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.     

Nucleus basalis magnocellularis and memory: differential effects of two neurotoxins

Although the cholinergic system is involved in memory, noncholinergic systems may also contribute to memory. Lesions of the nucleus basalis magnocellularis (NBM) produce behavioral impairments and reduction of cholinergic markers in the frontal cortex (FC). The present study compared the behavioral effects of lesions made with two different neurotoxins, ibotenic (IBO) acid and quisqualic (QUIS) acid. IBO or QUIS was injected into the NBM, and rats were tested in three different tasks: cued delayed nonmatch-to-sample (CDNMS), spatial delayed nonmatch-to-sample (SDNMS), and spatial two-choice simultaneous discrimination (STCSD). IBO producted a greater behavioral impairment than QUIS in the CDNMS and the SDNMS, although QUIS produced a greater drop in choline acetyltransferase (ChAT) activity in the cortex than IBO. At the end of behavioral testing, IBO rats, but not QUIS rats, were impaired in the retention of both tasks. The fact that QUIS lesions produced a greater loss of NBM cholinergic neurons, as determined by decreased ChAT activity, but less of a behavioral impairment in both a spatial and nonspatial task, suggests that the loss of noncholinergic NBM neurons must contribute to the memory impairments following NBM cell loss.     

Lateral and anterior thalamic lesions impair independent memory systems

Damage to the medial region of the thalamus, both in clinical cases (e.g., patients with infarcts or the Korsakoff's syndrome) and animal lesion models, is associated with variable amnesic deficits. Some studies suggest that many of these memory deficits rely on the presence of lateral thalamic lesions (LT) that include the intralaminar nuclei, presumably by altering normal function between the striatum and frontal cortex. Other studies suggest that the anterior thalamic nuclei (AT) may be more critical, as a result of disruption to an extended hippocampal system. Here, highly selective LT and AT lesions were made to test the prediction that these two regions contribute to two different memory systems. Only LT lesions produced deficits on a preoperatively acquired response-related (egocentric) working memory task, tested in a cross-maze. Conversely, only AT lesions impaired postoperative acquisition of spatial working memory, tested in a radial maze. These findings provide the first direct evidence of a double dissociation between the LT and AT neural aggregates. As the lateral and the anterior medial thalamus influence parallel independent memory processing systems, they may each contribute to memory deficits, depending on lesion extent in clinical and experimental cases of thalamic amnesia.     

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.     

Phthalic acid amygdalopetal lesion of the nucleus basalis magnocellularis induces reversible memory deficits in rats

The basolateral amygdala (BLA) is extensively implicated in emotional learning and memory. The current study investigated the contribution of cholinergic afferents to the BLA from the nucleus basalis magnocellularis in influencing aversive learning and memory. Sprague-Dawley rats were given permanent unilateral phthalic acid (300 ng) lesions of the nucleus basalis magnocellularis and were chronically implanted with cannulas aimed at the ipsilateral BLA. Lesioned rats showed a pronounced inhibitory avoidance task retention deficit that was attenuated by acute posttraining infusions of the muscarinic cholinergic agonist oxotremorine (4 ng) or the indirect agonist physostigmine (1 microg) into the BLA. Continuous multiple-trial inhibitory avoidance training and testing revealed that lesioned rats have a mild acquisition deficit, requiring approximately 1 additional shock to reach the criterion, and a pronounced consolidation deficit as indicated by a shorter latency to enter the shock compartment on the retention test. Because lesioned rats did not differ from sham-operated controls in performance on a spatial water maze task or in shock sensitivity, it is not likely that the memory impairments produced by the phthalic acid lesions are due to any general sensory or motor deficits. These findings suggest that the dense cholinergic projection from the nucleus basalis magnocellularis to the BLA is involved in both the acquisition and the consolidation of the aversive inhibitory avoidance task.     

Trial spacing is a determinant of cue interaction

Four conditioned lick suppression experiments with rats examined the effect of trial spacing on cue interaction. Experiments 1 and 2 found overshadowing to be eliminated with massed compound stimulus-outcome pairings and the usual trial spacing effect to be reversed with compound acquisition trials. Experiment 3 found that whether acquisition compound-outcome pairings were massed or spaced determined the effect of posttraining extinction treatment. Extinction of the overshadowing cue reduced responding following massed training and increased responding following spaced training. Extinction of the context decreased responding following massed training. Experiment 4 found the conditioning and devaluation results to be associative and stimulus specific. These results are in accord with the extended comparator hypothesis (J. C. Denniston, H. I. Savastano, & R. R. Miller, 2001).     

Differential effects of damage within the hippocampal region on memory for a natural, nonspatial Odor-Odor Association

Debate continues on whether the role of rodent hippocampus in memory is limited to the spatial domain. Recently, this controversy has been addressed with studies on the social transmission of food preference, an odor-odor association task with no spatial requirements. Multiple reports have concluded that damage to the hippocampal region impairs memory in this task, but there remain questions about the extent of damage essential to produce an impairment. Furthermore, a recent study () found no effect of hippocampal lesions on memory in this task. We tested animals with complete lesions of the hippocampus (H) lesions of the hippocampus plus subiculum (HS), and lesions of the adjacent, anatomically related cortices of the parahippocampal region (PHR). H lesions produced an impairment on spatial delayed alternation, but not on memory for the social transmission of food preference, whereas HS and PHR lesions produced severe and equivalent impairments on memory for the socially acquired food preference. We discuss possible explanations for the discrepancy with the results of and conclude that the hippocampus and subiculum together play a critical role in the formation of this form of nonspatial, relational memory.     

A facilitative role for corticosterone in the acquisition of a spatial task under moderate stress

Emotionally charged experiences alter memory storage via the activation of hormonal systems. Previously, we have shown that compared with rats trained for a massed spatial learning task in the water maze in warm water (25°C), animals that were trained in cold water (19°C) performed better and showed higher levels of the stress hormone corticosterone. Here, we examined whether manipulating the levels of corticosterone can determine the strength of spatial information acquisition and retention. Rats were injected with metyrapone (25, 50, and 75 mg/kg, i.p.) or with corticosterone (10 and 25 mg/kg, i.p.) and trained in a massed spatial task in either cold (19°C) or warm (25°C) water. We found that whereas animals injected with vehicle performed well in the spatial task in cold water (moderate stress), rats injected with the intermediate metyrapone dose showed impairment in performance. Moreover, whereas animals injected with vehicle on average did not perform well in warm water (mild stress), rats injected with the lower corticosterone dose showed improvement in performance in warm water. These two mirror experiments of corticosterone blockade and enhancement strongly suggest that corticosterone is instrumental in the acquisition and retention of the spatial learning task.     

Excitotoxic lesions of the parafascicular nucleus produce deficits in a socially transmitted food preference

The parafascicular (PF) nucleus, a posterior component of the intralaminar nuclei of the thalamus, is considered to be an essential structure in the feedback circuits of basal ganglia-thalamo-cortical systems that critically participate in cognitive processes. To study the PF contribution to processing of behaviorally significant information during specific episodes of learning, we investigated the effects of damaging the PF nucleus in the acquisition of a natural form of social olfactory learning, the socially transmitted food preference (STFP) task. This task is a non-spatial paradigm that exhibits some of the characteristics of relational memory because it requires that animals use information obtained in one episode to guide later behavior in different circumstances. Adult male Wistar rats were submitted to pretraining bilateral N-methyl-D-aspartate (0.15 M, pH 7.4) lesions of the PF (0.4 microl/side, 0.2 microl/min). The behavioral effects of PF lesions were compared to vehicle- and sham-operated control groups and two retention delays were considered in separate groups: immediately (Lesion-I, Vehicle-I, and Sham-I groups) and 24h after training (Lesion-24, Vehicle-24, and Sham-24 groups). PF lesions produced delay-independent impairments in the STFP suggesting that this nucleus might modulate the acquisition of this odor-odor association task. Results are discussed in the context of medial prefrontal cortex deafferentation induced by PF damage.     

Neurogenesis and the spacing effect: learning over time enhances memory and the survival of new neurons

Information that is spaced over time is better remembered than the same amount of information massed together. This phenomenon, known as the spacing effect, was explored with respect to its effect on learning and neurogenesis in the adult dentate gyrus of the hippocampal formation. Because the cells are generated over time and because learning enhances their survival, we hypothesized that training with spaced trials would rescue more new neurons from death than the same number of massed trials. In the first experiment, animals trained with spaced trials in the Morris water maze outperformed animals trained with massed trials, but there was not a direct effect of trial spacing on cell survival. Rather, animals that learned well retained more cells than animals that did not learn or learned poorly. Moreover, performance during acquisition correlated with the number of cells remaining in the dentate gyrus after training. In the second experiment, the time between blocks of trials was increased. Consequently, animals trained with spaced trials performed as well as those trained with massed, but remembered the location better two weeks later. The strength of that memory correlated with the number of new cells remaining in the hippocampus. Together, these data indicate that learning, and not mere exposure to training, enhances the survival of cells that are generated 1 wk before training. They also indicate that learning over an extended period of time induces a more persistent memory, which then relates to the number of cells that reside in the hippocampus.     

Effects of parafascicular excitotoxic lesions on two-way active avoidance and odor-discrimination

To investigate whether the parafascicular (PF) nucleus of the thalamus is involved in different learning and memory tasks, two experiments were carried out in adult male Wistar rats that were submitted to pre-training bilateral N-methyl-d-aspartate PF infusions (0.15M, pH 7.4; 1.2 microl/side, 0.2 microl/min). In Experiment 1, we evaluated the effects of PF lesions in two identical 30-trial training sessions, separated by a 24-h interval, of a two-way active avoidance conditioning. PF-lesioned rats exhibited impaired performance in both sessions, measured by number of avoidance responses. In Experiment 2, the effects of PF lesions were assessed in a training session (5 trials) and a 24-h retention test (2 retention trials and 2 relearning trials) of an odor-discrimination task. PF lesions did not significantly disrupt the acquisition or the first retention trial, which was not rewarded. However, lesioned animals' performance was clearly affected in subsequent trials, following the introduction of the single non-rewarded trial. Current data are discussed considering evidence that lesions of the PF nucleus affect learning and memory functions mediated by anatomically related areas of the frontal cortex and striatum.     

Hippocampal formation lesions impair performance in an odor-odor association task independently of spatial context

The rodent hippocampal system is known to play an important role in memory. Evidence that this role is not limited to spatial memory has come from studies using a variety of non-spatial memory tasks. One example is the social transmission of food preference paradigm, a task in which rats learn an odor-odor association with no explicit spatial memory component. However, because training and testing in this task typically take place in the same environment, it is possible that memory for the spatial context in which odors are experienced during training is critical to subsequent retention performance. If this is the case, it might be expected that lesions of the hippocampal system would impair memory performance by disrupting the establishment of a representation of the training environment. We addressed this issue by training rats in one spatial context and then testing them either in the same or a different spatial context. Normal control rats performed equally well when tested in an environment that was the same or different from that used during training, and the retention impairment exhibited by rats with hippocampus plus subiculum lesions was equivalent in the two test environments. These results support the view that the hippocampal system is necessary for the flexible expression of nonspatial memories even when the spatial context in which the memory is acquired is not critical to retrieval.     

Allocentric spatial learning by hippocampectomised rats: A further test of the “spatial mapping” and “working memory” theories of hippocampal function

This paper reports a series of three experiments that tested the “spatial-mapping” and “working-memory” theories of hippocampal function. The experimental designs incorporate separate reference- and working-memory procedures of a water-escape task, using both spatial and non-spatial learning. In Experiment 1 (Reference memory), rats with hippocampal (HC) or cortical (CC) lesions and unoperated (UNOP) rats learned to swim to a rigid visible escape platform while avoiding contact with a floating one. In the nonspatial task, the platforms each occupied any of 8 possible positions in the pool over successive trials but differed in appearance. In the spatial task, the platforms were of identical appearance but the safe one always occupied a single fixed location. The HC rats showed a highly specific spatial learning impairment but did learn to perform consistently above chance towards the end of training. In Experiment 2 (working memory), new groups of rats were trained on similar spatial and nonspatial tasks, but the platform designated correct-in terms of its visual appearance or its spatial location-was randomly changed each day. No animal learned the nonspatial task despite extensive training. Performance on the spatial version unexpectedly revealed an impairment in the CC as well as the HC group relative to the UNOP rats. However, the HCs again performed at above chance levels and demonstrated rapid (I-trial) spatial learning towards the end training. Experiment 3 used a place navigation matching-to-sample task examine spatial working memory further. Each day, an underwater platform was hidden at any of 4 possible locations, and the rats were given 2 trials to search for it. Both UNOP and CC rats located the platform faster on Trial 2 than on Trial 1, even when the inter-trial interval was long as 30min. HC rats were no faster on Trial 2 than on Trial 1. We conclude that hippocampal lesions (1) severely but partially impair spatial but not visual reference memory and (2) give rise to different patterns impairment in different working-mermory tasks. The results are a chal lenge to both the spatial-mapping and working-memory theories.     

Persistent impairments in hippocampal function following a brief series of photoperiod shifts in rats

The impact of an acute circadian disruption on learning and memory in male and female rats was examined. Circadian disruption was elicited using a brief series of photoperiod shifts. Previous research using male rats showed that acute circadian disruption during acquisition of a spatial navigation task impaired long-term retention and that chronic circadian disruption impaired acquisition of the same task. However, the long-term effects of acute circadian disruption following circadian re-entrainment and whether sex differences in response to circadian disruption exist are still unknown. For the present study, rats were trained on the standard, spatial version of the Morris water task (MWT) and a visual discrimination task developed for the eight-arm radial maze. After reaching asymptotic performance, behavioural training was terminated and the experimental group experienced a series of photoperiod shifts followed by circadian re-entrainment. Following circadian re-entrainment, the subjects were given retention tests on the MWT and visual discrimination task. Following retention testing, an extra-dimensional shift using the eight-arm radial maze was also performed. An acute episode of circadian disruption elicited via photoperiod shifts negatively impacted retention of spatial memory in male and female rats. Retention of the visual discrimination task and the ability to detect extra-dimensional shifts were not impaired. The observed impairments on the MWT indicate that hippocampal representations are susceptible to a small number of photoperiod shifts even if the association is acquired prior to rhythm manipulation and retention is assessed following rhythm stabilization. Effects were limited to a hippocampus-dependent task, indicating that impairments are specific, not global.     

Spatial memory in rats after 25 hours

We investigated the time course of spatial-memory decay in rats using an eight-arm radial maze. It is well established that performance remains high with retention intervals as long as 4 h, but declines to chance with a 24-h retention interval (Beatty, W. W., & Shavalia, D. A. (1980b). Spatial memory in rats: time course of working memory and effect of anesthetics. Behavioral & Neural Biology, 28, 454-462). It is possible that 24 h reflects a genuine retention limitation of rat spatial memory. Alternatively, it may be possible to identify factors that might support memory performance even after very long delays. The current experiment was conducted to test the above two hypotheses. We evaluated performance using two intertrial intervals (24 and 48 h) and two retention intervals (1 and 25 h). Increasing the intertrial interval produced an approximately constant increase in performance for both retention intervals. This improvement is consistent with a trial-spacing effect (i.e., the superiority of spaced over massed trials). Rat spatial memory apparently lasts at least 25 h.     

The avian hippocampus and short-term memory for spatial and non-spatial information

Three experiments investigated the role of the pigeon hippocampal formation (the hippocampus and area-parahippocampalis) in short-term memory for non-spatial and spatial information. The acquisition of delayed matching-to-sample and the short-term retention of non-spatial visual information, using a small set of sample stimuli, were unaffected by aspiration lesions of the hippocampus or the neostriatum (Experiment 1). Similarly, acquisition and short-term retention of non-spatial information using a successive, trial-unique, delayed non-matching-to-sample procedure were unaffected by hippocampal damage; the same birds had, however, displayed a profound autoshaping impairment (Experiment 2). Acquisition of a spatial delayed matching-to-sample task was unimpaired by hippocampal damage. However, lesioned animals were impaired following the introduction of retention intervals on this procedure (Experiment 3). The correspondence between the behavioural effects of hippocampal lesions in birds and mammals on short-term memory is discussed, and the implications of these results for avian hippocampal function are considered.     

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

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

Reward schedule effects in extinction: Intertrial interval, memory, and memory retrieval

Rats were trained in a runway such that partial reward occurred on Trial 1 of the day and consistent reward on subsequent massed trials (Group PRT1), or consistent reward occurred on Trial 1 of the day and partial reward on subsequent massed trials (Group PRTM). Under spaced (24-hr) extinction, Group PRT1 was more resistant to extinction than Group PRTM and under massed (1-min) extinction, Group PRTM was more resistant to extinction than Group PRT1. These findings suggest that (a) distinctive stimuli are associated with Trial 1 of the day and with subsequent massed trials, (b) these distinctive stimuli function as retrieval cues for memories, memory retrieval being independent of intertrial interval, and (c) behavior in extinction is controlled by a stimulus compound consisting of the memory of nonreward plus stimuli which accompany the memory of nonreward on rewarded acquisition trials.     

Brain activity during the encoding, retention, and retrieval of stimulus representations

Studies of delayed nonmatching-to-sample (DNMS) performance following lesions of the monkey cortex have revealed a critical circuit of brain regions involved in forming memories and retaining and retrieving stimulus representations. Using event-related functional magnetic resonance imaging (fMRI), we measured brain activity in 10 healthy human participants during performance of a trial-unique visual DNMS task using novel barcode stimuli. The event-related design enabled the identification of activity during the different phases of the task (encoding, retention, and retrieval). Several brain regions identified by monkey studies as being important for successful DNMS performance showed selective activity during the different phases, including the mediodorsal thalamic nucleus (encoding), ventrolateral prefrontal cortex (retention), and perirhinal cortex (retrieval). Regions showing sustained activity within trials included the ventromedial and dorsal prefrontal cortices and occipital cortex. The present study shows the utility of investigating performance on tasks derived from animal models to assist in the identification of brain regions involved in human recognition memory.     

Patterns of impaired verbal,spatial, and object working memory after thalamic lesions

Working memory processes in six individuals with isolated thalamic lesions were assessed. Participants were given a verbal, spatial, and object n-back task, each at three levels of task load (1-back, 2-back, and 3-back). Relative to a control group, the patients were impaired on the verbal and spatial n-back tasks, and possibly on the object n-back task as well. None of the patients showed impaired short-term memory as measured by digit span. Group differences on trials measuring matching, sequencing, and inhibitory abilities were consistent with other reports suggesting that thalamic lesions may impair the operation of executive processes.