Posttraining intrahippocampal estradiol injections enhance spatial memory in male rats: interaction with cholinergic systems

Male Long-Evans rats received an 8-trial training session in a spatial water maze task, followed by a unilateral posttraining intrahippocampal injection of either estradiol (1.0 microgram/0.5 microliter) or saline. Retention was tested 24 hr later, and latency to escape was used as a measure of memory. Retention test escape latencies of rats given intrahippocampal injections of estradiol were lower than those of saline-treated rats, indicating an enhancement of memory. Intrahippocampal injections of estradiol delayed 2 hr posttraining did not affect retention. In Experiment 2, the memory enhancing effect of intrahippocampal injection of estradiol was blocked by peripheral administration of a subeffective dose (0.1 mg/kg) of the cholinergic antagonist scopolamine. Intrahippocampal injections of estradiol enhance memory in male rats, and estradiol may influence memory through an interaction with muscarinic cholinergic systems.     

Double dissociation of hippocampal and dorsal-striatal memory systems by posttraining intracerebral injections of 2-amino-5-phosphonopentanoic acid.

Rats received an 8-trial training session on a spatial or cued task in a water maze, followed by a posttraining intracerebral injection of AP5 or saline. On a retention test 24 hr later, latency to mount the escape platform was used as a measure of memory. Intrahippocampal (10 μg), but not intra-dorsal striatal (2, 5, or 10 μg), injection of AP5 impaired memory in the spatial task. In contrast, intra dorsal striatal (2 μg), but not intrahippocampal (2, 5, or 10 μg) injection of AP5 impaired memory in the cued task. Intracerebral injections of AP5 delayed 2 hr posttraining were ineffective. The findings indicate a double dissociation of the roles of the hippocampus and dorsal striatum in memory, a role for N -methyl-{d}-aspartate receptor function in posttraining memory processes, and a glutamatergic modulation of both hippocampal and dorsal striatal memory processes, suggesting that different forms of memory may share a similar neurochemical basis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Involvement of hippocampal NMDA receptors in retention of shuttle avoidance conditioning in rats

The purpose of this research was to evaluate the role of hippocampal N-methyl-D-aspartate (NMDA) receptors in acquisition and consolidation of memory during shuttle avoidance conditioning in rats. Adult male Wistar rats were surgically implanted with cannulae aimed at the CA1 area of the dorsal hippocampus. After recovery from surgery, animals were trained and tested in a shuttle avoidance apparatus (30 trials, 0.5-mA footshock, 24-h training-test interval). Immediately before or immediately after training, animals received a bilateral intrahippocampal 0.5-microliter infusion containing 5.0 microgram of the NMDA competitive receptor antagonist aminophosphonopentanoic acid (AP5) or vehicle (phosphate-buffered saline, pH 7.4). Infusion duration was 2 min per side. Pre-training infusion of AP5 impaired retention test performance (mean +/- SEM number of conditioned responses (CRs) during retention test session was 16.47 +/- 1.78 in the vehicle group and 9.93 +/- 1.59 in the AP5 group; P < 0.05). Post-training infusion of AP5 did not affect retention (mean +/- SEM number of conditioned responses during retention test session was 18.46 +/- 1.94 in the vehicle group and 20.42 +/- 2.38 in the AP5 group; P > 0.10). This impairment could not be attributed to an effect on acquisition, motor activity or footshock sensitivity since AP5 affected neither training session performance measured by the number of CRs nor the number of intertrial crossings during the training session. These data suggest that NMDA receptors in the hippocampus are critical for retention of shuttle avoidance conditioning, in agreement with previous evidence showing a role of NMDA receptors in fear memory.     

NMDA receptor involvement in spatial delayed alternation in developing rats.

Two experiments examined the effect of the noncompetitive NMDA receptor antagonist, dizocilpine maleate (MK-801), on spatial working memory during development. Rats were trained on spatial delayed alternation (SDA) in a T-maze after ip administration of 0.06 mg/kg MK-801, 0.1 mg/kg MK-801, or saline on postnatal days (P) P23 and P33 (Experiment 1), or following bilateral intrahippocampal administration of 2.5 or 5.0 υg per side MK-801 or saline on P26 (Experiment 2). In Experiment 1, MK-801 dose-dependently impaired SDA learning at both ages. Because the same doses of systemic MK-801 have no effect on T-maze position discrimination learning, impairment of SDA by MK-801 likely reflects disruption of spatial working memory. Both doses of MK-801 abolished acquisition of SDA performance in Experiment 2. Disruption of hippocampal plasticity may account for the effects produced by systemic MK-801 administration. These results confirm and extend earlier lesion studies by implicating plasticity of hippocampal neurons in the ontogeny of spatial delayed alternation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pretraining does not ameliorate spatial learning deficits induced by intrahippocampal infusion of AP5.

Previous studies show discrepancies concerning the effects of pretraining on spatial learning deficits induced by blockade of the N-methyl-d-aspartate (NMDA) receptor. These inconsistencies might be attributed to the differences in the nature of the pretraining tasks and the method of blocking NMDA receptors. In the present study, the authors pretrained rats in a spatial water maze task. The authors then trained them with a novel spatial task in a novel environment under chronic blockade of hippocampal NMDA receptors by intrahippocampal infusion of 2-amino-5-phosphonopentanoic acid (AP5) using osmotic pumps. Although the rats had acquired the basic techniques needed to solve a water-maze spatial task during pretraining, those given high or low doses of AP5 showed acquisition deficits. As the spatial pretraining failed to ameliorate the acquisition deficits of a new task in a novel environment, it was suggested that NMDA receptors were necessary in forming spatial representations. Because neither dose of AP5 affected the performance of a spatial task in the retention phase, sensory motor disturbances could not have caused these deficits. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Promotion of colon carcinogenesis through increasing lipid peroxidation induced in rats by a high cholesterol diet

Recent studies suggest a role of the neural cell adhesion molecules L1 and NCAM in mechanisms of memory storage. In the present study we analyzed the effect of continuous intraventricular infusion of polyclonal antibodies directed against L1 (antiL1) or NCAM (antiNCAM) on the performance of male Wistar rats during the acquisition and retention of a spatial learning task (Morris water-maze). In this task animals have to learn the spatial position of a hidden escape platform in a water tank to escape onto it. During acquisition of the task animals with continuous infusion of antiNCAM - but not those infused with antiL1 - showed day-dependent attenuated learning in comparison to controls (P = 0.001). Control animals were either injected with vehicle (PBS) or with polyclonal antibodies raised against liver cell membrane. When the escape platform was removed during the retention test (transfer test), the performance of animals continuously infused with antiL1 as well as those continuously infused with antiNCAM showed an impaired search pattern when compared with the performance of control animals (P = 0.001 and 0.04, respectively). Whereas control animals spent up to 46% of their time searching for the platform in the correct quadrant, the time antiL1- and antiNCAM-infused animals spent in this quadrant was closer to chance level (30.5% and 36.5%), respectively). The present data provide additional support for an involvement of the two adhesion molecules L1 and NCAM in synaptic plasticity underlying memory storage.     

The opposite effects on cysteamine on the acquisition of two different tasks in mice are associated with bidirectional testing-induced changes in hippocampal adenylyl cyclase activity.

The hypothesis of a role for hippocampal somatostatin (SS-14) in learning and memory processes was further examined by means of 2 selective learning tasks that were previously shown to be either impaired (spatial discrimination task) or facilitated (barpressing task) by hippocampal lesions. Results showed that subcutaneous injections of cysteamine (160 mg/kg) (a) impaired acquisition of the spatial task while producing an opposite (i.e., facilitative) effect on acquisition of the barpressing task and (b) produced an up regulation of hippocampal adenylyl cyclase (AC) activity, which was antagonized by spatial discrimination training but enhanced by training in the barpressing task. Moreover, opposite task-dependent training induced changes in hippocampal AC activity was observed in saline-treated mice. These results suggest that bidirectional regulatory mechanisms of hippocampal function involving both SS-14 and ACs may occur as a function of the type of learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Rats with hippocampal lesions can learn a place response, but how long can they retain it?

Previous research has shown that electrolytic hippocampal lesions do not affect the acquisition of a place response if a special training procedure is used. However, 24 days later, the hippocampal rats manifest a profound deficit in the retention of the spatial information (J. A. J. Ramos, 2000). The goal of the present study was, therefore, to investigate how long the hippocampal rats can retain a place response. Results showed that, 3 days after the end of the training, lesioned rats remembered as well as the control rats, but this was no longer true 6 or 12 days after the training. This retention deficit was not observed when the spatial information was acquired by means of a guidance strategy. These results suggest that, when a special training procedure is used, the hippocampus is not necessary for the learning of a place task but is required for the formation of long-term spatial memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of NMDA-induced retrohippocampal lesions on performance of four spatial memory tasks known to be sensitive to hippocampal damage in the rat

Four separate cohorts of rats were employed to examine the effects of cytotoxic retrohippocampal lesions in four spatial memory tasks which are known to be sensitive to direct hippocampal damage and/or fornix-fimbria lesions in the rat. Selective retrohippocampal lesions were made by means of multiple intracerebral infusions of NMDA centred on the entorhinal cortex bilaterally. Cell damage typically extended from the lateral entorhinal area to the distal ventral subiculum. Experiment 1 demonstrated that retrohippocampal lesions spared the acquisition of a reference memory task in the Morris water maze, in which the animals learned to escape from the water by swimming to a submerged platform in a fixed location. In the subsequent transfer test, when the escape platform was removed, rats with retrohippocampal lesions tended to spend less time searching in the appropriate quadrant compared to controls. Experiment 2 demonstrated that the lesions also spared the acquisition of a working memory version of the water maze task in which the location of the escape platform was varied between days. In experiment 3, both reference and working memory were assessed using an eight-arm radial maze in which the same four arms were constantly baited between trials. In the initial acquisition, reference memory but not working memory was affected by the lesions. During subsequent reversal learning in which previously baited arms were now no longer baited and vice versa, lesioned animals made significantly more reference memory errors as well as working memory errors. In experiment 4, spatial working memory was assessed in a delayed matching-to-position task conducted in a two-lever operant chamber. There was no evidence for any impairment in rats with retrohippocampal lesions in this task. The present study demonstrated that unlike direct hippocampal damage, retrohippocampal cell loss did not lead to a general impairment in spatial learning, implying that the integrity of the retrohippocampus and/or its interconnection with the hippocampal formation is not critical for normal hippocampal-dependent spatial learning and memory. This outcome is surprising for a number of current hippocampal theories, and suggests that other cortical as well as subcortical inputs to the hippocampus might be of more importance, and further raises the question regarding the functional significance of the retrohippocampal region.     

Effects of nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester on spatial and cued leaning

An investigation was made of the effects of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on the acquisition and retention of two operantly conditioned discrimination tasks. Twenty Long-Evans rats were conditioned to approach one of two spatial locations that was either held constant across trials (spatial task) or was associated with a visual cue (illuminated lamp) that was randomly assigned to one of the locations on each trial (cued task). Rats were assigned to one of two treatment groups in which they received intraperitoneal injections of either NG-nitro-L-arginine methyl ester or saline approximately 2 h before sessions on each day of training. Analysis was made of the trial-by-trial performance in order to identify the characteristics of learning under each condition. Assessment of learning acquisition was based on the number of trials required to reach a criterion of 80% correct responses, whereas retention was assessed by the number of trials to criterion on each day after the criterion was initially reached. Analysis indicated that treatment groups did not differ significantly on acquisition or retention of either the spatial or cued task. These results indicate that inhibition of nitric oxide synthase does not interfere with the learning or retention of basic operant tasks that involve simple spatial or visual analysis. Whereas results from biochemical and physiological investigations have suggested an impact of nitric oxide synthase on behavioural function, behavioural investigations indicate a limited impact of nitric oxide synthase inhibition on learning and memory. Although these results do not discount the role of nitric oxide synthase in a hippocampal mechanism, they illustrate that behavioural analysis should be made in the context of multiple interacting neural systems. Viewed with previous behavioural research on the effects of NG-nitro-L-arginine methyl ester, these results indicate that nitric oxide synthase inhibition results in impairment of certain forms of learning whereas other forms are preserved.     

Retrieval associated cholinergic activity and its inhibition by memory updating

Both hippocampal cholinergic and glutamatergic systems are believed to be engaged in learning and memory. By measuring behavior and ex vivo second messenger inositol phosphate (IP) accumulation, we investigated biochemical responses of cholinergic receptors to retrieval and acquisition processes in rats trained in a spatial task. We report that in rats retrieving spatial information, carbachol--induced IP accumulation strongly and transiently increased above values observed in handled controls and rats acquiring new information, and that this increase was profoundly inhibited by N-methyl-D-aspartate (NMDA). These results suggest that memory retrieval, rather than formation of a memory trace, is related to increased responsiveness of the hippocampal cholinergic system, and that formation of a new memory trace, which updates long-term memory, inhibits this cholinergic activation, possibly by a learning-associated increase in NMDA receptor activation. Moreover, the present study shows that the distinction between acquisition and retrieval processes can be demonstrated on both a behavioral and biochemical level.     

Microinfusions of neurotensin antagonist SR 48692 within the nucleus accumbens core impair spatial learning in rats.

The involvement of neurotensin (NT) within the nucleus accumbens core (NAC) in behavior has been sparsely investigated. Moreover, little is known of what role NT within the ventral striatum has on spatial learning. The present study investigated whether NT receptors in the NAC are implicated in learning of spatial information. Male Long-Evans rats were trained on a food search spatial learning task. Rats were microinfused with either NT antagonist SR 48692 (50 nM/0.5 =L) or saline in the NAC before each training session. Rats treated with SR 48692 made more reference and working memory errors during the acquisition of spatial learning than did rats infused with saline. These results suggest that NT receptors contribute to NAC-mediated spatial learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Newborn organ weight and spontaneous hypertension: recombinant inbred strain study

This study investigated the effects of neonatal hippocampal ablation on the development of spatial learning and memory abilities in rats. Newborn rats sustained bilateral electrolytic lesions of the hippocampus or were sham-operated on postnatal day 1 (PN1). At PN20-25, PN50-55, or PN90-95, separate groups of rats were tested in a Morris water maze on a visible "cue" condition (visible platform in a fixed location of the maze), a spatial "place" condition (submerged platform in a fixed location), or a no-contingency "random" condition (submerged platform in a random location). Rats were tested for 6 consecutive days, with 12 acquisition trials and 1 retention (probe) trial per day. During acquisition trials, the rat's latency to escape the maze was recorded. During retention trials (last trial for each day, no escape platform available), the total time the rat spent in the probe quadrant was recorded. Data from rats with hippocampal lesions tested as infants (PN20-25) or as adults (PN50-55 and PN90-95) converged across measures to reveal that 1) spatial (place) memory deficits were evident throughout developmental testing, suggesting that the deficits in spatial memory were long-lasting, if not permanent, and 2) behavioral performance measures under the spatial (place) condition were significantly correlated with total volume of hippocampal tissue damage, and with volume of damage to the right and anterior hippocampal regions. These results support the hypothesis that hippocampal integrity is important for the normal development of spatial learning and memory functions, and show that other brain structures do not assume hippocampal-spatial memory functions when the hippocampus is damaged during the neonatal period (even when testing is not begun until adulthood). Thus, neonatal hippocampal damage in rats may serve as a rodent model for assessing treatment strategies (e.g., pharmacological) relevant to human perinatal brain injury and developmental disabilities within the learning and memory realm.     

Age-related deficits on the radial maze and in fear conditioning: hippocampal processing and consolidation

Young adult, middle-aged, and old male F-344 rats were assessed for their hippocampal ability. This was accomplished by examining the animals on two different paradigms, each incorporating a simultaneous measure of hippocampal-dependent and -independent processing. The animals were fear conditioned and then tested for retention of the conditioning context and tone. This was followed by an 8-arm radial maze task which combined spatial working and cued reference memory elements. The two paradigms are compared in terms of task demands, potential confounds, and validity for aging studies. The results indicate that the performance of the animals on the two tasks is correlated. Age-related deficits limited to the hippocampal aspects of the above tasks were found, with no deficits found in the analogous but hippocampus-independent aspects of these tasks. The function of the hippocampus in incorporating new memories is time-related. Therefore, the possibility of age-related changes in consolidation was examined. It has previously been shown on the fear conditioning paradigm that the hippocampus is involved in retention of the aversive context for approximately 28 days. In the present study, an attempt was made to test the animals for retention of the conditioning context both early into the period of consolidation (10 days) and after consolidation should have been completed (52 days). The results indicate that, initially, the old animals show comparable retention to young rats. When examined later, young animals showed a stronger retention of the conditioning context than they had previously. The aged rats, however, did not seem to benefit from this additional period of time and in fact showed a decrease in retention of the conditioning context. The data are interpreted in terms of consolidation, alternative explanations of the data are presented, and suggestions are given for future research. Finally, the implications of such age-related changes in hippocampal consolidation on learning and memory are discussed.     

Long-Term Memory for Spatial Locations in a Food-Storing Bird (Poecile atricapilla) Requires Activation of NMDA Receptors in the Hippocampal Formation During Learning.

Food-storing birds use a form of long-term memory to recover their hidden food caches that depends on the hippocampal formation (HF). The authors assessed whether food-storing birds' long-term memory for spatial locations requires N-methyl-D-aspartate receptor (NMDA-R)-dependent synaptic plasticity. Black-capped chickadees (Poecile atricapilla) were given bilateral infusions of the NMDA-R antagonist AP5 into the hippocampus, and their memory on a spatial reference memory task was assessed. NMDA-R inactivation during learning prevented formation of long-term spatial memories but did not affect short-term memory and retrieval processes. NMDA-R inactivation immediately following learning did not disrupt long-term memory formation. NMDA-R inactivation disrupted the learning of multiple serially encoded reward locations when a 180-min delay separated successive learning episodes, suggesting that NMDA-R activity has a role in the incorporation of new information into existing long-term memory, as well as in forming unitary long-term memories. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Systematic comparison of the effects of hippocampal and fornix-fimbria lesions on acquisition of three configural discriminations

The effects of lesions to the hippocampal system on acquisition of three different configural tasks by rats were tested. Lesions of either the hippocampus (kainic acid/colchicine) or fornix-fimbria (radiofrequency current) were made before training. After recovery from surgery, rats were trained to discriminate between simple and compound-configural cues that signaled the availability or nonavailability of food when a bar was pressed. When positive cues were present, one food pellet could be earned by pressing a lever after a variable time had elapsed. The trial terminated on food delivery (variable interval 15 s). This procedure eliminates some possible alternative explanations of the results of previous experiments on configural learning. Hippocampal lesions increased rates of responding and retarded acquisition of a negative patterning task (A+, B+, AB-); using a ratio measure of discrimination performance these lesions had a milder retarding effect on a biconditional discrimination (AX+, AY-, BY+, BX-), and they had no effect on a conditional context discrimination (X: A+, B-; Y: A-, B+). Fornix-fimbria lesions did not affect acquisition of any of these tasks but increased rates of responding. The results suggest that several task parameters determine the involvement of the hippocampus in configural learning; however, all tasks tested can also be learned to some extent in the absence of an intact hippocampal system, presumably by other learning/memory systems that remain intact following surgery. The lack of effect of fornix-fimbria lesions on any of these tasks suggests that retrohippocampal connections with other brain areas may mediate hippocampal contributions to the learning of some configural tasks. An analysis of these results and of experiments on spatial learning situations suggests that involvement of the hippocampus is a function of the degree to which correct performance depends on a knowledge of relationships among cues in a situation.     

New clinical issues in celiac disease

The present study examined, in rats with N-methyl-D-aspartate-induced lesions of the basolateral amygdala, the effects of long-term adrenalectomy (i.e. 12-13 weeks) on memory for spatial and cued learning in a water maze. In sham amygdala-lesioned rats, adrenalectomy induced impairments in acquisition and retention performance for the spatial, but not the cued water-maze task. The adrenalectomized rats sustained selective degeneration and death of granule cells in the dentate gyrus dorsal blade. Continuous supplementation of the animals' drinking water with an extremely low dose of corticosterone (20 microg/ml) did not block the retention deficit, but blocked the acquisition deficit and the dentate gyrus neurodegenerative changes. The finding that the memory impairments and dentate gyrus neurodegeneration are dissociable supports the view that the adrenalectomy-induced memory effects are due to the loss of activational effects of circulating adrenal hormones at the time of learning. In adrenalectomized rats which received corticosterone as well as those which did not, lesions of the basolateral amygdala blocked the impairing effects of adrenalectomy on spatial learning and memory. However, the basolateral amygdala lesions did not affect the neurodegenerative changes in the dentate gyrus. In conclusion, the present findings provide further evidence that the basolateral amygdala is involved in regulating stress hormone effects on learning and memory.     

Spatial learning and memory at defined points of the estrous cycle: Effects on performance of a hippocampal-dependent task.

Learning based on hippocampal-dependent spatial navigation in female rats was assessed at identified points in the estrous cycle corresponding to low (estrus) and high (proestrus) circulating estrogen. With background training in water-maze procedures, rats learned the location of an escape platform in the maze in a single session of 8 training trials. A strong spatial bias for the escape platform was also evident in a probe trial used to assess retention of learning 30 min after the training session. This entire protocol was completed in less than an hour. The performance of the estrus and proestrus rats was indistinguishable on all behavioral measures, irrespective of the stage of estrous cycle during the task. These results indicate that rapid learning and retention for spatial information over a relatively short interval may be preserved despite morphological alterations in hippocampal dendritic spine density in the normally cycling female rat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Metabolism of 4,7,10,13,16,19-docosahexaenoic acid in isolated perfused adult and newborn pig eyes

In rats, hippocampal lesions result in impairment of spatial navigation, although other learning abilities remain unaltered. When learning a left/right discrimination task, rats can use a spatial strategy (with external maze landmarks-Situation 1) or are forced to use an egocentric strategy (without external or internal maze cues-Situation 2). Little is known about the extrahippocampal systems involved in the utilization of egocentric strategy. It is suggested that striatum could play an important role in the learning abilities that are spared after hippocampal lesion. The aim of our study was to investigate which strategy is used by rats bearing hippocampal or caudate-putamen lesions in the acquisition of a left/right discrimination task in an elevated T-maze in both Situations 1 and 2. We also investigated the effect of each lesion on the reversal of discrimination in both situations. Acquisition was not altered in any of the situations; however, a transfer test showed that hippocampal-lesioned rats used a different strategy (egocentric) from control animals (spatial) in Situation 1. In addition, reversal of the discrimination was impaired in Situation 2. Caudate-putamen lesion produced a transient effect on reversal of discrimination only in the egocentric task (Situation 2), but did not impair acquisition of the task in either situation, thus suggesting that the animals were able to use either strategy.     

Morris water maze deficits in rats following traumatic brain injury: lateral controlled cortical impact

This experiment utilized a laterally placed controlled cortical impact model of traumatic brain injury (TBI) to assess changes on spatial learning and memory in the Morris water maze (MWM). Adult rats were subjected to one of two different levels of cortical injury, mild (1 mm) or moderate (2 mm) deformation, and subsequently tested for their ability to learn (acquisition) or remember (retention) a spatial task, 7 or 14 days after injury. Results revealed an injury-dependent deficit for experimental animals compared to sham-operated controls. Not only did the TBI result in longer escape latencies, but also significant deficits in search time and relative target visits. Although the moderately injured animals demonstrated significant histopathology in the cortex and hippocampus, mildly injured subjects demonstrated no obvious tissue destruction, but did manifest significant behavioral change. These results demonstrate that a laterally placed controlled cortical impact is capable of producing significant cognitive deficits on both acquisition and retention paradigms utilizing the MWM.