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.

Negative attributes of mixed-valence memories strengthen over long retention intervals and the degree of enhancement is predicted by individual differences in state anxiety.

Memories are multifaceted and can simultaneously contain positive and negative attributes. Here, we report that negative attributes of a mixed-valence memory dominate long-term recall. To induce a mixed-valence memory, running responses were randomly reinforced with either food (∼83% of trials) or footshock (∼17% of trials), or a noise conditioned stimulus (CS) was followed randomly with either food (∼80% of trials) or footshock (∼20% of trials). Control animals were consistently reinforced with only food. Mixed-valence training promoted unstable behavior (e.g., erratic approach and withdrawal from the food cup) and moderate levels of fear during the training regimens. After a 20-day retention interval, animals that were consistently reinforced with food exhibited intact approach responding, and similar responding was observed if animals were food deprived or satiated (i.e., the response was insensitive to motivation). However, animals that experienced the mixed-valence training expressed significantly enhanced and stable fear (consistent immobility) relative to the end of training, regardless of whether animals were food deprived or not, suggesting that fear transitioned to a state that was insensitive to motivation. The degree of fear expressed during long-term retention was predicted by measures of state anxiety obtained prior to the training, indicating that the enhancement of fear across the retention interval was related to individual differences in basal "anxiety." These results suggest that negative attributes of memories dominate long-term recall, particularly in animals expressing an anxious phenotype, and these observations have direct implications for the chronic nature of anxiety disorders and the exacerbation of fear that accompanies posttraumatic stress disorder. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A multi-faceted role of dual-state dopamine signaling in working memory, attentional control, and intelligence.

Genetic evidence strongly suggests that individual differences in intelligence will not be reducible to a single dominant cause. However, some of those variations/changes may be traced to tractable, cohesive mechanisms. One such mechanism may be the balance of dopamine D1 (D1R) and D2 (D2R) receptors, which regulate intrinsic currents and synaptic transmission in frontal cortical regions. Here, we review evidence from human, animal, and computational studies that suggest that this balance (in density, activity state, and/or availability) is critical to the implementation of executive functions such as attention and working memory, both of which are principal contributors to variations in intelligence. D1 receptors dominate neural responding during stable periods of short-term memory maintenance (requiring attentional focus), while D2 receptors play a more specific role during periods of instability such as changing environmental or memory states (requiring attentional disengagement). Here we bridge these observations with known properties of human intelligence. Starting from theories of intelligence that place executive functions (e.g., working memory and attentional control) at its center, we propose that dual-state dopamine signaling might be a causal contributor to at least some of the variation in intelligence across individuals and its change by experiences/training. Although it is unlikely that such a mechanism can account for more than a modest portion of the total variance in intelligence, our proposal is consistent with an array of available evidence and has a high degree of explanatory value. We suggest future directions and specific empirical tests that can further elucidate these relationships.

Déjà vu All Over Again: A Unitary Biological Mechanism for Intelligence Is (Probably) Untenable.

Nearly a century ago, Spearman proposed that "specific factors can be regarded as the 'nuts and bolts' of cognitive performance…, while the general factor is the mental energy available to power the specific engines". Geary (2018; 2019) takes Spearman's analogy of "mental energy" quite literally and doubles-down on the notion by proposing that a unitary energy source, the mitochondria, explains variations in both cognitive function and health-related outcomes. This idea is reminiscent of many earlier attempts to describe a low-level biological determinant of general intelligence. While Geary does an admirable job developing an innovative theory with specific and testable predictions, this new theory suffers many of the shortcomings of previous attempts at similar goals. We argue that Geary's theory is generally implausible, and does not map well onto known psychological and genetic properties of intelligence or its relationship to health and fitness. While Geary's theory serves as an elegant model of "what could be", it is less successful as a description of "what is".

The impact of environmental interventions among mouse siblings on the heritability and malleability of general cognitive ability.

General cognitive ability can be highly heritable in some species, but at the same time, is very malleable. This apparent paradox could potentially be explained by gene-environment interactions and correlations that remain hidden due to experimental limitations on human research and blind spots in animal research. Here, we shed light on this issue by combining the design of a sibling study with an environmental intervention administered to laboratory mice. The analysis included 58 litters of four full-sibling genetically heterogeneous CD-1 male mice, for a total of 232 mice. We separated the mice into two subsets of siblings: a control group (maintained in standard laboratory conditions) and an environmental-enrichment group (which had access to continuous physical exercise and daily exposure to novel environments). We found that general cognitive ability in mice has substantial heritability (24% for all mice) and is also malleable. The mice that experienced the enriched environment had a mean intelligence score that was 0.44 standard deviations higher than their siblings in the control group (equivalent to gains of 6.6 IQ points in humans). We also found that the estimate of heritability changed between groups (55% in the control group compared with non-significant 15% in the enrichment group), analogous to findings in humans across socio-economic status. Unexpectedly, no evidence of gene-environment interaction was detected, and so the change in heritability might be best explained by higher environmental variance in the enrichment group. Our findings, as well as the 'sibling intervention procedure' for mice, may be valuable to future research on the heritability, mechanisms and evolution of cognition.This article is part of the theme issue 'Causes and consequences of individual differences in cognitive abilities'.

Dopamine D1 receptor density in the mPFC responds to cognitive demands and receptor turnover contributes to general cognitive ability in mice.

In both humans and mice, performance on tests of intelligence or general cognitive ability (GCA) is related to dopamine D1 receptor-mediated activity in the prelimbic cortex, and levels of DRD1 mRNA predict the GCA of mice. Here we assessed the turnover rate of D1 receptors as well as the expression level of the D1 chaperone protein (DRiP78) in the medial PPC (mPFC) of mice to determine whether rate of receptor turnover was associated with variations in the GCA of genetically heterogeneous mice. Following assessment of GCA (aggregate performance on four diverse learning tests) mice were administered an irreversible dopamine receptor antagonist (EEDQ), after which the density of new D1 receptors were quantified. GCA was positively correlated with both the rate of D1 receptor recovery and levels of DRiP78. Additionally, the density of D1 receptors was observed to increase within 60 min (or less) in response to intense demands on working memory, suggesting that a pool of immature receptors was available to accommodate high cognitive loads. These results provide evidence that innate general cognitive abilities are related to D1 receptor turnover rates in the prefrontal cortex, and that an intracellular pool of immature D1 receptors are available to accommodate cognitive demands.

The paradox of intelligence: Heritability and malleability coexist in hidden gene-environment interplay.

Intelligence can have an extremely high heritability, but also be malleable; a paradox that has been the source of continuous controversy. Here we attempt to clarify the issue, and advance a frequently overlooked solution to the paradox: Intelligence is a trait with unusual properties that create a large reservoir of hidden gene-environment (GE) networks, allowing for the contribution of high genetic and environmental influences on individual differences in IQ. GE interplay is difficult to specify with current methods, and is underestimated in standard metrics of heritability (thus inflating estimates of "genetic" effects). We describe empirical evidence for GE interplay in intelligence, with malleability existing on top of heritability. The evidence covers cognitive gains consequent to adoption/immigration, changes in IQ's heritability across life span and socioeconomic status, gains in IQ over time consequent to societal development (the Flynn effect), the slowdown of age-related cognitive decline, and the gains in intelligence from early education. The GE solution has novel implications for enduring problems, including our inability to identify intelligence-related genes (also known as IQ's "missing heritability"), and the loss of initial benefits from early intervention programs (such as "Head Start"). The GE solution can be a powerful guide to future research, and may also aid policies to overcome barriers to the development of intelligence, particularly in impoverished and underprivileged populations. (PsycINFO Database Record

A broader phenotype of persistence emerges from individual differences in response to extinction.

The typical practice of averaging group performance during extinction gives the impression that responding declines gradually and homogeneously. However, previous studies of extinction in human infants have shown that some individuals persist in responding, whereas others abruptly cease responding. As predicted by theories of control, the infants who quickly resign typically display signs of sadness and despair when the expected reward is omitted. Using genetically diverse mice, here we observed a similar pattern of individual differences and the associated phenotypes. After learning to approach a food reward, upon extinction, some animals rapidly abandoned approach to the goal box, whereas other animals persisted in entering and searching the goal box. Interestingly, the persistent mice were slower to "give up" when confined to an inescapable pool of water (a test asserted to be indicative of susceptibility to depression) and exhibited a more extensive pattern of search for omitted rewards. Thus, extinction reveals a continuum in persistence, in which low values might reflect a susceptibility to the negative effects of stress and might predispose individuals to depression.

Individual differences: Case studies of rodent and primate intelligence.

Early in the 20th century, individual differences were a central focus of psychologists. By the end of that century, studies of individual differences had become far less common, and attention to these differences played little role in the development of contemporary theory. To illustrate the important role of individual differences, here we consider variations in intelligence as a compelling example. General intelligence (g) has now been demonstrated in at least 2 distinct genera: primates (including humans, chimpanzees, bonobos, and tamarins) and rodents (mice and rats). The expression of general intelligence varies widely across individuals within a species; these variations have tremendous functional consequence, and are attributable to interactions of genes and environment. Here we provide evidence for these assertions, describe the processes that contribute to variations in general intelligence, as well as the methods that underlie the analysis of individual differences. We conclude by describing why consideration of individual differences is critical to our understanding of learning, cognition, and behavior, and illustrate how attention to individual differences can contribute to more effective administration of therapeutic strategies for psychological disorders. (PsycINFO Database Record

The tendency for social submission predicts superior cognitive performance in previously isolated male mice.

The imposition of subordination may negatively impact cognitive performance in common social settings (e.g., the classroom), and likewise, laboratory studies of animals indicate that the stress associated with social defeat can impair cognitive performance. It is less clear whether an animal's predisposition for social subordination (i.e., a tendency that is expressed prior to experience with social defeat) is related to its cognitive abilities (e.g., "general" intelligence). Using genetically diverse CD-1 male mice, here we determined that in the absence of adult experience with social hierarchies or social defeat, the predisposition for social subordination was associated with superior general cognitive ability (aggregate performance across a battery of five learning tasks). The tendency for social subordination was not dependent on the mice' body weight, but both general cognitive ability and the tendency for social subordination were directly related to high stress reactivity (i.e., free corticosterone elevations induced by mild stress). This pattern of results suggests that submissive behavior and sensitivity to stress may be associated with superior cognitive potential, and this can reflect a native predisposition that precedes exposure to social pressures. More broadly, these results raise the possibility that socially subordinate animals evolved compensatory strategies to facilitate their survival, and that absent the imposition of subordination, normally submissive individuals may be better prepared for cognitive/academic achievement.

Evolution, brain size, and variations in intelligence.

Across taxonomic subfamilies, variations in intelligence (G) are sometimes related to brain size. However, within species, brain size plays a smaller role in explaining variations in general intelligence (g), and the cause-and-effect relationship may be opposite to what appears intuitive. Instead, individual differences in intelligence may reflect variations in domain-general processes that are only superficially related to brain size.

Heterozygous L1-deficient mice express an autism-like phenotype.

The L1CAM (L1) gene encodes a cell adhesion molecule that contributes to several important processes in the developing and adult nervous system, including neuronal migration, survival, and plasticity. In humans and mice, mutations in the X chromosome-linked gene L1 cause severe neurological defects in males. L1 heterozygous female mice with one functional copy of the L1 gene show complex morphological features that are different from L1 fully-deficient and wild-type littermate mice. However, almost no information is available on the behavior of L1 heterozygous mice and humans. Here, we investigated the behavior of heterozygous female mice in which the L1 gene is constitutively inactivated. These mice were compared to wild-type littermate females. Animals were assessed in five categories of behavioral tests: five tests for anxiety/stress/exploration, four tests for motor abilities, two tests for spatial learning, three tests for social behavior, and three tests for repetitive behavior. We found that L1 heterozygous mice express an autism-like phenotype, comprised of reduced social behaviors and excessive self-grooming (a repetitive behavior also typical in animal models of autism). L1 heterozygous mice also exhibited an increase in sensitivity to light, assessed by a reluctance to enter the lighted areas of novel environments. However, levels of anxiety, stress, motor abilities, and spatial learning in L1 heterozygous mice were similar to those of wild-type mice. These observations raise the possibility that using molecules known to trigger L1 functions may become valuable in the treatment of autism in humans.

The external-internal loop of interference: two types of attention and their influence on the learning abilities of mice.

Attention is a component of the working memory system, and is responsible for protecting task-relevant information from interference. Cognitive performance (particularly outside of the laboratory) is often plagued by interference, and the source of this interference, either external or internal, might influence the expression of individual differences in attentional ability. By definition, external attention (also described as "selective attention") protects working memory against sensorial distractors of all kinds, while internal attention (also called "inhibition") protects working memory against emotional impulses, irrelevant information from memory, and automatically-generated responses. At present, it is unclear if these two types of attention are expressed independently in non-human animals, and how they might differentially impact performance on other cognitive processes, such as learning. By using a diverse battery of four attention tests (with varying levels of internal and external sources of interference), here we aimed both to explore this issue, and to obtain a robust and general (less task-specific) measure of attention in mice. Exploratory factor analyses revealed two factors (external and internal attention) that in total, accounted for 73% of the variance in attentional performance. Confirmatory factor analyses found an excellent fit with the data of the model of attention that assumed an external and internal distinction (with a resulting correlation of 0.43). In contrast, a model of attention that assumed one source of variance (i.e., "general attention") exhibited a poor fit with the data. Regarding the relationship between attention and learning, higher resistance against external sources of interference promoted better new learning, but tended to impair performance when cognitive flexibility was required, such as during the reversal of a previously instantiated response. The present results suggest that there can be (at least) two types of attention that contribute to the common variance in attentional performance in mice, and that external and internal attentions might have opposing influences on the rate at which animals learn.

Dopamine D1 sensitivity in the prefrontal cortex predicts general cognitive abilities and is modulated by working memory training.

A common source of variance (i.e., "general intelligence") underlies an individual's performance across diverse tests of cognitive ability, and evidence indicates that the processing efficacy of working memory may serve as one such source of common variance. One component of working memory, selective attention, has been reported to co-vary with general intelligence, and dopamine D1 signaling in prefrontal cortex can modulate attentional abilities. Based on their aggregate performance across five diverse tests of learning, here we characterized the general cognitive ability (GCA) of CD-1 outbred mice. In response to a D1 agonist (SKF82958, 1 mg/kg), we then assessed the relationship between GCA and activation of D1 receptor (D1R)-containing neurons in the prelimbic region of the medial prefrontal cortex, the agranular insular cortex, and the dorsomedial striatum. Increased activation of D1R-containing neurons in the prelimbic cortex (but not the agranular insular cortex or dorsomedial striatum) was observed in animals of high GCA relative to those of low GCA (quantified by c-Fos activation in response to the D1 agonist). However, a Western blot analysis revealed no differences in the density of D1Rs in the prelimbic cortex between animals of high and low GCA. Last, it was observed that working memory training promoted an increase in animals' GCA and enhanced D1R-mediated neuronal activation in the prelimbic cortex. These results suggest that the sensitivity (but not density) of D1Rs in the prelimbic cortex may both regulate GCA and be a target for working memory training.

Voluntary aerobic exercise increases the cognitive enhancing effects of working memory training.

Increases in performance on tests of attention and learning are often observed shortly after a period of aerobic exercise, and evidence suggests that humans who engage in regular exercise are partially protected from age-related cognitive decline. However, the cognitive benefits of exercise are typically short-lived, limiting the practical application of these observations. Here, we explored whether physical exercise might induce lasting changes in general cognitive ability if that exercise was combined with working memory training, which is purported to broadly impact cognitive performance. Mice received either exercise treatment (6 weeks of voluntary running wheel access), working memory training (in a dual radial-arm maze), both treatments, or various control treatments. After this period of exercise, working memory training was initiated (alternating with days of exercise), and continued for several weeks. Upon completion of these treatments, animals were assessed (2-4 weeks later) for performance on four diverse learning tasks, and the aggregate performance of individual animals across all four learning tasks was estimated. Working memory training alone promoted small increases in general cognitive performance, although any beneficial effects of exercise alone had dissipated by the time of learning assessments. However, the two treatments in combination more than doubled the improvement in general cognitive performance supported by working memory training alone. Unlike the transient effects that acute aerobic exercise can have on isolated learning tasks, these results indicate that an acute period of exercise combined with working memory training can have synergistic and lasting impact on general cognitive performance.

The causes of variation in learning and behavior: why individual differences matter.

IN A SEMINAL PAPER WRITTEN FIVE DECADES AGO, CRONBACH DISCUSSED THE TWO HIGHLY DISTINCT APPROACHES TO SCIENTIFIC PSYCHOLOGY: experimental and correlational. Today, although these two approaches are fruitfully implemented and embraced across some fields of psychology, this synergy is largely absent from other areas, such as in the study of learning and behavior. Both Tolman and Hull, in a rare case of agreement, stated that the correlational approach held little promise for the understanding of behavior. Interestingly, this dismissal of the study of individual differences was absent in the biologically oriented branches of behavior analysis, namely, behavioral genetics and ethology. Here we propose that the distinction between "causation" and "causes of variation" (with its origins in the field of genetics) reveals the potential value of the correlational approach in understanding the full complexity of learning and behavior. Although the experimental approach can illuminate the causal variables that modulate learning, the analysis of individual differences can elucidate how much and in which way variables interact to support variations in learning in complex natural environments. For example, understanding that a past experience with a stimulus influences its "associability" provides little insight into how individual predispositions interact to modulate this influence on associability. In this "new" light, we discuss examples from studies of individual differences in animals' performance in the Morris water maze and from our own work on individual differences in general intelligence in mice. These studies illustrate that, opposed to what Underwood famously suggested, studies of individual differences can do much more to psychology than merely providing preliminary indications of cause-effect relationships.

The neuroscience of learning: beyond the Hebbian synapse.

From the traditional perspective of associative learning theory, the hypothesis linking modifications of synaptic transmission to learning and memory is plausible. It is less so from an information-processing perspective, in which learning is mediated by computations that make implicit commitments to physical and mathematical principles governing the domains where domain-specific cognitive mechanisms operate. We compare the properties of associative learning and memory to the properties of long-term potentiation, concluding that the properties of the latter do not explain the fundamental properties of the former. We briefly review the neuroscience of reinforcement learning, emphasizing the representational implications of the neuroscientific findings. We then review more extensively findings that confirm the existence of complex computations in three information-processing domains: probabilistic inference, the representation of uncertainty, and the representation of space. We argue for a change in the conceptual framework within which neuroscientists approach the study of learning mechanisms in the brain.

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.