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Background: Clinical anxiety is a generalized state characterized by feelings of apprehensive expectation and is distinct from momentary responses such as fear or stress. In contrast, most laboratory tests of anxiety focus on acute responses to momentary stressors., Methods: Apprehensive expectation was induced by subjecting mice (for 18 days) to manipulations in which a running response (experiment 1) or a conditioned stimulus (experiment 2) were unpredictably paired with reward (food) or punishment (footshock). Before this treatment, the mice were tested in an open field and light/dark box to assess momentary responses that are asserted to reflect state anxiety. After treatment, the mice were assessed for state anxiety in an elevated plus maze, social interaction test, startle response test, intrusive object burying test, and stress-induced corticosterone elevations. In experiment 3, we treated mice similarly to experiment 1, but after mixed-valence training, some mice received either no additional training, additional mixed-valence training, or were shifted to consistent (predictable) reinforcement with food., Results: We consistently observed an increase in anxiety-like behaviors after the experience with mixed-valence unpredictable reinforcement. This generalized anxiety persisted for at least 4 weeks after the mixed-valence training and could be reversed if the mixed-valence training was followed by predictable reinforcement with food., Conclusions: Results indicate that experience with unpredictable reward/punishment can induce a chronic state analogous to generalized anxiety that can be mitigated by exposure to stable, predictable conditions. This learned apprehension protocol provides a conceptually valid model for the study of the etiology and treatment of anxiety in laboratory animals., (© 2024 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.)

Background: Increased blood-brain barrier (BBB) permeability and amyloid-β (Aβ) peptides (especially Aβ1-42) (Aβ42) 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 Aβ42 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 Aβ42 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 Aβ42 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 Aβ42 and immunoglobulin G (IgG) into the brain parenchyma, selective neuronal binding of IgG and neuronal accumulation of Aβ42 in animals injected with both PT and Aβ42 compared to controls., Conclusion: Results highlight the potential synergistic role of BBB compromise and the influx of bloodborne Aβ42 into the brain in both the initiation and progression of neuropathologic and cognitive changes associated with AD.

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).

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 (D 1 R) and D2 (D 2 R) 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Matzel and Sauce.)

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"., Competing Interests: The authors declare no conflict of interest.

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.

Behavioural and cognitive processes play important roles in mediating an individual's interactions with its environment. Yet, while there is a vast literature on repeatable individual differences in behaviour, relatively little is known about the repeatability of cognitive performance. To further our understanding of the evolution of cognition, we gathered 44 studies on individual performance of 25 species across six animal classes and used meta-analysis to assess whether cognitive performance is repeatable. We compared repeatability ( R ) in performance (1) on the same task presented at different times (temporal repeatability), and (2) on different tasks that measured the same putative cognitive ability (contextual repeatability). We also addressed whether R estimates were influenced by seven extrinsic factors (moderators): type of cognitive performance measurement, type of cognitive task, delay between tests, origin of the subjects, experimental context, taxonomic class and publication status. We found support for both temporal and contextual repeatability of cognitive performance, with mean R estimates ranging between 0.15 and 0.28. Repeatability estimates were mostly influenced by the type of cognitive performance measures and publication status. Our findings highlight the widespread occurrence of consistent inter-individual variation in cognition across a range of taxa which, like behaviour, may be associated with fitness outcomes.This article is part of the theme issue 'Causes and consequences of individual differences in cognitive abilities'., (© 2018 The Author(s).)

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'., (© 2018 The Author(s).)

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.

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, ((c) 2018 APA, all rights reserved).)

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, ((c) 2017 APA, all rights reserved).)

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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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.

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., (Copyright © 2015. Published by Elsevier B.V.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2013 Elsevier B.V. All rights reserved.)

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.

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.

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.

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)., (Copyright © 2012 Elsevier B.V. All rights reserved.)

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., ((c) 2012 APA, all rights reserved.)

"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., (Copyright © 2011 Elsevier B.V. All rights reserved.)

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.

Background: Genetically heterogeneous mice express a trait that is qualitatively and psychometrically analogous to general intelligence in humans, and as in humans, this trait co-varies with the processing efficacy of working memory (including its dependence on selective attention). Dopamine signaling in the prefrontal cortex (PFC) has been established to play a critical role in animals' performance in both working memory and selective attention tasks. Owing to this role of the PFC in the regulation of working memory, here we compared PFC gene expression profiles of 60 genetically diverse CD-1 mice that exhibited a wide range of general learning abilities (i.e., aggregate performance across five diverse learning tasks)., Methodology/principal Findings: Animals' general cognitive abilities were first determined based on their aggregate performance across a battery of five diverse learning tasks. With a procedure designed to minimize false positive identifications, analysis of gene expression microarrays (comprised of ≈25,000 genes) identified a small number (<20) of genes that were differentially expressed across animals that exhibited fast and slow aggregate learning abilities. Of these genes, one functional cluster was identified, and this cluster (Darpp-32, Drd1a, and Rgs9) is an established modulator of dopamine signaling. Subsequent quantitative PCR found that expression of these dopaminergic genes plus one vascular gene (Nudt6) were significantly correlated with individual animal's general cognitive performance., Conclusions/significance: These results indicate that D1-mediated dopamine signaling in the PFC, possibly through its modulation of working memory, is predictive of general cognitive abilities. Furthermore, these results provide the first direct evidence of specific molecular pathways that might potentially regulate general intelligence.

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., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Accumulating evidence indicates that the storage and processing capabilities of the human working memory system co-vary with individuals' performance on a wide range of cognitive tasks. The ubiquitous nature of this relationship suggests that variations in these processes may underlie individual differences in intelligence. Here we briefly review relevant data which supports this view. Furthermore, we emphasize an emerging literature describing a trait in genetically heterogeneous mice that is quantitatively and qualitatively analogous to general intelligence (g) in humans. As in humans, this animal analog of g co-varies with individual differences in both storage and processing components of the working memory system. Absent some of the complications associated with work with human subjects (e.g., phonological processing), this work with laboratory animals has provided an opportunity to assess otherwise intractable hypotheses. For instance, it has been possible in animals to manipulate individual aspects of the working memory system (e.g., selective attention), and to observe causal relationships between these variables and the expression of general cognitive abilities. This work with laboratory animals has coincided with human imaging studies (briefly reviewed here) which suggest that common brain structures (e.g., prefrontal cortex) mediate the efficacy of selective attention and the performance of individuals on intelligence test batteries. In total, this evidence suggests an evolutionary conservation of the processes that co-vary with and/or regulate "intelligence" and provides a framework for promoting these abilities in both young and old animals.

Background: PEA-15 is a phosphoprotein that binds and regulates ERK MAP kinase and RSK2 and is highly expressed throughout the brain. PEA-15 alters c-Fos and CREB-mediated transcription as a result of these interactions. To determine if PEA-15 contributes to the function of the nervous system we tested mice lacking PEA-15 in a series of experiments designed to measure learning, sensory/motor function, and stress reactivity., Results: We report that PEA-15 null mice exhibited impaired learning in three distinct spatial tasks, while they exhibited normal fear conditioning, passive avoidance, egocentric navigation, and odor discrimination. PEA-15 null mice also had deficient forepaw strength and in limited instances, heightened stress reactivity and/or anxiety. However, these non-cognitive variables did not appear to account for the observed spatial learning impairments. The null mice maintained normal weight, pain sensitivity, and coordination when compared to wild type controls., Conclusion: We found that PEA-15 null mice have spatial learning disabilities that are similar to those of mice where ERK or RSK2 function is impaired. We suggest PEA-15 may be an essential regulator of ERK-dependent spatial learning.

Learning impairments and the instability of memory are defining characteristics of cognitive aging. However, it is unclear if deficits in the expression of new memories reflect an accelerated decay of the target memory or a consequence of inefficient learning. Here, aged mice (19-21-mo old) exhibited acquisition deficits (relative to 3-5-mo old mice) on three learning tasks, although these deficits were overcome with additional training. When tested after a 30-d retention interval, the performance of aged animals was impaired if initial learning had been incomplete. However, if trained to equivalent levels of competence, aged animals exhibited no retention deficits relative to their young counterparts. These results suggest that age-related "memory" impairments can be overcome through a more effective learning regimen.

In addition to its role in axon growth and neuronal migration, the close homolog of L1 (CHL1), a member of the L1 family of cell adhesion molecules, is involved in synaptic plasticity. To date, little has been done to disassociate the role of CHL1 during adulthood from its role during development. To address this issue, mice conditionally deficient in CHL1 (lacking CHL1 only after the third postnatal week) were tested relative to littermate controls as adults in five learning tasks and several tests of working memory (including duration and selective attention). CHL1-deficient mice showed no impairments in the learning tasks compared with wild-type controls. CHL1 deletion had no effect on selective attention despite its widespread impairment of working memory duration. These results suggest a role for CHL1 in the adult-brain in the short-term maintenance of information.

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.

"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.

Cell adhesion molecules, such as neuronal cell adhesion molecule (Nr-CAM), mediate cell-cell interactions in both the developing and mature nervous system. Neuronal cell adhesion molecule is believed to play a critical role in cell adhesion and migration, axonal growth, guidance, target recognition and synapse formation. Here, wild-type, heterozygous and Nr-CAM null mice were assessed on a battery of five learning tasks (Lashley maze, odor discrimination, passive avoidance, spatial water maze and fear conditioning) previously developed to characterize the general learning abilities of laboratory mice. Additionally, all animals were tested on 10 measures of sensory/motor function, emotionality and stress reactivity. We report that the Nr-CAM deletion had no impact on four of the learning tasks (fear conditioning, spatial water maze, Lashley maze and odor discrimination). However, Nr-CAM null mice exhibited impaired performance on a task that required animals to suppress movement (passive avoidance). Although Nr-CAM mutants expressed normal levels of general activity and body weights, they did exhibit an increased propensity to enter stressful areas of novel environments (the center of an open field and the lighted side of a dark/light box), exhibited higher sensitivity to pain (hot plate) and were more sensitive to the aversive effects of foot shock (shock-induced freezing). This behavioral phenotype suggests that Nr-CAM does not play a central role in the regulation of general cognitive abilities but may have a critical function in regulating impulsivity and possibly an animal's susceptibility to drug abuse and addiction.

It has been established that both domain-specific (e.g. spatial) as well as domain-general (general intelligence) factors influence human cognition. However, the separation of these processes has rarely been attempted in studies using laboratory animals. Previously, we have found that the performances of outbred mice across a wide range of learning tasks correlate in such a way that a single factor can explain 30- 44% of the variance between animals. This general learning factor is in some ways qualitatively and quantitatively analogous to general intelligence in humans. The complete structure of cognition in mice, however, has not been explored due to the limited sample sizes of our previous analyses. Here we report a combined analysis from 241 CD-1 mice tested in five primary learning tasks, and a subset of mice tested in two additional learning tasks. At least two (possibly three) of the seven learning tasks placed explicit demands on spatial and/or hippocampus-dependent processing abilities. Consistent with previous findings, we report a robust general factor influencing learning in mice that accounted for 38% of the variance across tasks. In addition, a domain-specific factor was found to account for performance on that subset of tasks that shared a dependence on hippocampal and/or spatial processing. These results provide further evidence for a general learning/cognitive factor in genetically heterogeneous mice. Furthermore (and similar to human cognitive performance), these results suggest a hierarchical structure to cognitive processes in this genetically heterogeneous species.

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., ((PsycINFO Database Record (c) 2007 APA, all rights reserved).)

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.

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.

For at least 40 years, there has been a recurring argument concerning the nature of experimental amnesia, with one side arguing that amnesic treatments interfere with the formation of enduring memories and the other side arguing that these treatments interfere with the expression of memories that were effectively encoded. The argument appears to stem from a combination of (1) unclear definitions and (2) real differences in the theoretical vantages that underlie the interpretation of relevant data. Here we speak to how the field might avoid arguments that are definitional in nature and how various hypotheses fare in light of published data. Existing but often overlooked data favor very rapid (milliseconds) synaptic consolidation, with experimental amnesia reflecting, at least in part, deficits in retrieval rather than in the initial storage of information.

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.

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.

Using an identified synapse in the nervous system of the mollusc Hermissenda, the influence of somatic calcium accumulation on regulated synaptic transmission was investigated. Hair cells in Hermissenda project onto postsynaptic B photoreceptors where they mediate inhibitory postsynaptic potentials (IPSPs). Intracellular recordings in combination with bath perfusion of calcium channel modulators indicated that L-type channels were present on the hair cell soma but not on the terminal branches. In contrast, P/Q and an unidentified channel type (similar to N-type channels) contributed additively to transmitter release from the hair cell. Antibodies raised against rat brain channel proteins detected L- (alpha1(C)) and P/Q-type (alpha1(A)) channels in lysates of the Hermissenda nervous system, indicating a homology between the Hermissenda channels and their mammalian counterparts. To mimic somatic calcium channel 'leak', hair cells were exposed to the L-type channel agonist +/-BAY K 8644. Exposure to +/-BAY K 8644 resulted in a rapid (<2 min) increase (40%) in the amplitude of the spike after-hyperpolarization in the hair cell, and was associated with a reduction in evoked firing frequency. This reduction in rate of discharge induced a proportional decrease in the amplitude of compound IPSPs recorded in the postsynaptic B photoreceptors. From Fura-2 emissions we determined that +/-BAY K 8644 induced a rapid (<2 min) and persistent increase (70%) in somatic calcium concentration, followed by a slower elevation of calcium in the medial axon (>30 min) and subsequently in the terminal branches (>40 min), suggesting that excessive somatic calcium had diffused or induced a propagation along the axon. Corresponding with a 56% rise in terminal calcium (50-60 min post agonist), postsynaptic potentials declined to 70% of baseline amplitude. These results suggest that prolonged somatic L-channel 'leak' can interfere with regulated transmitter release, both by reducing the rate of presynaptic discharge and by promoting terminal calcium accumulation that may oppose transmitter release. Such effect may have implications for the age-related learning deficits that often accompany somatic calcium 'leak'.

In laboratory studies, the assessment of memory is typically associated with overt behavioral responses. Thus, it has been difficult to determine whether the enhancement of hippocampal sensory-evoked potentials that often accompany memory formation are the neurophysiological manifestation of a memory "trace" or are a secondary product of the behavioral expression of the memory. We addressed this issue by examining changes in evoked hippocampal field potentials during sensory preconditioning, a form of behaviorally silent relational learning that requires an intact hippocampus for execution. Rats were exposed to presentations of a white noise (S1) that terminated with a tone (S2). These pairings of ostensibly "neutral" stimuli supported no change in the behavior elicited by the noise. However, if the tone was subsequently paired with mild footshock (US), suppression of ongoing licking behavior (indicative of fear) was elicited by the noise, indicating that the animal had associated the noise with tone (S1-S2), and had represented the noise-tone-shock (S1-S2-US) relationship. Pre-training neurotoxic lesions of the hippocampus had no effect on conditioned suppression to tone after tone-shock (S2-US) pairings, but disrupted the expression of continued suppression to noise (S1) after tone-shock pairings. In a second experiment, sensory-evoked field potentials in the dorsal hippocampus were recorded with extracellular electrodes. No changes in the hippocampal response evoked by white noise were observed after pairings of noise and tone, i.e., no evidence for a memory trace could be detected. In contrast, after tone was paired with footshock, two short-latency negative potentials within the noise-evoked field response increased in amplitude, a response often presumed to reflect a neurophysiological correlate of memory storage. In total, these results suggest that although the hippocampus critically contributes to the processing of a behaviorally silent associative memory, there may be no role for changes in the amplitude of hippocampal sensory-evoked field potentials in storing representations of the relationships between sensory experiences.

It is well established that the hippocampal formation is critically involved in the acquisition of trace memories, a paradigm in which the conditioned (CS) and unconditioned stimuli (US) are separated by a temporal gap (Solomon et al., 1986). The structure is reportedly not critical for the acquisition of delay memories, where the CS and the US overlap in time (Berger & Orr, 1983; Schmaltz & Theios, 1972). Based on these results, it is often stated that the hippocampus is involved in "filling the gap" or otherwise associating the two stimuli in time. However, in addition to the presence of a temporal gap, there are other differences between trace and delay conditioning. The most apparent difference is that animals require many more trials to learn the trace task, and thus it is inherently more difficult than the delay task. Here, we tested whether the hippocampus was critically involved in delay conditioning, if it was rendered more difficult such that the rate of acquisition was shifted to be analogous to trace conditioning. Groups of rats received excitotoxic lesions to the hippocampus, sham lesions or were left intact. Using the same interstimulus intervals (ISI), control animals required more trials to acquire the trace than the delay task. As predicted, animals with hippocampal lesions were impaired during trace conditioning but not delay conditioning. However, when the delay task was rendered more difficult by extending the ISI (a long delay task), animals with hippocampal lesions were impaired. In addition, once the lesioned animal learned the association between the CS and the US during delay conditioning, it could learn and perform the trace CR. Thus, the role of the hippocampus in classical conditioning is not limited to learning about discontiguous events in time and space; rather the structure can become engaged simply as a function of task difficulty., (Copyright 2001 Elsevier Science.)

Type B photoreceptors in Hermissenda exhibit increased excitability (e.g., elevated membrane resistance and lowered spike thresholds) consequent to the temporal coincidence of a light-induced intracellular Ca(2+) increase and the release of GABA from presynaptic vestibular hair cells. Convergence of these pre- and postsynaptically stimulated biochemical cascades culminates in the activation of protein kinase C (PKC). Paradoxically, exposure of the B cell to light alone generates an inositol triphosphate-regulated rise in diacylglycerol and intracellular Ca(2+), co-factors sufficient to stimulate conventional PKC isoforms, raising questions as to the unique role of synaptic stimulation in the activation of PKC. GABA receptors on the B cell are coupled to G proteins that stimulate phospholipase A(2) (PLA(2)), which is thought to regulate the liberation of arachidonic acid (AA), an "atypical" activator of PKC. Here, we directly assess whether GABA binding or PLA(2) stimulation liberates AA in these cells and whether free AA potentiates the stimulation of PKC. Free fatty-acid was estimated in isolated photoreceptors with the fluorescent indicator acrylodan-derivatized intestinal fatty acid-binding protein (ADIFAB). In response to 5 microM GABA, a fast and persistent increase in ADIFAB emission was observed, and this increase was blocked by the PLA(2) inhibitor arachidonyltrifluoromethyl ketone (50 microM). Furthermore, direct stimulation of PLA(2) by melittin (10 microM) increased ADIFAB emission in a manner that was kinetically analogous to GABA. In response to simultaneous exposure to the stable AA analogue oleic acid (OA, 20 microM) and light (to elevate intracellular Ca(2+)), B photoreceptors exhibited a sustained (>45 min) increase in excitability (membrane resistance and evoked spike rate). The excitability increase was blocked by the PKC inhibitor chelerythrine (20 microM) and was not induced by exposure of the cells to light alone. The increase in excitability in the B cell that followed exposure to light and OA persisted for > or =90 min when the pairing was conducted in the presence of the protein synthesis inhibitor anisomycin (1 microm), suggesting that the synergistic influence of these signaling agents on neuronal excitability did not require new protein synthesis. These results indicate that GABA binding to G-protein-coupled receptors on Hermissenda B cells stimulates a PLA(2) signaling cascade that liberates AA, and that this free AA interacts with postsynaptic Ca(2+) to synergistically stimulate PKC and enhance neuronal excitability. In this manner, the interaction of postsynaptic metabotropic receptors and intracellular Ca(2+) may serve as the catalyst for some forms of associative neuronal/synaptic plasticity.

The observation that retrieval returns a stable memory into a labile state cannot be readily explained by any simple version of consolidation theory. This finding has been interpreted as evidence for the need to reconsolidate a memory after reactivating it. However, as we discuss in this commentary, other behavioural observations indicate that even this modification to consolidation theory may be insufficient to describe the dynamic properties of memory.

Though once of central importance to psychologists and neurophysiologists alike, the elucidation of neural substrates for individual differences in learning no longer attracts a broad research effort and occupies a place of largely historical interest to the contemporary disciplines. The decline in interest in this subject ensued in part from the perception, arrived at decades ago, that individual differences in learning were not quantified as easily as had once been presumed. Furthermore, the dominant hypotheses in the field defied testing within the constraints imposed by the complex and largely inaccessible vertebrate nervous system. Using a 'model systems' approach where the individual cells and synaptic interactions that comprise a neural network can be identified, we have returned to this question and have established a framework by which we can begin to discern the basis for much of the variability between individuals in their capacity to learn. In the marine mollusc Hermissenda, we have found that a common influence on transmitter exocytosis is expressed homogeneously throughout the nervous system regardless of transmitter system or receptor class. Though uniformly expressed within an individual, this influence on synaptic efficacy is differentially expressed between animals. Importantly, the basal efficiency of exocytosis expressed in an individual nervous system is strongly correlated with the degree to which activity-dependent forms of neuronal/synaptic facilitation can be induced in that nervous system, and predicts the capacity for the intact animal to learn a Pavlovian association. Furthermore, we have established that a decline in basal synaptic efficacy in aged animals, arising from chronic presynaptic Ca(2+) 'leak', may contribute to age-related learning impairments. Because certain fundamental components of the exocytotic cascade are conserved widely across cell types, transmitter systems and species, the principles that we describe may have broad implications for understanding normal variability in learning, but also, in the development of specific strategies to compensate for mild learning deficits and age-related cognitive decline.

The hypothesis that an individual's capacity for learning might be predicted or influenced by basal levels of synaptic efficacy has eluded empirical tests, owing in part to the inability to compare between animals single identified synaptic responses in the mammalian brain. To overcome this limitation, we have focused our analysis on the invertebrate Hermissenda, whose nervous system is composed of identifiable cells and synaptic interactions. Hermissenda were exposed to paired presentations of light and rotation such that the light came to elicit a learned defensive motor response. An animal's rate of learning was strongly correlated with the amplitude of the synaptic potential evoked in that animal's visual (light sensitive) receptors in response to stimulation of presynaptic vestibular (rotation sensitive) hair cells. In naive animals, strong correlations between the amplitude of both inhibitory and excitatory synaptic potentials were observed between synapses distributed throughout an animal's nervous system, and this conservation of synaptic efficacy was largely attributable to a common influence on transmitter release. These observations suggest that basal synaptic efficacy may be uniformly regulated throughout a nervous system, and provide direct evidence that the basal efficacy of synaptic transmission predicts, and possibly contributes to, individual differences between animals in their capacity to learn.