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Background: Increased blood-brain barrier (BBB) permeability and amyloid-ß (Aß) peptides (especially Aß1-42) (Aß42) have been linked to Alzheimer's disease (AD) pathogenesis, but the nature of their involvement in AD-related neuropathological changes leading to cognitive changes remains poorly understood. Objective: To test the hypothesis that chronic extravasation of bloodborne Aß42 peptide and brain-reactive autoantibodies and their entry into the brain parenchyma via a permeable BBB contribute to AD-related pathological changes and cognitive changes in a mouse model. Methods: The BBB was rendered chronically permeable through repeated injections of Pertussis toxin (PT), and soluble monomeric, fluorescein isothiocyanate (FITC)-labeled or unlabeled Aß42 was injected into the tail-vein of 10-month-old male CD1 mice at designated intervals spanning ∼3 months. Acquisition of learned behaviors and long-term retention were assessed via a battery of cognitive and behavioral tests and linked to neuropathological changes. Results: Mice injected with both PT and Aß42 demonstrated a preferential deficit in the capacity for long-term retention and an increased susceptibility to interference in selective attention compared to mice exposed to PT or saline only. Immunohistochemical analyses revealed increased BBB permeability and entry of bloodborne Aß42 and immunoglobulin G (IgG) into the brain parenchyma, selective neuronal binding of IgG and neuronal accumulation of Aß42 in animals injected with both PT and Aß42 compared to controls. Conclusion: Results highlight the potential synergistic role of BBB compromise and the influx of bloodborne Aß42 into the brain in both the initiation and progression of neuropathologic and cognitive changes associated with AD.

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"General intelligence" is purported to influence diverse domain-specific learning abilities in humans, and previous research indicates that an analogous trait is expressed in CD-1 outbred mice. In humans and mice, exploratory tendencies are predictive of general cognitive abilities, such that higher cognitive abilities are associated with elevated levels of exploration. However, in mice, repeated exposure to novel environments outside the home cage has been found to up-regulate exploratory tendencies but has no commensurate effect on general learning abilities, suggesting that exploratory tendencies do not causally influence general cognitive performance. This leaves open the question of what is responsible for the robust relationship observed between exploration and general learning abilities? In the present experiments, we find that differential rates of habituation (e.g., to a novel open field) between animals of high and low general learning abilities accounts for the relationship between exploration and learning abilities. First, we up-regulated exploration by exposing mice to a series of novel environments. Similar to its lack of effect on learning tasks, this up-regulation of exploration had no commensurate effect on habituation to novel objects or stimuli. Next we examined the relationship between general learning abilities and exploration under conditions where habituation had a high or low impact on exploratory behaviors. A strong correlation between general learning abilities and exploration was observed under conditions where the levels of habituation (to a novel object or an open field) between animals of high and low general learning abilities were allowed to vary. However, this same correlation was attenuated when the level of habituation attained by animals of high and low general learning abilities was asymptotic or held constant across animals. In total, these results indicate that the relationship between exploration and general learning abilities is accounted for by the impact of habituation (itself a form of learning) on behaviors indicative of exploration.

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A defining characteristic of age-related cognitive decline is a deficit in general cognitive performance. Here we use a testing and analysis regimen that allows us to characterize the general learning abilities of young (3-5 mo old) and aged (19-21 mo old) male and female Balb/C mice. Animals' performance was assessed on a battery of seven diverse learning tasks. Aged animals exhibited deficits in five of the seven tasks and ranked significantly lower than their young counterparts in general learning abilities (aggregate performance across the battery of tasks). Aging added variability to common core performance (i.e., general learning ability), which translated into increased variability on the individual cognitive tasks. Relatedly, general learning abilities did not differ between the two ages among the best quartile of learners (i.e., cognitive abilities were spared in a subsample of the aged animals). Additionally, working memory capacity (resistance to interference) and duration (resistance to decay) accounted for significantly more of the variability in general learning abilities in aged relative to young animals. Tests of 15 noncognitive performance variables indicated that an increase in body weight (and an associated decrease in general activity) was characteristic of those aged animals which exhibited deficient general learning abilities. These results suggest the possibility that general cognitive deficits in aged animals reflect a failure of specific components of the working memory system, and may be related to variations in body weight and an associated decrease in activity.

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"General cognitive ability" describes a trait that transcends specific learning domains and impacts a wide range of cognitive skills. Individual animals (including humans) exhibit wide variations in their expression of this trait. We have previously determined that the propensity for exploration is highly correlated with the general cognitive abilities of individual outbred mice. Here, we asked if inducing an increase in exploratory behaviors would causally promote an increase in animals' general learning abilities. In three experiments, juvenile and young-adult male CD-1 outbred mice were exposed to 12 novel environments starting at post-natal days 39 (juvenile) and 61 (young adult), after which they underwent a series of cognitive and exploratory tests as adults (beginning at post-natal day 79). Exposure to novel environments promoted increases in exploration (across multiple measures) on two different tasks, including an elevated plus maze. However, a subsequent test of general learning abilities (aggregate performance across five distinct learning tasks) determined that exposure to novel environments as juveniles or young-adults had no effect on general learning abilities in adulthood. Therefore, while exposure to novel environments promotes long-lasting increases in mice's exploratory tendencies, these increases in exploration do not appear to causally impact general learning abilities.

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It has previously been reported that general learning ability (GLA) correlates positively with exploratory tendencies in individual outbred mice. This finding suggests the possibility that variations in stress reactivity modulate GLA and thus its relationship to exploratory tendencies. Here, the authors investigated the potential role of stress reactivity in regulating this relationship by assessing the effects of the anxiolytic chlorodiazepoxide (CDP; 10 mg/kg) on subjects' performance in a battery of diverse learning tasks as well as exploratory behaviors and stress reactivity. CDP-treated mice exhibited reductions in stress-induced corticosterone levels and behavioral reactivity to mild stressors and a corresponding increase in exploration. However, CDP-treated mice did not exhibit facilitated acquisition of any of the learning tasks and expressed GLA comparable to controls. Results indicate that although reduced stress reactivity promotes exploration, this does not translate into an up-regulation of GLA, suggesting that the relationship between GLA and exploration is not mediated by stress reactivity. The authors propose that variations in GLA reflect individuals' propensity for novelty seeking, whereas exploration reflects both stress reactivity and novelty seeking, the latter of which may underlie the relationship between exploration and GLA.

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A single factor (i.e., general intelligence) can account for much of an individuals' performance across a wide variety of cognitive tests. However, despite this factor's robustness, the underlying process is still a matter of debate. To address this question, we developed a novel battery of learning tasks to assess the general learning abilities (GLAs) of mice. Using this battery, we previously reported a strong relationship between GLA and a task designed to tax working memory capacity (i.e., resistance to competing demands). Here we further explored this relationship by investigating which aspects of working memory (storage or processing) best predict GLAs in mice. We found that a component of working memory, selective attention, correlated with GLA comparably to working memory capacity. However, this relationship was not found for two other components of working memory, short-term memory capacity and duration. These results provide further evidence that variations in aspects of working memory and executive functions covary with general cognitive abilities.

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Across multiple learning tasks (that place different sensory, motor, and information processing demands on the animals), we have found that the performance of mice is commonly regulated by a single factor ("general learning") that accounts for 30-40% of the variance across individuals and tasks. Furthermore, individuals' general learning abilities were highly correlated with their propensity to engage in exploration in an open field, a behavior that is potentially stress-inducing. This relationship between exploration in the open field and general learning abilities suggests the possibility that variations in stress sensitivity/responsivity or related emotional responses might directly influence individuals' general learning abilities. Here, the relationship of sensory/motor skills and stress sensitivity/emotionality to animals' general learning abilities were assessed. Outbred (CD-1) mice were tested in a battery of six learning tasks as well as 21 tests of exploratory behavior, sensory/motor function and fitness, emotionality, and stress reactivity. The performances of individual mice were correlated across six learning tasks, and the performance measures of all learning tasks loaded heavily on a single factor (principal component analysis), accounting for 32% of the variability between animals and tasks. Open field exploration and seven additional exploratory behaviors (including those exhibited in an elevated plus maze) also loaded heavily on this same factor, although general activity, sensory/motor responses, physical characteristics, and direct measures of fear did not. In a separate experiment, serum corticosterone levels of mice were elevated in response to a mild environmental stressor (confinement on an elevated platform). Stress-induced corticosterone levels were correlated with behavioral fear responses, but were unsystematically related to individuals' propensity for exploration. In total, these results suggest that although general learning abilities are strongly related to individuals' propensity for exploration, this relationship is not attributable to variations in sensory/motor function or the individuals' physiological or behavioral sensitivity to conditions that promote stress or fear.

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Up to 50% of an individuals' performance across a wide variety of distinct cognitive tests can be accounted for by a single factor (i.e., "general intelligence"). Despite its ubiquity, the processes or mechanisms regulating this factor are a matter of considerable debate. Although it has been hypothesized that working memory may impact cognitive performance across various domains, tests have been inconclusive due to the difficulty in isolating working memory from its overlapping operations, such as verbal ability. We address this problem using genetically diverse mice, which exhibit a trait analogous to general intelligence. The general cognitive abilities of CD-1 mice were found to covary with individuals' working memory capacity, but not with variations in long-term retention. These results provide evidence that independent of verbal abilities, variations in working memory are associated with general cognitive abilities, and further, suggest a conservation across species of mechanisms and/or processes that regulate cognitive abilities.

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The present study examined the interrelationships between feeding responses produced by mu opioid receptor agonists and melanocortin-3 or 4 (MC-3/4) receptor antagonists. Feeding induced by the mu-sensitive opioid peptide, beta-endorphin (betaEND, 10 microg, i.c.v.) was significantly and dose-dependently reduced by pretreatment with the MC-3/4 receptor agonist, melanotan-II (MTII: 0.01-10 nmol, i.c.v.). Moreover, the selective mu opioid antagonist, beta-funaltrexamine (betaFNA: 2-20 mug, i.c.v.), significantly and dose-dependently reduced feeding and weight gain elicited by the potent MC-3/4 receptor antagonist, SHU-9119 (0.5 nmol, i.c.v.), especially at those intake periods (24-48 h) when SHU-9119 produced maximal ingestive effects. These data extend previous findings demonstrating interactions between opioid and melanocortin receptors in the mediation of food intake.

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Human performance on diverse tests of intellect are impacted by a "general" regulatory factor that accounts for up to 50% of the variance between individuals on intelligence tests. Neurobiological determinants of general cognitive abilities are essentially unknown, owing in part to the paucity of animal research wherein neurobiological analyses are possible. We report a methodology with which we have assessed individual differences in the general learning abilities of laboratory mice. Abilities of mice on tests of associative fear conditioning, operant avoidance, path integration, discrimination, and spatial navigation were assessed. Tasks were designed so that each made unique sensory, motor, motivational, and information processing demands on the animals. A sample of 56 genetically diverse outbred mice (CD-1) was used to assess individuals' acquisition on each task. Indicative of a common source of variance, positive correlations were found between individuals' performance on all tasks. When tested on multiple test batteries, the overall performance ranks of individuals were found to be highly reliable and were "normally" distributed. Factor analysis of learning performance variables determined that a single factor accounted for 38% of the total variance across animals. Animals' levels of native activity and body weights accounted for little of the variability in learning, although animals' propensity for exploration loaded strongly (and was positively correlated) with learning abilities. These results indicate that diverse learning abilities of laboratory mice are influenced by a common source of variance and, moreover, that the general learning abilities of individual mice can be specified relative to a sample of peers.

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Antisense (AS) oligodeoxynucleotides targeting G-protein alpha-subunits distinguish feeding responses of morphine and its metabolite, as well as nocturnal and deprivation-induced feeding. The present study examined whether feeding elicited by beta-endorphin (betaEND) or dynorphin A(1-17) was altered by ventricularly-applied G(i)alpha(1), G(i)alpha(2), G(i)alpha(3), G(s)alpha, G(o)alpha, G(q)alpha or G(x/z)alpha AS probes, or a nonsense (NS) control. The betaEND-induced feeding was reduced by the G(i)alpha(1) and G(x/z)alpha AS probes, and increased by G(i)alpha(2) or G(i)alpha(3) AS treatment. Dynorphin-induced feeding was attenuated by G(i)alpha(1) and G(o)alpha AS treatment. Yet, G(s)alpha or G(q)alpha AS and NS treatments failed to alter opioid agonist-induced feeding. These data provide initial characterization of potential effector signaling pathways mediating betaEND and dynorphin-induced feeding.

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Ventricular administration of the opioid dynorphin A(1-17) induces feeding in rats. Because its pharmacological characterization has not been fully identified, the present study examined whether a dose-response range of general and selective opioid antagonists as well as antisense oligodeoxynucleotide (AS ODN) opioid probes altered daytime feeding over a 4-h time course elicited by dynorphin. Dynorphin-induced feeding was significantly reduced by a wide range of doses (5-80 nmol i.c.v.) of the selective kappa(1)-opioid antagonist nor-binaltorphamine. Correspondingly, AS ODN probes directed against either exons 1 and 2, but not 3 of the kappa-opioid receptor clone (KOR-1) reduced dynorphin-induced feeding, whereas a missense oligodeoxynucleotide control probe was ineffective. Furthermore, AS ODN probes directed against either exons 1 or 2, but not 3 of the kappa(3)-like opioid receptor clone (KOR-3/ORL-1) also attenuated dynorphin-induced feeding. Although the selective mu-antagonist beta-funaltrexamine (20-80 nmol) reduced dynorphin-induced feeding, an AS ODN probe directed only against exon 1 of the mu-opioid receptor clone was transiently effective. Neither general (naltrexone, 80 nmol) nor delta (naltrindole, 80 nmol)-selective opioid antagonists were particularly effective in reducing dynorphin-induced feeding, and an AS ODN probe targeting the individual exons of the delta-opioid receptor clone failed to significantly reduce dynorphin-induced feeding. These converging antagonist and AS ODN data firmly implicate the kappa(1)-opioid receptor and the KOR-1 and KOR-3/ORL-1 opioid receptor genes in the mediation of dynorphin-induced feeding.

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