A Chronic Increase in Blood-Brain Barrier Permeability Facilitates Intraneuronal Deposition of Exogenous Bloodborne Amyloid-Beta1-42 Peptide in the Brain and Leads to Alzheimer's Disease-Relevant Cognitive Changes in a Mouse Model.

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.

Evidence for a Mixed Timing and Counting Strategy in Mice Performing a Mechner Counting Task.

Numerosity, or the ability to understand and distinguish between discrete quantities, was first formalized for study in animals by Mechner (1958a). Rats had to press one lever (the counting lever) n times to arm food release from pressing a second lever (the reward lever). The only cue that n presses had been made to the counting lever was the animal's representation of how many times it had pressed it. In the years that have passed since, many researchers have modified the task in meaningful ways to attempt to tease apart timing-based and count-based strategies. Strong evidence has amassed that the two are fundamentally different and separable skills but, to date, no study has effectively examined the differential contributions of the two strategies in Mechner's original task. By examining performance mid-trial and correlating it with whole-trial performance, we were able to identify patterns of correlation consistent with counting and timing strategies. Due to the independent nature of these correlation patterns, this technique was uniquely able to provide evidence for strategies that combined both timing and counting components. The results show that most mice demonstrated this combined strategy. This provides direct evidence that mice can and do use numerosity to complete Mechner's original task. A rational agent with fallible estimates of both counts made and time elapsed in making them should use both estimates when deciding when to switch to the second lever.

The imposition of, but not the propensity for, social subordination impairs exploratory behaviors and general cognitive abilities.

Imposed social subordination, such as that which accompanies physical defeat or alienation, has been associated with impaired cognitive function in both human and non-human animals. Here we examined whether domain-specific and/or domain-general learning abilities (c.f. general intelligence) are differentially influenced by the imposition of social subordination. Furthermore, we assessed whether the impact of subordination on cognitive abilities was the result of imposed subordination per se, or if it reflected deficits intrinsically expressed in subjects that are predisposed to subordination. Subordinate and dominant behaviors were assessed in two groups of CD-1 male mice. In one group (Imposed Stratification), social stratification was imposed (through persistent physical defeat in a colonized setting) prior to the determination of cognitive abilities, while in the second group (Innate Stratification), an assessment of social stratification was made after cognitive abilities had been quantified. Domain-specific learning abilities were measured as performance on individual learning tasks (odor discrimination, fear conditioning, spatial maze learning, passive avoidance, and egocentric navigation) while domain-general learning abilities were determined by subjects' aggregate performance across the battery of learning tasks. We observed that the imposition of subordination prior to cognitive testing decreased exploratory tendencies, moderately impaired performance on individual learning tasks, and severely impaired general cognitive performance. However, similar impairments were not observed in subjects with a predisposition toward a subordinate phenotype (but which had not experienced physical defeat at the time of cognitive testing). Mere colonization, regardless of outcome (i.e., stratification), was associated with an increase in stress-induced serum corticosterone (CORT) levels, and thus CORT elevations were not themselves adequate to explain the effects of imposed stratification on cognitive abilities. These findings indicate that absent the imposition of subordination, individuals with subordinate tendencies do not express learning impairments. This observation could have important ramifications for individuals in environments where social stratification is prevalent (e.g., schools or workplace settings).

Covariation of learning and "reasoning" abilities in mice: evolutionary conservation of the operations of intelligence.

Contemporary descriptions of human intelligence hold that this trait influences a broad range of cognitive abilities, including learning, attention, and reasoning. Like humans, individual genetically heterogeneous mice express a "general" cognitive trait that influences performance across a diverse array of learning and attentional tasks, and it has been suggested that this trait is qualitatively and structurally analogous to general intelligence in humans. However, the hallmark of human intelligence is the ability to use various forms of "reasoning" to support solutions to novel problems. Here, we find that genetically heterogeneous mice are capable of solving problems that are nominally indicative of inductive and deductive forms of reasoning, and that individuals' capacity for reasoning covaries with more general learning abilities. Mice were characterized for their general learning ability as determined by their aggregate performance (derived from principal component analysis) across a battery of five diverse learning tasks. These animals were then assessed on prototypic tests indicative of deductive reasoning (inferring the meaning of a novel item by exclusion, i.e., "fast mapping") and inductive reasoning (execution of an efficient search strategy in a binary decision tree). The animals exhibited systematic abilities on each of these nominal reasoning tasks that were predicted by their aggregate performance on the battery of learning tasks. These results suggest that the coregulation of reasoning and general learning performance in genetically heterogeneous mice form a core cognitive trait that is analogous to human intelligence.

General learning ability regulates exploration through its influence on rate of habituation.

"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.

Longitudinal attentional engagement rescues mice from age-related cognitive declines and cognitive inflexibility.

Learning, attentional, and perseverative deficits are characteristic of cognitive aging. In this study, genetically diverse CD-1 mice underwent longitudinal training in a task asserted to tax working memory capacity and its dependence on selective attention. Beginning at 3 mo of age, animals were trained for 12 d to perform in a dual radial-arm maze task that required the mice to remember and operate on two sets of overlapping guidance (spatial) cues. As previously reported, this training resulted in an immediate (at 4 mo of age) improvement in the animals' aggregate performance across a battery of five learning tasks. Subsequently, these animals received an additional 3 d of working memory training at 3-wk intervals for 15 mo (totaling 66 training sessions), and at 18 mo of age were assessed on a selective attention task, a second set of learning tasks, and variations of those tasks that required the animals to modify the previously learned response. Both attentional and learning abilities (on passive avoidance, active avoidance, and reinforced alternation tasks) were impaired in aged animals that had not received working memory training. Likewise, these aged animals exhibited consistent deficits when required to modify a previously instantiated learned response (in reinforced alternation, active avoidance, and spatial water maze). In contrast, these attentional, learning, and perseverative deficits were attenuated in aged animals that had undergone lifelong working memory exercise. These results suggest that general impairments of learning, attention, and cognitive flexibility may be mitigated by a cognitive exercise regimen that requires chronic attentional engagement.

Working memory training promotes general cognitive abilities in genetically heterogeneous mice.

In both humans and mice, the efficacy of working memory capacity and its related process, selective attention, are each strongly predictive of individuals' aggregate performance in cognitive test batteries [1-9]. Because working memory is taxed during most cognitive tasks, the efficacy of working memory may have a causal influence on individuals' performance on tests of "intelligence" [10, 11]. Despite the attention this has received, supporting evidence has been largely correlational in nature (but see [12]). Here, genetically heterogeneous mice were assessed on a battery of five learning tasks. Animals' aggregate performance across the tasks was used to estimate their general cognitive abilities, a trait that is in some respects analogous to intelligence [13, 14]. Working memory training promoted an increase in animals' selective attention and their aggregate performance on these tasks. This enhancement of general cognitive performance by working memory training was attenuated if its selective attention demands were reduced. These results provide evidence that the efficacy of working memory capacity and selective attention may be causally related to an animal's general cognitive performance and provide a framework for behavioral strategies to promote those abilities. Furthermore, the pattern of behavior reported here reflects a conservation of the processes that regulate general cognitive performance in humans and infrahuman animals.

Up-regulation of exploratory tendencies does not enhance general learning abilities in juvenile or young-adult outbred mice.

"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.