Effects of opiate antagonists on spatial memory in young and aged rats

The effects of post-training opiate antagonist administration on spatial memory were assessed in young and aged male Long Evans rats. In Experiment I rats were trained to visit each arm of an eight-arm radial maze once in a session to obtain a food reward placed at the end of each arm. During training aged rats required significantly more trials to achieve criterion performance when compared to young mature rats. However, administration of the opiate antagonist naloxone (2.0 mg/kg) immediately after each training trial did not significantly alter the rate of achieving accurate performance in either age group. In Experiment II young and aged rats that were previously trained to a comparable criterion on the radial maze were tested on the same maze apparatus in novel spatial environments. When animals were exposed to novel spatial information, the effects of post-trial opiate antagonists were examined using a within-subjects counter-balanced design. In Experiment IIa naloxone (2 mg/kg) enhanced the performance of both young and aged rats. In Experiment IIB naltrexone (1.0 mg/kg) was found to have a comparable effect of enhancing the performance of both age groups. In addition, in Experiment IIb a significant age-related deficit was found in rats tested in novel spatial environments. These results indicate that opiate antagonists are capable of improving memory for new spatial information in both young and aged rats on a task that is sensitive to behavioral deficits during normal aging.     

Dissociation of data-based and expectancy-based memory following hippocampal lesions in rats

Sham-operated and nonoperated animals or animals with hippocampal lesions were presented with sets of trials to test both expectancy-based and data-based memory within the same task. During the study phase of each trial the animals were presented with a constant sequence of five arms on an eight-arm radial maze followed by a test phase in which a recognition test requiring a win-stay rule was used. Expectancy-based memory was measured during the study phase of the trials as a pattern of correct or incorrect orienting responses in anticipation of the ensuing doors in the constant sequence. Both groups of animals acquired correct orienting responses at the same rate, emitted the same pattern of correct orienting responses, and made the same number and pattern of intralist and extralist intrusion errors. Data-based memory was measured during the test phase of the trial as correct recognition test performance. During the test phase the animals with hippocampal lesions were impaired relative to controls on both immediate and 24-h recognition tests. These results suggest that the hippocampus might mediate only data-based, but not expectancy-based, memory and imply a possible dissociation between expectancy-based and data-based memory systems.     

Visual discrimination learning and transfer in rats with hippocampal lesions

Two experiments were performed on rats with hippocampal brain damage and on a control group with neocortical lesions. In the first experiment the hippocampal group learned a difficult visual discrimination as promptly as the controls, and neither group was subsequently impaired by adding relevant or irrelevant background cues to the original stimuli. In the second experiment the animals learned a simultaneous visual discrimination in which the stimuli differed in both brightness and orientation. The hippocampal group was impaired relative to the controls on acquisition, and showed poorer transfer to stimuli differing only in brightness or orientation. The results are incompatible with the hypothesis which attempts to explain the effects of hippocampal damage by a widespread reduction in sensory gating, but they are consistent with a more restricted version of the same hypothesis.     

Electrolytic lesions of dorsal CA3 impair episodic-like memory in rats

Episodic memory is the ability to recollect one's past experiences occurring in an unique spatial and temporal context. In non-human animals, it is expressed in the ability to combine "what", "where" and "when" factors to form an integrated memory system. During the search for its neural substrates, the hippocampus has attracted a lot of attentions. Yet, it is not yet possible to induce a pure episodic-like memory deficit in animal studies without being confounded by impairments in the spatial cognition. Here, we present a lesion study evidencing direct links between the hippocampus CA3 region and the episodic-like memory in rats. In a spontaneous object exploration task, lesioned rats showed no interaction between the temporal and spatial elements in their memory associated with the objects. In separate tests carried out subsequently, the same animals still expressed abilities to process spatial, temporal, and object recognition memory. In conclusions, our results support the idea that the hippocampus CA3 has a particular status in the neural mechanism of the episodic-like memory system. It is responsible for combining information from different modules of cognitive processes.     

A comparison of the effects of fimbria-fornix, hippocampal, or entorhinal cortex lesions on spatial reference and working memory in rats: short versus long postsurgical recovery period.

Using a radial maze task and different postoperative recovery periods, this experiment assessed and compared the reference and working memory performances of adult Long-Evans male rats subjected to entorhinal cortex, fimbria-fornix, and hippocampus lesions. Sham-operated rats were used as controls. In order to see whether the duration of the postsurgical recovery period would influence acquisition of the complex radial maze task, training began 1 month following surgery (Delay 1) for half the rats in each group, while for the other half training was started 6.5 months following surgery (Delay 2). The results indicated that at both recovery periods the entorhinal cortex lesions failed to affect either working or reference memory in the spatial task. Conversely, both fimbria-fornix and hippocampus lesions impaired both reference and working memory. While the reference memory deficit was generally similar in both fimbria-fornix and hippocampal lesion groups, analysis of the results for working memory indicated that at the longer delay rats with fimbria-fornix lesions were still impaired but in animals that had the hippocampus removed, working memory did not differ from that of controls. These results suggest that there was some recovery in those rats with hippocampal lesions (e.g., on the working memory task) but both hippocampal and fimbria-fornix animals were still impaired compared to controls when training was delayed 6.5 months following the operations.     

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

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

Kv4 potassium channels modulate hippocampal EPSP-spike potentiation and spatial memory in rats

Kv4 channels regulate the backpropagation of action potentials (b-AP) and have been implicated in the modulation of long-term potentiation (LTP). Here we showed that blockade of Kv4 channels by the scorpion toxin AmmTX3 impaired reference memory in a radial maze task. In vivo, AmmTX3 intracerebroventricular (i.c.v.) infusion increased and stabilized the EPSP-spike (E-S) component of LTP in the dentate gyrus (DG), with no effect on basal transmission or short-term plasticity. This increase in E-S potentiation duration could result from the combination of an increase in excitability of DG granular cells with a reduction of GABAergic inhibition, leading to a strong reduction of input specificity. Radioactive in situ hybridization (ISH) was used to evaluate the amounts of Kv4.2 and Kv4.3 mRNA in brain structures at different stages of a spatial learning task in naive, pseudoconditioned, and conditioned rats. Significant differences in Kv4.2 and Kv4.3 mRNA levels were observed between conditioned and pseudoconditioned rats. Kv4.2 and Kv4.3 mRNA levels were transiently up-regulated in the striatum, nucleus accumbens, retrosplenial, and cingulate cortices during early stages of learning, suggesting an involvement in the switch from egocentric to allocentric strategies. Spatial learning performance was positively correlated with the levels of Kv4.2 and Kv4.3 mRNAs in several of these brain structures. Altogether our findings suggest that Kv4 channels could increase the signal-to-noise ratio during information acquisition, thereby allowing a better encoding of the memory trace.     

Effects of stress and hippocampal NMDA receptor antagonism on recognition memory in rats

Exposures to uncontrollable stress have been shown to alter ensuing synaptic plasticity in the hippocampus and interfere with hippocampal-dependent spatial memory in rats. The present study examined whether stress, which impairs hippocampal long-term potentiation (LTP), also affects (nonspatial) hippocampal-dependent object-recognition memory, as tested on the visual paired comparison task (VPC) in rats. After undergoing an inescapable restraint–tailshock stress experience, rats exhibited markedly impaired recognition memory at the 3-h (long) familiarization-to-test phase delay but not at the 5-min (short) delay. In contrast, unstressed control animals showed robust recognition memory (i.e., they exhibited reliable preferences for novel over familiar objects) at both short- and long-delay periods. The impairing effect of stress on long-delay recognition memory was transient because 48 h after undergoing stress experience, animals performed normally at the long delay. Similar to stress, microinfusions of DL-2-amino-5-phosphonovaleric acid (APV), a competitive N-methyl-D-aspartate receptor (NMDAR) antagonist that blocks LTP, into the dorsal hippocampus selectively impaired object-recognition memory at the long-delay period. Together, these results suggest that stress and intrahippocampal administration of APV affect recognition memory by influencing synaptic plasticity in the hippocampus.

[The following individuals kindly provided reagents, samples, or unpublished information as indicated in the paper H. Blair.]

     

Serial memory for sound-specified locations: Effects of spatial uncertainty and motor suppression

The current study examined four factors that were expected to influence recognition accuracy of previously retrieved events: remoteness of the event, rated emotionality of the event, the type of changes that were made to the original memory report, and the plausibility of these changes. This was done in a study with 33 participants who were tested for recognition accuracy of original and altered reports a year after they had initially reported these autobiographical memories. Participants evaluated original and altered reports as being authentic or not. High recognition accuracy occurred for report evaluations of events that were recent, that contained central changes, and that had higher emotional intensity ratings. Recognition errors were more likely to occur when the original events were remote and when altered reports contained peripheral and plausible changes. These findings demonstrate the vulnerability of recognition accuracy in older adults under difficult retrieval conditions.     

Equivalent spatial location memory deficits in rats with medial septum or hippocampal formation lesions and patients with dementia of the Alzheimer's type

College students, healthy elderly subjects, patients diagnosed with mild or moderate dementia of the Alzheimer's type, as well as rats with small or large lesions of the medial septum (MS), dorsal hippocampal formation (DHF) or nucleus basalis magnocellularis (NBM) were tested on an item memory task for a five- or six-item list of varying spatial locations. Equivalent patterns of item memory deficits as a function of serial order position were observed in rats with small or large MS or DHF lesions and patients with mild or moderate dementia of the Alzheimer's type. No deficits were found for NBM-lesioned rats. The results provide support for the possibility that rats with MS and DHF lesions mimic the mnemonic symptomatology of patients with Alzheimer's disease.     

Ethanol state-dependent memory: involvement of dorsal hippocampal muscarinic and nicotinic receptors

In the present study, the effects of bilateral injections of cholinergic agents into the hippocampal CA1 regions (intra-CA1) on ethanol state-dependent memory were examined in mice. A single-trial step-down passive avoidance task was used for the assessment of memory retention in adult male NMRI mice. Pre-training intraperitoneal injection (i.p.) of ethanol (0.25, 0.5 and 1 g/kg) dose dependently induced impairment of memory retention. Pre-test administration of ethanol (0.5 and 1 g/kg, i.p.) induced state-dependent retrieval of the memory acquired under pre-training ethanol (1 g/kg, i.p.) influence. Pre-test intra-CA1 injection of physostigmine (2.5 and 5 μg/mouse, intra-CA1) or nicotine (0.3 and 0.5 μg/mouse, intra-CA1) improved pre-training ethanol (1 g/kg)-induced retrieval impairment. Moreover, pre-test administration of physostigmine (2.5 and 5 μg/mouse, intra-CA1) or nicotine (0.3 and 0.5 μg/mouse, intra-CA1) with an ineffective dose of ethanol (0.25 g/kg) significantly restored the retrieval and induced ethanol state-dependent memory. Pre-test intra-CA1 injection of the muscarinic receptor antagonist, atropine (4 and 8 μg/mouse, intra-CA1) or the nicotinic receptor antagonist, mecamylamine (2 and 4 μg/mouse, intra-CA1) 5 min before the administration of ethanol (1 g/kg, i.p.) dose dependently inhibited ethanol state-dependent memory. Pre-test intra-CA1 administration of physostigmine (0.5, 2.5 and 5 μg/mouse), atropine (2, 4 and 8 μg/mouse), nicotine (0.1, 0.3 and 0.5 μg/mouse) or mecamylamine (1, 2 and 4 μg/mouse) alone cannot affect memory retention. These findings implicate the involvement of a dorsal hippocampal cholinergic mechanism in ethanol state-dependent memory and also it can be concluded that there may be a cross-state dependency between ethanol and acetylcholine.     

Effects of dehydroepiandrosterone sulfate and progesterone on spatial learning and memory in young and aged mice

Young (2-4 months) and aged (14-16 months) male Swiss-Webster albino mice (n = 7 per group) were subcutaneously injected with 20 mg/kg/day dehydroepiandrosterone sulfate (DHEAS), progesterone (P), DHEAS + P, or vehicle control and trained over a 5-day period in a Morris water maze. The subjects were tested 48 hr after training for memory recall as measured by latencies to locate the hidden platform, and trunk blood was collected immediately thereafter. As expected, latency to platform decreased for all groups over the 6 testing days, with aged mice taking longer to reach platform than did young mice. However, results did not support the hypotheses that DHEAS-treated mice would exhibit shorter latencies and that P-treated mice would show longer latencies to platform in comparison with age-matched controls. These results raise doubts about the effectiveness of commercially available supplements claiming to promote enhanced memory in humans.     

Effects of anterior or dorsomedial thalamic ibotenic lesions on learning and memory in rats

Sprague-Dawley rats were used to study the effects of ibotenic acid lesions of the anterior (A.Th.) and the dorsomedial (MD) thalamic nuclei on learning and memory. Memory was assessed by employing a temporal alternation task in a straight alley with varying intertrial intervals. In addition, spatial orientation and response flexibility were evaluated on a radial maze and on a spatial reversal task (SSDR). The results indicated that MD rats required more trials to learn the temporal alternation task and exhibited impaired performance compared to A.Th. and control groups at the shortest delay (15 s). In contrast, compared to the control group, A.Th. subjects which required less trials to master the task and exhibited normal performance at the 15-s delay were impaired when the intertrial interval was increased to 45 s. Whatever the lesion, no impairments were found in the SSDR or the radial maze while only MD lesions were found to result in a night hyperactivity associated with greater food and water consumptions. These findings indicate that A.Th. and MD are differentially involved in learning and memory processes. It is suggested that the MD is mostly involved in registering new information while the A.Th. plays a role in the maintenance of information over time.     

Influence of dorsal hippocampal lesions and MMP inhibitors on spontaneous recovery following a habituation/classical conditioning head–shake task

The present investigation combined a classical conditioning paradigm with a head–shake response (HSR) habituation task in order to evaluate the importance of dorsal hippocampal neural plasticity to spontaneous recovery. In the first experiment animals exhibited rapid HSR habituation (air stimulus to the ear) and an 85% level of spontaneous recovery following a 24 h inter-session interval. The addition of a brief tone prior to the air stimulus produced a similar pattern of habituation during the first session, but the level of spontaneous recovery was reduced (44%) during Session II. In a second experiment dorsal hippocampal lesioned rats placed on this tone/HSR paradigm responded with an 87% level of spontaneous recovery during Session II; while neocortex lesioned control rats indicated significantly reduced levels of spontaneous recovery (55%). In a third experiment bilateral injections of a general MMP inhibitor, FN-439, into the dorsal hippocampus resulted in high levels of spontaneous recovery (81%); while control rats injected with artificial cerebrospinal fluid displayed a significant attenuation of spontaneous recovery (45%). Finally, animals bilaterally injected with a specific MMP-3 inhibitor into the dorsal hippocampus indicated very similar results to those obtained following FN-439 injection. These findings indicate that animals prepared with dorsal hippocampal lesions, or injections with an MMP inhibitor, revealed an impaired association between the tone and air stimulus thus maximum spontaneous recovery was present 24 h later. Thus, it appears that the dorsal hippocampus influences habituation by conserving responses and reducing spontaneous recovery when a temporally contingent signaling cue is present.