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Dietary cis-fatty acids that increase protein F1 phosphorylation enhance spatial memory.

Activation of protein kinase C (PKC) facilitates long-term potentiation (LTP), a model of memory, and increases its substrate protein F1 (aka GAP43) phosphorylation in direct relation to synaptic enhancement. Unsaturated fatty acids (c-FAs) which activate purified PKC, when injected into hippocampus, enhance LTP. To determine if dietary c-FAs could alter memory itself as well as brain PKC substrate (F1) metabolism, rats were maintained for 10 weeks on fatty acid diets enriched in mono-unsaturated oleic acid (OA; 20% olive oil, w/w), or a mono- and di-unsaturated mixture of oleate/linoleate (O/L; 20% corn oil), or a saturated fatty acid diet of laurate/myristate (L/M; 20% hydrogenated coconut oil). The O/L diet group was superior to the OA and L/M groups in spatial memory performance after the first two weeks of acquisition and in later achievement of criterion performance. The O/L diet had a significantly higher hippocampal protein F1 in vitro phosphorylation than in both the OA and L/M in trained and non-trained animals. Significantly, animals that made fewer errors showed higher F1 phosphorylation (r = -0.70). Diet both increases brain PKC substrate phosphorylation and enhances maze learning, confirming the feasibility of enhancing learning and memory by dietary regimens derived from basic neurochemical studies of synaptic plasticity.

Animals↗

Characterization of high voltage spindles and spatial memory in young, mature and aged rats.

EEG was recorded from rats of three age groups, and high voltage spindles (HVS) were measured during waking immobility. Total mean spindling times in 4- (young), 10- (mature) and 22- (aged) month-old rats were 0.3 +/- 0.1, 20.4 +/- 7.4 and 33.4 +/- 14.9 s, respectively. Spatial memory was assessed in these rats using a discrimination version of the Morris water maze. Performance (as measured by number of choice errors) was compared with the extent of HVS activity by characterizing rats as "spindling" if the total average duration of HVS discharges exceeded 5 s, and "non-spindling" if these discharges averaged less than 5 s. Spindling and nonspindling rats had similar performance during training; however, on a 14-day retention trial, spindling rats had a significantly higher mean error score of 2.8 +/- 0.5 compared with 1.2 +/- 0.3 for nonspindling rats (p = 0.011). These results show that spindling activity increases in mature and aged rats, and that HVS discharges may be an electrophysiological change that parallels the progression of brain dysfunction associated with memory impairment.

Action Potentials↗

Development of reference and working spatial memory in preschool children.

Three groups of preschool children (aged 18 to 28, 33 to 42, and 47 to 58 months) were given a radial search test similar to the radial arm maze used with nonhuman subjects. The children searched for chocolate sweets among 10 labeled locations in a room, 5 of which were baited with a sweet. Older children outperformed the intermediate group, who in turn outperformed the youngest group in requiring fewer choices to retrieve all of the sweets. Working memory and reference memory aspects of performance were then separated: Reference memory (restriction of choices to the baited subset) in older children was superior to that in the youngest group but not to that in the intermediate group. In terms of working memory (avoidance of repeat responses to already visited locations), the older group made fewer errors than the intermediate group, who, in turn, made fewer errors than the youngest group. We concluded that working and reference components of spatial memory in children may share common elements, perhaps the ability to recognize places as familiar, although reference memory may develop earlier than working memory.

Attention↗

Cerebral hypoperfusion yields capillary damage in the hippocampal CA1 area that correlates with spatial memory impairment.

The impact of chronic cerebral hypoperfusion on cognitive function and cerebral capillary morphology in the hippocampus was examined. Young adult Wistar rats were subjected to permanent ligation of both common carotid arteries (two-vessel occlusion). One month after vascular occlusion, a small but non-significant impairment in the acquisition of spatial information was registered compared with sham-operated controls. Two months after surgery, the occluded animals displayed an impaired performance throughout the training period. One year after surgery, the acquisition curves demonstrated a significant attenuation of the learning rate in the occluded rats group, whereas no significant differences in long-term retention were observed. Thus, chronic hypoperfusion induced by two-vessel occlusion gave rise to impairment of spatial memory. Following behavioural testing, the rats were killed at the age of 17 months, and capillaries in the CA1 and dentate gyrus were examined using transmission electron microscopy. Typical age-related capillary abnormalities such as degenerative pericytes and thickened basement membranes (with or without fibrosis) were detected in the hippocampus of sham animals. In occluded rats, the occurrence of capillaries displaying such abnormalities almost doubled in the CA1 region, but was similar in the dentate gyrus, compared with sham controls. A highly significant correlation was found between the last Morris maze performance and the percentage of capillaries with deposits in the basement membrane in the hippocampal CA1 area of occluded rats, which was not present in the sham animals. We conclude that a long-term hypoperfusion accelerated the development of age-related ultrastructural aberrations of capillaries in the hippocampal CA1 area, but not in the dentate gyrus. Thus, not only neurons, but also capillaries in the hippocampal CA1 area are sensitive to an impaired microcirculation. Moreover, the cognitive performance of hypoperfused rats correlated closely with the condition of the capillaries in the CA1 area, suggesting that capillary integrity is one of the important determinants of brain function in conditions that compromise cerebral microcirculation.

Animals↗

Spatial memory deficits, increased phosphorylation of the transcription factor CREB, and induction of the AP-1 complex following experimental brain injury.

Traumatic brain injury causes both short- and long-term neurological impairments. A cascade of biochemical changes triggered by the injury may increase the expression of several genes, which has been hypothesized to contribute to the observed cognitive deficits. The mechanism(s) of induction for these genes is not yet known. We present evidence that lateral cortical impact injury in rats that produces spatial memory deficits also increases phosphorylation of the transcription factor CREB (cAMP response element binding). Subsequent to the phosphorylation of CREB, c-Fos expression and the AP-1 complex are enhanced. The temporal and spatial activation of c-Fos is consistent with it being induced by phosphorylated CREB proteins. Thus, CREB-mediated gene activation may contribute to the observed behavioral deficits. Further elucidation of the biochemical and pathophysiological changes will be of importance for clinical therapy.

Animals↗

Genetic differences in response to novelty and spatial memory using a two-trial recognition task in mice.

A two-trial memory task, based on a free-choice exploration paradigm in a Y-maze, was previously developed to study recognition processes in Sprague-Dawley rats. Because this paradigm avoids the use of electric shock or deprivation that may have nonspecific effects and does not require learning of a rule, it may be particularly useful for studying memory in mice. Four inbred strains (Balb/cByJ, DBA/2J, C57BL/6J, and SJL/J), an F1 hybrid (C57BL/6 x SJL/J), and one outbred strain (CD1) were used to validate this task in mice and to characterize a strain distribution in response to novelty and working memory. Exploration was measured with a short (2 min) intertrial interval (ITI) between acquisition and retrieval, while memory was examined with longer intervals (30 min, 1 h, and 2 h). A study of the time course of the response to novelty revealed varying degrees of preference and/or habituation to novelty among the different strains, with CD1 exhibiting a very high response to novelty and others showing lower (C57 x SJL hybrids) to complete absence (SJL) of exploration of novelty. Memory span, assessed with increasing ITIs, varied widely among strains from 30 min (C57 x SJL hybrids) to at least 2 h (C57 and BALB). Such demonstrated sensitivity to a wide range of behavioral phenotypes supports the use of this spatial memory task as an effective tool for the study of genetic influences on the response to novelty and recognition processes in mice.

Animals↗

Comparing matching ability, spatial memory, and ideational fluency in boys and girls.

The purpose of our study was to examine whether girls and boys show patterns of problem-solving ability similar to those attributed by Kimura in 1992 to women and men, respectively. Subjects were 28 girls and 24 boys, aged 5-11 years, who were tested individually on matching ability, spatial memory, and ideational fluency, tasks on which women reportedly outperform men. No significant gender differences in these problem-solving abilities were found. On ideational fluency, the youngest girls were seven times more likely than young boys to give whimsical responses, but older girls were then times less likely than older boys to give whimsical responses. These results suggest that the patterns of visuospatial problem-solving abilities that Kimura ascribed to women and men are not present in preadolescent girls and boys.

Aptitude↗

Sexual orientation related differences in spatial memory.

The purpose of this study was to investigate and extend previously reported sex differences in object location memory by comparing the performance of heterosexual and homosexual males and females. Subjects were 240 healthy, right-handed heterosexual and homosexual males and females. They were instructed to study 16 common, gender-neutral objects arranged randomly in an array and subsequently tested for object recall, object recognition and spatial location memory. Females recalled significantly more objects than males, although there were no group differences in object recognition. Decomposition of significant interactions between sex and sexual orientation on spatial location memory (controlling for differences in object recall, age and IQ) revealed that heterosexual females and homosexual males scored better than heterosexual males, and no different from each other. There were no differences between homosexual and heterosexual females. The findings suggest that homosexual males and heterosexual females encode, store and retrieve positional and relational information about spatial layouts similarly, pointing to within-sex variations in the neural architecture underlying spatial memory.

Female↗

Spatial memory and hippocampal pallium through vertebrate evolution: insights from reptiles and teleost fish.

The forebrain of vertebrates shows great morphological variation and specialized adaptations. However, an increasing amount of neuroanatomical and functional data reveal that the evolution of the vertebrate forebrain could have been more conservative than previously realized. For example, the pallial region of the teleost telencephalon contains subdivisions presumably homologous with various pallial areas in amniotes, including possibly a homologue of the medial pallium or hippocampus. In mammals and birds, the hippocampus is critical for encoding complex spatial information to form map-like cognitive representations of the environment. Here, we present data showing that the pallial areas of reptiles and fish, previously proposed as homologous to the hippocampus of mammals and birds on an anatomical basis, are similarly involved in spatial memory and navigation by map-like or relational representations of the allocentric space. These data suggest that early in vertebrate evolution, the medial pallium of an ancestral fish group that gave rise to the extant vertebrates became specialized for processing and encoding complex spatial information, and that this functional trait has been retained through the evolution of each independent vertebrate lineage.

Animals↗

Human hippocampus and viewpoint dependence in spatial memory.

Virtual reality was used to sequentially present objects within a town square and to test recognition of object locations from the same viewpoint as presentation, or from a shifted viewpoint. A developmental amnesic case with focal bilateral hippocampal pathology showed a massive additional impairment when tested from the shifted viewpoint compared with a mild, list length-dependent, impairment when tested from the same viewpoint. While the same-view condition could be solved by visual pattern matching, the shifted-view condition requires a viewpoint independent representation or an equivalent mechanism for translating or rotating viewpoints in memory. The latter mechanism was indicated by control subjects' response latencies in the shifted-view condition, although the amnesic case is not impaired in tests of mental rotation of single objects. These results show that the human hippocampus supports viewpoint independence in spatial memory, and suggest that it does so by providing a mechanism for viewpoint manipulation in memory. In addition, they suggest an extremely sensitive test for human hippocampal damage, and hint at the nature of the hippocampal role in episodic recollection.

Adult↗

The role of attention in a spatial memory task in Alzheimer disease patients.

Memory and attention are interrelated cognitive processes that most likely influence the functioning of each other, yet they are often difficult to distinguish in psychological experiments. Young, aged adults, and patients with Alzheimer disease (AD) were tested on a delay response task measuring spatial memory that also placed high demands on attentional resources. Aged adults performed as well as young, suggesting that neither attentional nor memory abilities were exceeded in either group. However, AD subjects were severely impaired on this task. Two further experiments with AD patients examined the relative contribution of attentional and memory deficits in the performance of this population. Both memory and attentional impairments were found; however, errors due to memory factors were more closely related to severity of disease as measured on the Folstein Mini-Mental State Examination than were errors of attentional origin. These studies demonstrate the necessity of accounting for attentional components in studies examining memory, especially in patients with AD.

Adult↗

Spatial memory of body linear displacement: what is being stored?

The ability to evaluate traveled distance is common to most animal species. Head trajectory in space is measured on the basis of the converging signals of the visual, vestibular, and somatosensory systems, together with efferent copies of motor commands. Recent evidence from human studies has shown that head trajectory in space can be stored in spatial memory. A fundamental question, however, remains unanswered: How is movement stored? In this study, humans who were asked to reproduce passive linear whole-body displacement distances while blindfolded were also able to reproduce velocity profiles. This finding suggests that a spatiotemporal dynamic pattern of motion is stored and can be retrieved with the use of vestibular and somesthetic cues.

Acceleration↗

Low-density lipoprotein receptor-knockout mice display impaired spatial memory associated with a decreased synaptic density in the hippocampus.

The low-density lipoprotein receptor (LDLR) is the first described receptor for apolipoprotein E (apoE). We hypothesize that the absence of the LDLR, similar to the absence of apoE, results in impaired learning and memory processes. Six-month-old homozygous Ldlr-/- and wild-type littermates (Ldlr+/+), maintained on a standard lab chow diet, were used. Unlike humans, Ldlr-/- mice, under these conditions, do not develop atherosclerosis. The results of the Morris water escape task revealed an impaired spatial memory in the Ldlr-/- mice in comparison with Ldlr+/+ mice. Also in a T-maze task, the working memory performance of the Ldlr-/- mice was impaired. Furthermore, Ldlr-/- mice, in comparison with Ldlr+/+ mice, display a decreased number of synaptophysin-immunoreactive presynaptic boutons in the hippocampus CA1. In conclusion, the results show in mice deficiency for the LDLR results in impaired hippocampal-dependent memory functions. A decrease in the number of presynaptic boutons may underlay these behavioral alterations. Therefore, the LDLR may be an important receptor for apoE in the central nervous system.

Animals↗

The CRH1 antagonist CP154,526 failed to alter ischemia-induced neurodegeneration and spatial memory deficits in rats but inhibited behavioral activity in the novel open field.

Corticotropin-releasing hormone (CRH) has been implicated in ischemia-induced neurotoxicity, due in part to excitatory effects at the hippocampus, and the demonstrated neuroprotective effects of centrally administered, non-specific CRH antagonists. However, a number of issues remain to be clarified from these studies, including the relative contribution of CRH receptor subtypes, and the efficacy of these compounds to alter ischemia-induced behavioral impairments. In the current study, a highly selective, systemically administered CRH1 antagonist (CP154,526) failed to reverse global ischemia-induced cell death in hippocampal CA1 neurons or spatial memory impairments as assessed in the radial arm maze. Similarly, central administration of alpha-helical CRH failed to confer protection against ischemic damage. Interestingly, CRH1 antagonism reversed ischemia-induced hyperactivity in a novel open field, suggesting that modulation of this behavior is independent of effects on hippocampal CA1 cell loss. Failure of the current study to demonstrate neuroprotective effects of either the selective or non-selective CRH antagonists tested challenges the proposed neurotoxic role of CRH in global ischemia. These findings are discussed in relationship to recent findings reconsidering the participation of CRH in excitotoxic-mediated cellular damage.

Animals↗

Excitotoxic lesions centered on perirhinal cortex produce delay-dependent deficits in a test of spatial memory.

Rats with bilateral electrolytic or ibotenic acid lesions that were centred in perirhinal cortex displayed a significant delay-dependent deficit on a delayed nonmatch to position task in the T maze. Although the removal of prominent extramaze visual cues did not affect the performance of these rats, rotating the maze between the sample and test phases did, indicating that rats were using a spatial strategy. Interestingly, a further group of rats with hippocampal and perirhinal damage displayed deficits that may reflect a dysfunction in the use of inertial cues. These results suggest that both electrolytic and excitotoxic lesions of perirhinal cortex produce spatial memory impairments but that these impairments are qualitatively different than those exhibited following hippocampal damage.

Analysis of Variance↗

Spatial memory and perspective taking.

Giving directions or describing an environment often requires assuming perspectives other than one's own. We employed a spatial perspective-taking task to investigate how describing familiar versus novel perspectives affects subsequent memory. One participant (the director) viewed a display of objects from a single perspective and described the display to another participant (the matcher) from a perspective that varied by 0 degrees, 45 degrees, 90 degrees, 135 degrees, or 180 degrees from the viewing perspective. Following the description, we assessed the director's memory for the display, using judgments of relative direction, scene recognition, and map drawing. The participants imagined and recognized familiar views faster and/or more accurately than novel views. Moreover, different tasks showed different degrees of facilitation for the visually perceived and described views, suggesting multiple representations for different aspects of spatial memory. These findings emphasize the importance of understanding distinctions among spatial experiences and underscore differences in the tasks used to probe spatial memory.

Female↗

Spatial memory in middle-aged female rats: assessment of estrogen replacement after ovariectomy.

Previous studies have shown that estrogen influences diverse aspects of neuronal function and morphology and modulates acquisition of various memory tasks in young adult female rodents. It is not clear whether estrogen is critical for optimal memory function in middle-aged female animals, i.e. when cyclicity gradually declines. We trained young adult (5 months) and older (10 months) female Long-Evans rats on a win-shift (delay) 12-arm radial maze (7 arms blocked pre-delay). Rats were preoperatively trained to criterion (< or =2 errors/trial for 3 days) with no delay then with a 60 s delay. All rats were ovariectomized when the age groups were 9 (Y) and 14 months (MA), respectively. Following recovery and retraining to criterion, each rat underwent consecutive treatment cycles with vehicle (Oil) or 17-beta-estradiol benzoate (E). Each 6-day acute treatment cycle, modeled after protocols previously shown to induce morphological and electrophysiological plasticity in the hippocampus at 24-48 h after estrogen injection, consisted of two consecutive daily injections of 10 microg E or Oil (0.1 ml subcutaneously) on Days 1-2 (Oil-Oil or E-E), testing on Days 3-4 at 60 s or 6 h delays, with Days 5-6 comprising of washout days. Each rat received a total of 4 treatment cycles, alternating between Oil and E cycles, in counterbalanced order. Estrogen treatment had no effect in either age group on pre-delay or post-delay errors at either 60 s or 6 h delays. The data indicate that the cyclic estrogen replacement regimen does not influence spatial memory function in young or middle-aged animals in the hippocampal-dependent appetitive radial maze task. Discussion of these unexpected results includes consideration of important experimental design factors that differ between our study and some previous reports, such as the extensive training and task experience our subject received prior to testing for estrogen effects.

Age Factors↗

Electrolytic lesions of the ventral subiculum weakly alter spatial memory but potentiate amphetamine-induced locomotion.

Adult Long-Evans male rats were subjected to electrolytic lesions of the ventral subiculum, and tested for locomotor activity in the home cage, reference and working memory in the water maze, working memory in the radial maze, and D-amphetamine-induced locomotion (1mg/kg, i.p.). When compared to their sham-operated counterparts, lesioned rats showed nocturnal hyperactivity, no reference memory deficit, but working memory was impaired in the water maze and during the initial stage of radial-maze testing. Their locomotor responsiveness to D-amphetamine was exaggerated. Histological verifications confirmed lesions in the ventral subiculum. Material stained for acetylcholinesterase activity indicated septohippocampal and commissural/associational sprouting, accounting for partial damage to the perforant paths. These results showed that ventral subiculum lesions (i) do not alter the capability of rats to learn repeatedly presented spatial information, and (ii) impair, but do not prevent, spatial working memory, suggesting that the ventral subiculum is preferentially involved in short-term memory for spatial locations. Given the electrolytic nature of the lesion, the lesion-induced potentiation of the locomotor response to amphetamine is probably easier explained by partial disruption of the perforant paths than by damage to neurons of the ventral subiculum.

Acetylcholinesterase↗