Unpredictable Mixed-Valence Outcomes Induce a Chronic and Reversible Generalized Anxiety-like Phenotype in Male Mice.

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).

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-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.

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).

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, of those variations/changes may be traced to tractable, cohesive mechanisms. One such mechanism may be the balance of dopamine D1 (DR) and D2 (DR) receptors, which regulate intrinsic currents and synaptic transmission in frontal cortical regions.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

Learning, attentional, and perseverative deficits are characteristic of cognitive aging. In this study, genetically diverse CD-1 mice underwent longitudinal training in a task asserted to tax working memory capacity and its dependence on selective attention. Beginning at 3 mo of age, animals were trained for 12 d to perform in a dual radial-arm maze task that required the mice to remember and operate on two sets of overlapping guidance (spatial) cues.

A dopaminergic gene cluster in the prefrontal cortex predicts performance indicative of general intelligence in genetically heterogeneous mice.

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.

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

In both humans and mice, the efficacy of working memory capacity and its related process, selective attention, are each strongly predictive of individuals' aggregate performance in cognitive test batteries [1-9]. Because working memory is taxed during most cognitive tasks, the efficacy of working memory may have a causal influence on individuals' performance on tests of "intelligence" [10, 11]. Despite the attention this has received, supporting evidence has been largely correlational in nature (but see [12]).

Deletion of PEA-15 in mice is associated with specific impairments of spatial learning abilities.

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.