Hippocampal stimulation disrupts spatial working memory even 8 h after acquisition

The present experiment used hippocampal stimulation to determine the temporal gradient of consolidation of spatial working memory. Rats were trained to perform a spatial working memory task on a radial maze with 12 arms. Each rat went to the ends of 6 arms to obtain a food reward. After 8 h, the rat chose among all the arms to find the ones not previously chosen (and consequently still having food). During some test sessions, the hippocampus was stimulated electrically either at a current level just high enough to produce an electrophysiological seizure, or at a current level below this seizure threshold. Stimulation occurred at one of five intervals (0 to 8 h) following the completion of the first six choices. During other test sessions, the hippocampus was not stimulated. After seizure stimulation, the number of retroactive errors (returning to arms chosen prior to stimulation) increased at all delay intervals; the number of proactive errors (returning to arms chosen after stimulation) increased only with the delay of 8 h. Subthreshold stimulation had no influence on either type of error. These results indicate that normal hippocampal function is required for the maintenance of spatial information in working memory, and that the time course of consolidation of this information is significantly greater than that seen in other types of memory, or consolidation may not take place at all.     

Generation disrupts memory for intrinsic context but not extrinsic context

Although generation typically enhances item memory, the effect is subject to a number of theoretically important limitations. One potential limitation concerns context memory but there has been debate about whether generation actually enhances or disrupts memory for contextual details. Five experiments assessed the effect of generation on context memory for perceptual attributes of the study stimulus (intrinsic context). The results indicate that despite enhancing item memory, generation disrupts memory for intrinsic context. This result generalized over different intrinsic details (print colour and font), different generation manipulations, and several methodological factors identified in earlier research as potential moderators of this negative generation effect. Despite the negative generation effect on intrinsic context, contextual details external to the target item (extrinsic context) are not disrupted. In a sixth experiment, a visually based generation task (letter transposition) enhanced context memory for the extrinsic detail of location. Coupled with earlier research, the results indicate that generation disrupts context memory for intrinsic details but either does not harm or enhances memory for extrinsic context.     

Generation disrupts memory for intrinsic context but not extrinsic context

Although generation typically enhances item memory, the effect is subject to a number of theoretically important limitations. One potential limitation concerns context memory but there has been debate about whether generation actually enhances or disrupts memory for contextual details. Five experiments assessed the effect of generation on context memory for perceptual attributes of the study stimulus (intrinsic context). The results indicate that despite enhancing item memory, generation disrupts memory for intrinsic context. This result generalized over different intrinsic details (print colour and font), different generation manipulations, and several methodological factors identified in earlier research as potential moderators of this negative generation effect. Despite the negative generation effect on intrinsic context, contextual details external to the target item (extrinsic context) are not disrupted. In a sixth experiment, a visually based generation task (letter transposition) enhanced context memory for the extrinsic detail of location. Coupled with earlier research, the results indicate that generation disrupts context memory for intrinsic details but either does not harm or enhances memory for extrinsic context.     

Cholinergic modulation of hippocampal CA1 basal-dendritic long-term potentiation

Extensive research suggests that long-term potentiation (LTP) may serve as a cellular mechanism for memory and that alterations in synaptic plasticity may underlie the gross memory impairments observed in patients with Alzheimer's disease. Cholinergic facilitation of hippocampal LTP in the behaving rat is a useful model for the study of the effects of anticholinesterase or other drugs on synaptic plasticity. Field excitatory postsynaptic potentials were recorded from the hippocampal CA1 region following excitation of the basal dendrites in behaving male Long-Evans rats. LTP was induced by a high-frequency train (200 Hz for 0.5s duration) following injection of the acetylcholinesterase inhibitor eserine sulfate (0.5 mg/kg, i.p.), specific muscarinic M1 receptor antagonist pirenzepine (21.2 microg/microl, i.c.v.), or saline (i.p. or i.c.v.). Pirenzepine was found to block basal-dendritic LTP when LTP was induced during walking, but not when LTP was induced during immobility. Eserine facilitated LTP when induction occurred during either immobility or walking. The present study demonstrates that an anticholinesterase enhances LTP in CA1 of the behaving rat, and that facilitation of basal-dendritic LTP during walking is mediated by muscarinic M1 receptors.     

Hippocampal long-term potentiation, memory, and longevity in mice that overexpress mitochondrial superoxide dismutase

Superoxide has been shown to be critically involved in several pathological manifestations of aging animals. In contrast, superoxide also can act as a signaling molecule to modulate signal transduction cascades required for hippocampal synaptic plasticity. Mitochondrial superoxide dismutase (SOD-2 or Mn-SOD) is a key antioxidant enzyme that scavenges superoxide. Thus, SOD-2 may not only prevent aging-related oxidative stress, but may also regulate redox signaling in young animals. We used transgenic mice overexpressing SOD-2 to study the role of mitochondrial superoxide in aging, synaptic plasticity, and memory-associated behavior. We found that overexpression of SOD-2 had no obvious effect on synaptic plasticity and memory formation in young mice, and could not rescue the age-related impairments in either synaptic plasticity or memory in old mice. However, SOD-2 overexpression did decrease mitochondrial superoxide in hippocampal neurons, and extended the lifespan of the mice. These findings increase our knowledge of the role of mitochondrial superoxide in physiological and pathological processes in the brain.     

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.     

Inhibition of matrix metalloproteinase activity disrupts reconsolidation but not consolidation of a fear memory

The reconsolidation hypothesis posits that memories that have been reactivated can be either enhanced or disrupted by pharmacological manipulation. Synaptic plasticity is presumed to underlie the reconsolidation process. Matrix metalloproteinases are proteins that regulate the extracellular matrix involved in plasticity events, and these proteins have recently been shown to influence learning and memory. However, all studies on the role of matrix metalloproteinases in learning and memory have employed tasks that rely on contextual cues. The goal of this study was to determine the extent to which FN-439 would disrupt the consolidation and/or reconsolidation of a fear memory associated with a conditioned stimulus that signaled tone-shock pairings and that was independent of contextual cues. Male Sprague-Dawley rats were given infusions of FN-439 (35 microg intracerebroventricular) 30 min prior to conditioning (tone-shock paired association) or 30 min prior to a single reactivation session given 24h after conditioning. Administration of FN-439 did not disrupt consolidation of the freezing response when the tone (conditioned stimulus) was presented. In contrast, FN-439 infusion disrupted reconsolidation of the fear memory in a reactivation-dependent manner. The reduced freezing behavior was not due to a decrease in general anxiety levels, since FN-439 had no effect on the percent of open-arm time or open-arm entries in an elevated-plus maze task. Thus, we demonstrated for the first time that matrix metalloproteinase inhibition in the brain is capable of disrupting the reconsolidation of a tone-shock association memory that does not depend on contextual cues. The finding that a fear response to a previously paired conditioned stimulus can be disrupted by treatment with an MMP inhibitor during a single reactivation session suggests that this class of compounds may have therapeutic potential for posttraumatic stress disorder and/or simple phobias.     

Neonatal tactile stimulation enhances spatial working memory, prefrontal long-term potentiation, and D1 receptor activation in adult rats

Environmental stimuli during neonatal periods play an important role in the development of cognitive function. In this study, we examined the long-term effects of neonatal tactile stimulation (TS) on spatial working memory (SWM) and related mechanisms. We also investigated whether TS-induced effects could be counteracted by repeated short periods of maternal separation (MS). Wistar rat pups submitted to TS were handled and marked transiently per day during postnatal days 2–9 or 10–17. TS/MS pups were stimulated in the same way as TS pups and then individually separated from their mother for 1 h/day. Their nontactile stimulated (NTS) siblings served as controls. In adulthood, TS and TS/MS rats showed better performance in two versions of the delayed alternation task and superior in vivo long-term potentiation of the hippocampo–prefrontal cortical pathway when compared with controls. Furthermore, there were more doses of A77636 (a selective dopamine D1 agonist) to significantly improve SWM performance in TS and TS/MS rats than in NTS rats, suggesting that activation of prefrontal D1 receptors in TS and TS/MS rats is more optimal for SWM function than in NTS rats. MS did not counteract TS-induced effects because no significant difference was found between TS/MS and TS animals. These data indicate that in early life, external tactile stimulation leads to long-term facilitative effects in SWM-related neural function.     

Visual but not spatial working memory deficit in children with spina bifida

Twenty children with spina bifida and twenty controls were assessed on a battery of visuospatial working memory tests. Children with spina bifida performed as well as the control group in the visuospatial test and in the forward and backward versions of the Corsi test, but were impaired in the 'House Visual Span.' This test, designed in our lab, provides specific information regarding visual ability to discriminate between pictorial targets and lures, and requires specific visual processing of stimuli. These results are discussed in terms of working memory models and are viewed as supporting the distinction between the visual and spatial components of working memory.     

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

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

Implicit,long-term spatial contextual memory

Learning and memory of novel spatial configurations aids behaviors such as visual search through an implicit process called contextual cuing (M. M. Chun & Y. Jiang, 1998). The present study provides rigorous tests of the implicit nature ofcontextual cuing. Experiment 1 used a recognition test that closely matched the learning task, confirming that memory traces of predictive spatial context were not accessible to conscious retrieval. Experiment 2 gave explicit instructions to encode visual context during learning, but learning was not improved and conscious memory remained undetectable. Experiment 3 illustrates that memory traces for spatial context may persist for at least 1 week, suggesting along-term component of contextual cuing. These experiments indicate that the learning and memory of spatial context in the contextual cuing task are indeed implicit. The results have implications for understanding the neural substrate of spatial contextual learning, which may depend on an intact medial temporal lobe system that includes the hippocampus (Mi. M. Chun & E. A. Phelps, 1999).     

Spatial memory in rats: electroconvulsive shock selectively disrupts working memory but spares reference memory

In two experiments rats were trained until they displayed highly accurate spatial memories when a 4-h delay was imposed between the to-be-remembered event (TBRE) and the retention test in a 12-arm radial maze. If the procedure tested only working memory (WM) electronvulsive shock (ECS) 2 h after the TBRE produced amnesia but ECS immediately after the TBRE was ineffective. If the testing procedure also involved a reference memory (RM) component, ECS degraded WM regardless of whether it was given 0 or 2 h after the TBRE. RM was not affected. With either training procedure administering ECS 2 h before the TBRE was ineffective. Thus, in the radial maze truly old spatial RM was immune to disruption by ECS while more recent WM was vulnerable. Possible explanations of the data are presented.     

Forgotten but not gone: savings for pictures and words in long-term memory

Five experiments examined the relearning of words, simple line-drawing pictures, and complex photographic pictures after retention intervals of 1 to 10 weeks. For those items that were neither recalled nor recognized, the identical item was relearned better than an unrelated control item, as measured by a recall test following relearning. This relearning advantage in recall held for all three classes of material and extended to the cross-modality case (i.e., picture-word and word-picture) and the same-referent case (i.e., two pictures of the same object). However, recognition tests of relearning failed to detect this same relearning advantage for apparently forgotten items. Taken together, these findings conflict with the existing account of savings. Most fundamental, the classic argument that relearning serves a trace-strengthening function is undetermined by the observed recall-recognition contrast. An alternative explanation of savings is suggested wherein relearning assists retrieval of information, thereby affecting recall in particular.     

Dissociation and memory fragmentation: experimental effects on meta-memory but not on actual memory performance

The relation between state dissociation and fragmentary memory was investigated by assessing both actual memory performance and meta-memory. From a sample of 330 normal subjects, two subsamples were selected on basis of trait dissociation, as measured by the Dissociative Experience Scale. Twenty subjects scoring above 30 and 20 subjects scoring below 10 were selected. Subjects watched an extremely aversive film, after which state dissociation was measured by the Peri-traumatic Dissociative Experience Scale. Four hours later memory fragmentation was assessed in two ways. Actual fragmentation was measured by a sequential memory task, and perceived fragmentation (meta-memory) was measured using a visual analogue scale. Subjects who tended to dissociate during the film judged their recollections of the film as more fragmentary. Although this finding is in line with clinical reports given by trauma victims, it was not sustained by objective evidence. That is, no effect was observed of state dissociation on the sequential memory task. The present findings suggest that the claim that dissociation induces memory fragmentation may have to be confined to meta-memory. Implications of this divergence between actual memory and meta-memory are discussed.     

Divided attention at retrieval disrupts knowing but not remembering

The view that remember and know responses can be explained within a dual-process framework has recently been questioned (e.g., Gardiner, Konstantinou, Karayianni, & Gregg, 2005). The aims of the present study were to investigate further discrepancies between remember/know (R/K) studies and dual-process models of recognition memory. In two experiments participants were required to make old/new and R/K decisions under full and divided attention conditions. Experiment 1 used a two-step R/K procedure and showed that attention during retrieval reduced overall recognition performance. Experiment 2 used a one-step R/K procedure and showed that dividing attention at retrieval only affected know responses, suggesting that knowing but not remembering relies on controlled retrieval processes. These findings and findings from recent research provide evidence that is inconsistent with the dual-process explanation for R/K research.