Hippocampal CA1 kindling but not long-term potentiation disrupts spatial memory performance

Long-term synaptic enhancement in the hippocampus has been suggested to cause deficits in spatial performance. Synaptic enhancement has been reported after hippocampal kindling that induced repeated electrographic seizures or afterdischarges (ADs) and after long-term potentiation (LTP) defined as synaptic enhancement without ADs. We studied whether repeated stimulations that gave LTP or ADs resulted in spatial performance deficits on the radial arm maze (RAM) and investigated the minimal number of ADs required for such deficits. Three experimental groups were run as follows: (1) 5 hippocampal ADs in 1 d (5-AD group), (2) 10 hippocampal ADs in 2 d (10-AD group), and (3) 12 -frequency primed-burst stimulations (PBSs) in 2 d in order to induce LTP without ADs (LTP group). Each experimental group was run together with a control group during the same time period. Rats were first trained in a spatial task on a radial arm maze with four of the eight arms baited, then given control or experimental treatment, and maze performance was tested in the first week (1-4 d) and fourth week (22-25 d) after treatment. Basal dendritic population excitatory postsynaptic potentials (pEPSPs) and medial perforant path (MPP)-evoked dentate gyrus population spike and polysynaptic CA1 excitation were recorded before and after experimental and control treatment. Spatial memory errors, in particular reference memory errors, were significantly higher in the 10-AD kindled group than any other group on the first and fourth week after treatment. Spatial memory errors were not significantly different in the 5-AD and LTP groups as compared with any control groups at any time. Basal dendritic pEPSP in CA1 was enhanced for about 1 wk after 12 PBSs, 10 ADs, or 5 ADs, while the dentate gyrus population spike and CA1 polysynaptic excitation evoked by MPP was increased for up to 4 wk after 10 ADs, but not 12 PBSs. Thus, distributed alteration of multiple synaptic transmission in the entorhinal-hippocampal circuit, but not LTP at the basal dendritic synapses in CA1, may disrupt spatial performance after 10 hippocampal ADs.     

Infusion of protein synthesis inhibitors in the entorhinal cortex blocks consolidation but not reconsolidation of object recognition memory

Memory consolidation and reconsolidation require the induction of protein synthesis in some areas of the brain. Here, we show that infusion of the protein synthesis inhibitors anisomycin, emetine and cycloheximide in the entorhinal cortex immediately but not 180 min or 360 min after training in an object recognition learning task hinders long-term memory retention without affecting short-term memory or behavioral performance. Inhibition of protein synthesis in the entorhinal cortex after memory reactivation involving either a combination of familiar and novel objects or two familiar objects does not affect retention. Our data suggest that protein synthesis in the entorhinal cortex is necessary early after training for consolidation of object recognition memory. However, inhibition of protein synthesis in this cortical region after memory retrieval does not seem to affect the stability of the recognition trace.     

A male advantage for spatial and object but not verbal working memory using the n-back task

Sex-related differences have been reported for performance and neural substrates on some working memory measures that carry a high cognitive load, including the popular n-back neuroimaging paradigm. Despite some evidence of a sex effect on the task, the influence of sex on performance represents a potential confound in neuroimaging research. The present study investigated sex-related differences in verbal, spatial, and common object versions of the high cognitive load "n-back" working memory task. Eighteen male and 18 female undergraduates completed all 3 versions of the task. A mixed ANOVA, with Sex (male and female) as the between-subjects factor and Condition (verbal, spatial, and object) as the within-subjects repeated measure revealed that males were significantly more accurate than females on the spatial and object versions of the n-back task and performed equivalently to females on the verbal version of the task. Although the expected female advantage for verbal working memory was not found using this effortful n-back task, these results support a male advantage for high cognitive load spatial and object working memory. Future research should take into account the influence of sex on performance of the n-back task, and examine sex-related differences in working memory using other paradigms.     

On the role of hippocampal protein synthesis in the consolidation and reconsolidation of object recognition memory

Upon retrieval, consolidated memories are again rendered vulnerable to the action of metabolic blockers, notably protein synthesis inhibitors. This has led to the hypothesis that memories are reconsolidated at the time of retrieval, and that this depends on protein synthesis. Ample evidence indicates that the hippocampus plays a key role both in the consolidation and reconsolidation of different memories. Despite this fact, at present there are no studies about the consequences of hippocampal protein synthesis inhibition in the storage and post-retrieval persistence of object recognition memory. Here we report that infusion of the protein synthesis inhibitor anisomycin in the dorsal CA1 region immediately or 180 min but not 360 min after training impairs consolidation of long-term object recognition memory without affecting short-term memory, exploratory behavior, anxiety state, or hippocampal functionality. When given into CA1 after memory reactivation in the presence of familiar objects, ANI did not affect further retention. However, when administered into CA1 immediately after exposing animals to a novel and a familiar object, ANI impaired memory of both of them. The amnesic effect of ANI was long-lasting, did not happen after exposure to two novel objects, following exploration of the context alone, or in the absence of specific stimuli, suggesting that it was not reversible but was contingent on the reactivation of the consolidated trace in the presence of a salient, behaviorally relevant novel cue. Our results indicate that hippocampal protein synthesis is required during a limited post-training time window for consolidation of object recognition memory and show that the hippocampus is engaged during reconsolidation of this type of memory, maybe accruing new information into the original trace.     

Encoding, consolidation, and retrieval of contextual memory: differential involvement of dorsal CA3 and CA1 hippocampal subregions

Studies on human and animals shed light on the unique hippocampus contributions to relational memory. However, the particular role of each hippocampal subregion in memory processing is still not clear. Hippocampal computational models and theories have emphasized a unique function in memory for each hippocampal subregion, with the CA3 area acting as an autoassociative memory network and the CA1 area as a critical output structure. In order to understand the respective roles of the CA3- and CA1-hippocampal areas in the formation of contextual memory, we studied the effects of the reversible inactivation by lidocaine of the CA3 or CA1 areas of the dorsal hippocampus on acquisition, consolidation, and retrieval of a contextual fear conditioning. Whereas infusions of lidocaine never impaired elementary tone conditioning, their effects on contextual conditioning provided interesting clues about the role of these two hippocampal regions. They demonstrated first that the CA3 area is necessary for the rapid elaboration of a unified representation of the context. Secondly, they suggested that the CA1 area is rather involved in the consolidation process of contextual memory. Third, they showed that CA1 or CA3 inactivation during retention test has no effect on contextual fear retrieval when a recognition memory procedure is used. In conclusion, our findings point as evidence that CA1 and CA3 subregions of the dorsal hippocampus play important and different roles in the acquisition and consolidation of contextual fear memory, whereas they are not required for context recognition.     

Remodeling of hippocampal mossy fibers is selectively induced seven days after the acquisition of a spatial but not a cued reference memory task

Relating storage of specific information to a particular neuromorphological change is difficult because behavioral performance factors are not readily disambiguated from underlying cognitive processes. This issue is addressed here by demonstrating robust reorganization of the hippocampal mossy fiber terminal field (MFTF) when adult rats learn the location of a hidden platform but not when rats learn to locate a visible platform. Because the latter task requires essentially the same behavioral performance as the former, the observed MFTF growth is seen as the consequence of specific input-dependent hippocampal activity patterns selectively generated by processing of extramaze but not intramaze cues. Successful performance on the hidden platform task requires formation of spatial memory. Increased MFTFs in hidden platform-trained rats are observed 7 d but not 2 d after training nor in swim controls. These results suggest that structural plasticity of the mossy fiber:CA3 circuit may contribute to the maintenance of long-lasting memory but not to the initial storage of the spatial context.     

Reversible inactivation of the hippocampal mossy fiber synapses in mice impairs spatial learning, but neither consolidation nor memory retrieval, in the Morris navigation task

The role played by hippocampal mossy fibers in the learning and memory processes implemented in the Morris swimming navigation task has been studied in C57BL/6 mice by selective and reversible inactivation of mossy fiber synaptic fields by diethyldithiocarbamate. The functional integrity of the mossy fibers proved essential for the storage of the spatial representation on the modifiable synapses of the recurrent collaterals of the CA3 pyramidal cells, whereas it is not necessary for the consolidation and recall of spatial memories. The results suggest that mossy fibers are preferentially involved in new learning. They are consistent with the hypothesis that the hippocampal CA3 region might act as an autoassociation memory.     

Endurance factors improve hippocampal neurogenesis and spatial memory in mice

Physical activity improves learning and hippocampal neurogenesis. It is unknown whether compounds that increase endurance in muscle also enhance cognition. We investigated the effects of endurance factors, peroxisome proliferator-activated receptor δ agonist GW501516 and AICAR, activator of AMP-activated protein kinase on memory and neurogenesis. Mice were injected with GW for 7 d or AICAR for 7 or 14 d. Two weeks thereafter mice were tested in the Morris water maze. AICAR (7 d) and GW improved spatial memory. Moreover, AICAR significantly, and GW modestly, elevated dentate gyrus neurogenesis. Thus, pharmacological activation of skeletal muscle may mediate cognitive effects.     

Scopolamine infused into perirhinal cortex improves object recognition memory by blocking the acquisition of interfering object information

In a previous study, we reported apparently paradoxical facilitation of object recognition memory following infusions of the cholinergic muscarinic receptor antagonist scopolamine into the perirhinal cortex (PRh) of rats. We attributed these effects to the blockade by scopolamine of the acquisition of interfering information. The present study tested this possibility directly by modifying the spontaneous object recognition memory task to allow the presentation of a potentially interfering object either before the sample phase or in the retention delay between the sample and choice phases. Presentation of an object between the sample and choice phases disrupted subsequent recognition of the sample object (retroactive interference), and intra-PRh infusions of scopolamine prior to the presentation of the irrelevant object prevented this retroactive interference effect. Moreover, presentation of an irrelevant object prior to the sample phase interfered proactively with sample object recognition, and intra-PRh infusions of scopolamine prior to the presentation of the pre-sample object prevented this proactive interference effect. These results suggest that blocking muscarinic cholinergic receptors in PRh can disrupt the acquisition of potentially interfering object information, thereby facilitating object recognition memory. This finding provides further, strong evidence that acetylcholine is important for the acquisition of object information in PRh.     

The effect of spatial and nonspatial contextual information on visual object memory

Recent research has found visual object memory can be stored as part of a larger scene representation rather than independently of scene context. The present study examined how spatial and nonspatial contextual information modulate visual object memory. Two experiments tested participants’ visual memory by using a change detection task in which a target object's orientation was either the same as it appeared during initial viewing or changed. In addition, we examined the effect of spatial and nonspatial contextual manipulations on change detection performance. The results revealed that visual object representations can be maintained reliably after viewing arrays of objects. Moreover, change detection performance was significantly higher when either spatial or nonspatial contextual information remained the same in the test image. We concluded that while processing complex visual stimuli such as object arrays, visual object memory can be stored as part of a comprehensive scene representation, and both spatial and nonspatial contextual changes modulate visual memory retrieval and comparison.     

Word imagery but not age of acquisition affects episodic memory

Evidence is presented from two experiments and from a reanalysis of data published by Christian, Bickley, Tarka, and Clayton (1978) that the chronological age at which a word is acquired does not affect free recall or recognition memory. Morris’s (1981) report, that late acquired words are better recalled than early acquired words, was not replicated and appears to be attributable to a difference in the emotionality value of his lists. Although the data are consistent with an interpretation in terms of semantic, but not episodic, memory tasks’ being sensitive to word age of acquisition, it is suggested that a more fine-grained analysis is necessary.     

Post-encoding emotional arousal enhances consolidation of item memory,but not reality-monitoring source memory

The current study examined whether the effect of post-encoding emotional arousal on item memory extends to reality-monitoring source memory and, if so, whether the effect depends on emotionality of learning stimuli and testing format. In Experiment 1, participants encoded neutral words and imagined or viewed their corresponding object pictures. Then they watched a neutral, positive, or negative video. The 24-hour delayed test showed that emotional arousal had little effect on both item memory and reality-monitoring source memory. Experiment 2 was similar except that participants encoded neutral, positive, and negative words and imagined or viewed their corresponding object pictures. The results showed that positive and negative emotional arousal induced after encoding enhanced consolidation of item memory, but not reality-monitoring source memory, regardless of emotionality of learning stimuli. Experiment 3, identical to Experiment 2 except that participants were tested only on source memory for all the encoded items, still showed that post-encoding emotional arousal had little effect on consolidation of reality-monitoring source memory. Taken together, regardless of emotionality of learning stimuli and regardless of testing format of source memory (conjunction test vs. independent test), the facilitatory effect of post-encoding emotional arousal on item memory does not generalize to reality-monitoring source memory.     

Negative emotion elicited in high school students enhances consolidation of item memory,but not source memory

The study examined the effect of negative emotion on consolidation of both item and source memory. Participants learned words read by either a male or female. Then they watched either a negative or a neutral video clip. Memory tests were carried out either 25 min or 24 h after learning. The study yielded the following findings. First, negative emotion enhanced consolidation of item memory as measured by recognition memory in the 25-min delay, and enhanced consolidation of item memory as measured by free recall in both the 25-min and the 24-h delay. Second, negative emotion had little effect on consolidation of source memory, either in the 25-min or the 24-h delay. These findings provide evidence for the differential effects of negative emotion on item memory and source memory and have implications for using emotion as a strategy to intervene memory consolidation.     

Long-term continuous, but not daily, environmental enrichment reduces spatial memory decline in aged male mice

Although environmental enrichment improves spatial memory and alters synaptic plasticity in aged rodents, it is unclear whether all types of enrichment treatments yield similar benefits. The present study examined the effects in aged male mice of three types of enrichment on spatial memory in Morris water maze and radial arm maze tasks, and on levels of the presynaptic protein synaptophysin in several brain regions. Non-enriched young and aged males were compared with males exposed to one of the following treatments for 10 weeks: 5 min of daily handling, 3 h of daily basic enrichment, or 24 h of continuous complex enrichment. Young controls outperformed aged controls in both tasks. Neither daily handling nor daily enrichment affected spatial memory or synaptophysin levels. In contrast, continuous enrichment significantly reduced age-related spatial memory decline in both tasks, such that this group was statistically indistinguishable from young controls in most measures of performance. Continuously enriched mice were also significantly better than other aged mice in several spatial memory measures. Despite these improvements, synaptophysin levels in the continuous enrichment group were significantly lower than those of young and aged controls in the frontoparietal cortex, hippocampus, and striatum, suggesting a negative relationship between synaptophysin levels and spatial memory in aged males. These data demonstrate that different types of enrichment in aged male mice have disparate effects on spatial memory, and that the relationship between enrichment-induced changes in synaptophysin levels and spatial memory in aged males differs from that we have previously reported in aged female mice.     

Disconnection analysis of CA3 and DG in mediating encoding but not retrieval in a spatial maze learning task

The dentate gyrus (DG) subregion of the hippocampus has been shown to be involved in encoding but not retrieval in a spatial maze task (modified Hebb-Williams maze). The first experiment in this study examined whether a lesion to the CA3 would contribute to a similar encoding deficit. A DG group was included in order to replicate previous results. Relative to controls, animals receiving CA3 lesions were impaired in encoding, not retrieval, on the modified Hebb-Williams maze--similar to a group that received DG lesions. This suggests the possibility that CA3 and DG are working together to mediate encoding processes. The second experiment in this study was designed to test the interaction between CA3 and DG using a disconnection paradigm. Animals with contralateral lesions (CA3 lesioned in one hemisphere, DG lesioned in the other hemisphere) showed a significant disruption effect on encoding, but not retrieval, when compared with animals with ipsilateral lesions (CA3 and DG lesioned in the same hemisphere, leaving the other hemisphere intact). This suggests an interaction between CA3 and DG in supporting encoding but not retrieval processes in a spatial maze learning task.     

In vitro hippocampal gamma oscillation power as an index of in vivo CA3 gamma oscillation strength and spatial reference memory

Neuronal synchronisation at gamma frequencies (30-100 Hz) has been implicated in cognition and memory. Gamma oscillations can be studied in various in vitro models, but their in vivo validity and their relationship with reference memory remains to be proven. By using the natural variation of wild type C57bl/6J mice, we assessed the relationships between reference memory and gamma oscillations recorded in hippocampal area CA3 in vivo and in vitro. Local field potentials (LFPs) were recorded from area CA3 in behaviourally-characterised freely moving mice, after which hippocampal slices were prepared for recordings in vitro of spontaneous gamma oscillations and kainate-induced gamma oscillations in CA3. The gamma-band power of spontaneous oscillations in vitro correlated with that of CA3 LFP oscillations during inactive behavioural states. The gamma-band power of kainate-induced oscillations correlated with the activity-dependent increase in CA3 LFP gamma-band power in vivo. Kainate-induced gamma-band power correlated with Barnes circular platform performance and object location recognition, but not with object novelty recognition. Kainate-induced gamma-band power was larger in mice that recognised the aversive context, but did not correlate with passive avoidance delay. The correlations between behavioural and electrophysiological measures obtained from the same animals show that the gamma-generating capacity of the CA3 network in vitro is a useful index of in vivo gamma strength and supports an important role of CA3 gamma oscillations in spatial reference memory.