, our findings lend support to a novel therapeutic strategy, based on vitamins E and C, to cognitive impairments in post-menopausal women.     

Hippocampal expression of the orphan nuclear receptor gene hzf-3/nurr1 during spatial discrimination learning

The immediate-early gene hzf-3, also known as nurr1, is a member of the inducible orphan nuclear receptor family and is one candidate in the search for genes associated with learning and memory processes. Here we report that acquisition of a spatial food search task is accompanied by elevated levels of hzf-3 mRNA in the hippocampus. Adult male Long-Evans rats were handled, food-restricted, and allowed to habituate to the maze prior to training. During acquisition, rats were given one training session per day for 5 days. Each training session consisted of five trials in which animals searched the maze for food located in 4 of 16 holes in the floor of the maze. Training resulted in spatial acquisition of the task. Northern blot analysis showed significant increases in hippocampal hzf-3 mRNA 3 h after training in the maze. Next, brains were obtained from Naive, Habituated, Day 1, Day 3, and Day 5 animals and processed for in situ hybridization. The results showed significant increases of hzf-3 mRNA in CA1 and CA3 subregions of the dorsal hippocampus during acquisition of the task. We conclude that expression of the hzf-3 gene in the brain is associated with long-term spatial memory processes. The present results are the first to implicate an orphan nuclear receptor in long-term information storage in the hippocampus.     

Simultaneous training on two hippocampus-dependent tasks facilitates acquisition of trace eyeblink conditioning

A common cellular alteration, reduced post-burst afterhyperpolarization (AHP) in CA1 neurons, is associated with acquisition of the hippocampus-dependent tasks trace eyeblink conditioning and the Morris water maze. As a similar increase in excitability is correlated with these two learning paradigms, we sought to determine the interactive behavioral effects of training animals on both tasks by using either a consecutive or simultaneous training design. In the consecutive design, animals were trained first on either the trace eyeblink conditioning task for six sessions, followed by training on the water maze task for six sessions, or vice versa. The simultaneous design consisted of six or 11 training days; animals received one session/day of both trace eyeblink conditioning and water maze training. Separate groups were used for consecutive and simultaneous training. Animals trained on both tasks simultaneously were significantly facilitated in their ability to acquire the trace eyeblink conditioning task; no effect of simultaneous training was seen on the water maze task. No effect was seen on acquisition for either task when using the consecutive training design. Taken together, these findings provide insight into how the hippocampus processes information when animals learn multiple hippocampus-dependent tasks.     

Dietary restriction inhibits spatial learning ability and hippocampal cell proliferation in rats1

Abstract: We investigated the effect of dietary restriction on spatial learning ability and hippocampal cell proliferation in adult rats using two spatial learning tasks and immunohistochemical staining with 5‐bromo‐2′‐deoxyuridine (BrdU). Sixteen rats were divided into restricted or ad lib feeding groups at 70 days of age, and were trained in the delayed‐matching‐to‐place (DMTP) task (a working memory task) from 93 days of age, and then the Morris water maze task (a reference memory task). Dietary restriction had no effect on the DMTP task with 30 s delay and on the water maze task. However, in the DMTP task with 30 min delay, restricted rats performed significantly more poorly than ad lib rats. Quantitative analysis of hippocampal cell proliferation revealed that the density of newborn cells in restricted rats was significantly lower than that in ad lib rats. These results suggest that a loss of proliferating capacity in the hippocampus may be a candidate for an anatomical and biological basis for the cognitive decline caused by dietary restriction.     

A test of the reward-value hypothesis

Rats retain source memory (memory for the origin of information) over a retention interval of at least 1 week, whereas their spatial working memory (radial maze locations) decays within approximately 1 day. We have argued that different forgetting functions dissociate memory systems. However, the two tasks, in our previous work, used different reward values. The source memory task used multiple pellets of a preferred food flavor (chocolate), whereas the spatial working memory task provided access to a single pellet of standard chow-flavored food at each location. Thus, according to the reward-value hypothesis, enhanced performance in the source memory task stems from enhanced encoding/memory of a preferred reward. We tested the reward-value hypothesis by using a standard 8-arm radial maze task to compare spatial working memory accuracy of rats rewarded with either multiple chocolate or chow pellets at each location using a between-subjects design. The reward-value hypothesis predicts superior accuracy for high-valued rewards. We documented equivalent spatial memory accuracy for high- and low-value rewards. Importantly, a 24-h retention interval produced equivalent spatial working memory accuracy for both flavors. These data are inconsistent with the reward-value hypothesis and suggest that reward value does not explain our earlier findings that source memory survives unusually long retention intervals.     

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 learning in the 5-HT1B receptor knockout mouse: selective facilitation/impairment depending on the cognitive demand

Age-related memory decline is associated with a combined dysfunction of the cholinergic and serotonergic systems in the hippocampus and frontal cortex, in particular. The 5-HT1B receptor occupies strategic cellular and subcellular locations in these structures, where it plays a role in the modulation of ACh release. In an attempt to characterize the contribution of this receptor to memory functions, 5-HT1B receptor knockout (KO) mice were submitted to various behavioral paradigms carried out in the same experimental context (water maze), which were aimed at exposing mice to various levels of memory demand. 5-HT1BKO mice exhibited a facilitation in the acquisition of a hippocampal-dependent spatial reference memory task in the Morris water maze. This facilitation was selective of task difficulty, showing thus that the genetic inactivation of the 5-HT1B receptor is associated with facilitation when the complexity of the task is increased, and reveals a protective effect on age-related hippocampal-dependent memory decline. Young-adult and aged KO and wild-type (WT) mice were equally able to learn a delayed spatial matching-to-sample working memory task in a radial-arm water maze with short (0 or 5 min) delays. However, 5-HT1BKO mice, only, exhibited a selective memory impairment at intermediate and long (15, 30, and 60 min) delays. Treatment by scopolamine induced the same pattern of performance in wild type as did the mutation for short (5 min, no impairment) and long (60 min, impairment) delays. Taken together, these studies revealed a beneficial effect of the mutation on the acquisition of a spatial reference memory task, but a deleterious effect on a working memory task for long delays. This 5-HT1BKO mouse story highlights the problem of the potential existence of "global memory enhancers."     

Vestibular stimulation disrupts acquisition of place navigation in the Morris water tank task

The significance of vestibular input for place navigation in the Morris water maze was examined in 11 hooded rats. A 5-min rotation (2 Hz) immediately preceding retrieval of an overtrained place navigation task prolonged escape latencies by about 10 s corresponding to circular swimming induced by postrotatory aftereffects, but did not otherwise interfere with target location. A 1-min rotation immediately following the acquisition trial in the working memory version of the water maze task did not deteriorate performance in the retrieval trial performed 5 min later. Two components of the acquisition trial, i.e., active search of the hidden target (up to 1 min) and latent learning during the 30-s stay on the platform, contribute almost equally to the formation of the working memory trace. A 1-min rotation immediately preceding the isolated platform learning component impaired subsequent retrieval but was ineffective when applied 3 min earlier. Latent learning was completely disrupted when the platform with the animal was rotated during the entire 30-s stay on the target platform or when the 30-s stay on the stationary platform was followed 0 or 3 min later by a 30-s rotation on the platform. The interfering effect of the latter procedure was suppressed by covering the platform with the animal by an opaque cylinder. It is concluded that vestibular cues are particularly important for the orientation of the animal in the gravitation field and for the estimation of the angles between vectors plotted from the animal toward external landmarks. Agreement between vestibular and visual signals is a prerequisite of efficient navigation.     

Involvement of the hippocampal CA3-region in acquisition and in memory consolidation of spatial but not in object information in mice

This study investigates the implication of the hippocampal CA3-region in the different phases of learning and memory in spatial and non-spatial tasks. For that purpose, we performed focal injections of diethyldithiocarbamate (DDC) into the CA3-region of the dorsal hippocampus. The DDC chelates most of the heavy metals in the brain which blocks selectively and reversibly the synapses containing heavy metals, i.e., the mossy fibres synaptic buttons and synapses of the dendrites of pyramidal cells. The effects of temporal inactivation of the CA3-region was examined in a non-associative task, the spatial open-field, designed to estimate the ability of mice to react to spatial changes, and in the object recognition task, designed to estimate the ability of mice to identify a familiar object. The results show that DDC induced a specific impairment on learning and memory consolidation in the spatial open-field but had no effect on recall in this task. In the object recognition task, DDC did not induce any impairment in the different phases of learning and memory. These data demonstrate that the hippocampal CA3-region is specifically implicated in spatial information processing and seems to be involved not only in acquisition but also in consolidation of spatial information.     

Protective effect of practice on cognition during aging: implications for predictive characteristics of performance and efficacy of practice

In the present study, the effect of previous experience on spatial memory, which required the retention of information either over long intervals or within a single session, was longitudinally tested in the water maze in male F-344 rats that were from 6 to 24 months of age. Performance in these tasks was found to be age-dependent (Markowska, 1999). Other behavioral tasks in the straight alley and with a visible platform in the water maze controlled the noncognitive components of performance. For all tasks, performance was significantly correlated between 12-month-old and 18-month-old rats, indicating that cognitive performance at the early, but not advanced, stage of aging could be predicted from performance at a younger age if the novelty of the first exposure to the task was eliminated. The protective effect of experience was more robust in the reference memory task as compared to the working memory task and was modified by age when training was initiated. Behavior during the probe trials was more sensitive to the effect of aging and more resistant to the beneficial effect of practice as compared to the performance in the platform trials. The speed of swimming of experienced rats progressively decreased with age only when tested in the cognitive tasks but not in the straight alley. This indicates that speed of swimming during cognitive tasks does not exclusively reflect the ability to swim, but might be also affected by the cognitive demands of the task. Protective effect of experience on cognition was not modified by restriction in diet.     

Behavioral functions of the CA3 subregion of the hippocampus

From a behavioral perspective, the CA3a,b subregion of the hippocampus plays an important role in the encoding of new spatial information within short-term memory with a duration of seconds and minutes. This can easily be observed in tasks that require rapid encoding, novelty detection, one-trial short-term or working memory, and one-trial cued recall primarily for spatial information. These are tasks that have been assumed to reflect the operations of episodic memory and require interactions between CA3a,b and the dentate gyrus via mossy fiber inputs into the CA3a,b. The CA3a,b is also important for encoding of spatial information requiring multiple trials including the acquisition of arbitrary and relational associations. These tasks tend to be non-episodic and can be mediated by arbitrary and conjunctive operations. All these tasks are assumed to operate within an autoassociative network function of the CA3 region. The output from CA3a,b via the fimbria and the medial and lateral perforant path inputs play a supporting role in the neural circuit that supports the operation of these tasks. The CA3a,b also plays a role in sequential processing of information in cooperation with CA1 based on the Schaffer collateral output from CA3a,b to CA1. The CA3a,b also supports retrieval of short-term memory information based on a spatial pattern completion process. Finally, CA3c may, in cooperation with the dentate gyrus, serve an important role in processing the geometry of the environment.     

Longitudinal attentional engagement rescues mice from age-related cognitive declines and cognitive inflexibility

Learning, attentional, and perseverative deficits are characteristic of cognitive aging. In this study, genetically diverse CD-1 mice underwent longitudinal training in a task asserted to tax working memory capacity and its dependence on selective attention. Beginning at 3 mo of age, animals were trained for 12 d to perform in a dual radial-arm maze task that required the mice to remember and operate on two sets of overlapping guidance (spatial) cues. As previously reported, this training resulted in an immediate (at 4 mo of age) improvement in the animals' aggregate performance across a battery of five learning tasks. Subsequently, these animals received an additional 3 d of working memory training at 3-wk intervals for 15 mo (totaling 66 training sessions), and at 18 mo of age were assessed on a selective attention task, a second set of learning tasks, and variations of those tasks that required the animals to modify the previously learned response. Both attentional and learning abilities (on passive avoidance, active avoidance, and reinforced alternation tasks) were impaired in aged animals that had not received working memory training. Likewise, these aged animals exhibited consistent deficits when required to modify a previously instantiated learned response (in reinforced alternation, active avoidance, and spatial water maze). In contrast, these attentional, learning, and perseverative deficits were attenuated in aged animals that had undergone lifelong working memory exercise. These results suggest that general impairments of learning, attention, and cognitive flexibility may be mitigated by a cognitive exercise regimen that requires chronic attentional engagement.     

The effects of guanfacine, alpha-2 agonist, on the performance of young and aged rats in spatial navigation task.

The aim of the present experiment was to study the effects of a low dose (0.001 mg/kg) of guanfacine, alpha-2 agonist, on the acquisition and retention of a water maze task measuring spatial reference memory in young and aged rats. Aged rats were impaired in the acquisition of this task. Both young and aged rats treated with guanfacine had shorter escape latencies than their saline treated counterparts. However, guanfacine treatment increased the speed of swimming in aged rats. According to the results of the probe trial, guanfacine may slightly improve the acquisition/retention of water maze task in young rats, whereas it may slightly impair the acquisition/retention of aged rats. The results suggest that a low dose of guanfacine administered peripherally may have different effects on young and aged rats in water maze performance, and a low dose of guanfacine does not improve spatial reference memory in aged rats.     

Bidirectional interactions between circadian entrainment and cognitive performance

Circadian rhythms influence a variety of physiological and behavioral processes; however, little is known about how circadian rhythms interact with the organisms' ability to acquire and retain information about their environment. These experiments tested whether rats trained outside their endogenous active period demonstrate the same rate of acquisition, daily performance, and remote memory ability as their nocturnally trained counterparts in tasks of sustained attention and spatial memory. Furthermore, we explored how daily task training influenced circadian patterns of activity. We found that rats demonstrate better acquisition and performance on an operant task requiring attentional effort when trained during the dark-phase. Time of day did not affect acquisition or performance on the Morris water maze; however, when animals were retested 2 wk after their last day of training, they showed better remote memory if training originally occurred during the dark-phase. Finally, attentional, but not spatial, task performance during the light-phase promotes a shift toward diurnality and the synchronization of activity to the time of daily training; this shift was most robust when the demands on the cognitive control of attention were highest. Our findings support a theory of bidirectional interactions between cognitive performance and circadian processes and are consistent with the view that the circadian abnormalities associated with shift-work, aging, and neuropsychiatric illnesses may contribute to the deleterious effects on cognition often present in these populations. Furthermore, these findings suggest that time of day should be an important consideration for a variety of cognitive tasks principally used in psychological and neuroscience research.     

Cognitive performances and locomotor activity following dentate granule cell damage in rats: role of lesion extent and type of memory tested

Intradentate injection of colchicine is one of the techniques used to destroy granule cells. This study compared the behavioral effects of various amounts of colchicine (1.0, 3.0, and 6.0 microg; Col 1, Col 3, and Col 6, respectively) injected into the dentate gyrus of adult Long-Evans male rats. Starting 10 days after lesion surgery, behavioral testing assessed home-cage and open-field locomotion, alternation in a T-maze, water-maze, and radial-maze learning according to protocols placing emphasis on reference, and working memory. All of these tasks are sensitive to hippocampal disruption. Histological verifications showed that the extent of the lesions depends on the dose of colchicine (index of dentate gyrus shrinkage: -33% in Col 1, -54% in Col 3, and -67% in Col 6 rats). Colchicine dose-dependently increased nocturnal home cage activity (an effect found 10 days but not 5 months after surgery), but had no significant effect on open-field locomotion or T-maze alternation. A dose-dependent reference memory impairment was found during the acquisition of spatial navigation in the water maze; Col 3 and Col 6 rats were more impaired than Col 1 rats. During the probe trial (platform removed), control rats spent a longer distance swimming over the platform area than all rats with colchicine lesions. In the working memory version of the test, all rats with colchicine lesions showed significant deficits. The deficits were larger in Col 3 and Col 6 rats compared to Col 1 rats. The lesions had no effect on swimming speed. In the radial-maze test, there was also a dose-dependent working memory impairment. However, reference memory was disrupted in a manner that did not differ among the three groups of lesioned rats. Our data are in line with the view that the dentate gyrus plays an important role in the acquisition of new information and is an integral neural substrate for spatial reference and spatial working memory. They also suggest that damage to granule cells might have more pronounced effects on reference than on working memory in the radial maze. Finally, they demonstrate that part of the variability in the conclusions from previous experiments concerning the role of granule cells in cognitive processes, particularly in spatial learning and memory, may be due to the type of tests used and/or the extent of the damage produced.     

Transient activation of the CA3 Kappa opioid system in the dorsal hippocampus modulates complex memory processing in mice

The hippocampus plays a central role in various forms of complex learning and memory. Opioid peptides and receptors are abundant in the hippocampus. These peptides are co-released with glutamate from mossy fiber- and lateral perforant path-synapses. In this study, we evaluated the functional relevance of the CA3 Kappa opioid receptors (KOR) by transient pharmacological activation or inactivation using single bilateral intrahippocampal microinjections of a selective agonist (U50,488H, 1 or 2.5 nmol), a selective antagonist (nor-binaltorphimine, norBNI 5 nmol) or a mixture of both. C57Bl/6J mice were tested in a fear conditioning paradigm (FC) or in a modified version of the water maze task thought to reveal how flexibly animals can learn and manipulate spatial information (WM). In FC, the agonist (2.5 nmol) decreased context-induced (but not tone-induced) freezing whereas norBNI had no effect. The impairment caused by the agonist U50,488H was blocked by the injection of norBNI, suggesting that overstimulation of CA3-KOR impairs the acquisition and consolidation of contextual fear-related memory. In the WM task, mice were trained repeatedly each day to find a hidden platform. After having reached this goal, the platform position was changed the next day for a new task. U50,488H injection before the last task abolished the previously acquired ability to find rapidly a new platform location, whereas adding norBNI reversed this impairment. Thus, in the mouse, even partial and topographically restricted activation of CA3-KOR entails impairments in two different hippocampus-dependent tasks, indicating functional relevance of the kappa opioid system.