ABSTRACTStudies have shown that substance use liability is associated with novelty seeking, anxiety‐like behavior, and pain sensitivity. We examined whether common genetic variation in outbred Sprague–Dawley rats explained variation in behavioral measures from three assays with established links to substance use: locomotor response to a novel environment, elevated plus maze, and tail flick. We estimated single‐nucleotide polymorphism heritability and performed genome‐wide association analyses using permutation‐derived significance thresholds (N = 534–654 rats across traits). Heritability estimates ranged from 0.14 to 0.38 across 11 traits. Three independent loci were identified: chromosome 1 for elevated plus maze open‐arm behavior (α = 0.05), chromosome 14 for elevated plus maze immobility (α = 0.10), and chromosome 17 for tail flick latency (α = 0.05). Candidate genes included Slc18a2, Gfra1, and Pdzd8 (chromosome 1); Rel and Bcl11a (chromosome 14); and Eci2 and Eci3 (chromosome 17). We compared these loci with our genome‐wide association study of a F2 intercross of selectively bred high‐ and low‐responder rats, originally derived from Sprague–Dawleys, that model individual differences in externalizing and internalizing behavior. The current loci are distinct from the ones identified in the bred lines. This difference likely reflects selection history in the high‐ and low‐responder F2s, which focused on facets of exploratory locomotion, while loci for anxiety and pain sensitivity traits were identified in the outbreds. This highlights the benefit of using both outbred and selectively bred rats to probe causal variants contributing to individual differences in substance use liability. The current outbred findings implicate monoaminergic signaling, transcriptional control, and lipid metabolism as testable mechanisms for addiction‐relevant behaviors.

Reeler mice have a mutation in the reelin gene. As a result, Reeler mice lack cortical layers, yet their brains are still largely functional. However, Reeler mice display strong motor phenotypes, including ataxic gait and tics, and we posit that their whisking behaviour might also be disrupted. We used high-speed video to film and track whisker movements in 9 adult Reeler mice and 9 age-matched controls in three whisker movement assessment tasks, including our established novel object exploration and open field tasks, as well as a new open field habituation task. Overall, whisker movements in Reeler mice were highly conserved during the novel object exploration and open field tasks, and they demonstrated all behaviourally relevant whisking features during exploratory contact with an object, including contact-induced asymmetry, spread reduction, and decreasing whisker speeds following object contact. In the habituation task, whisker angular position and whisker spread decreased between the first consecutive sessions in all mice, suggesting that the animals were less focused on sampling the area as they got more familiar with the environment. However, only Reeler mice were affected by more extensive habituation. We suggest that whisker-dependent sensory function is surprisingly intact in Reeler mice. However, our observed habituation-related changes in Reeler mice whisker movements suggest some behavioural differences in these mice, which is a likely result of their disorganised cortex due to reelin deficiency.

ABSTRACTHeritability of cognitive function is estimated to be 50%–80%. Genome‐wide association studies (GWASs) have identified multiple cognitive function‐associated loci, primarily in the European population. However, those in Asian populations, particularly in individuals of Japanese ancestry, remain limited. Hence, this GWAS aimed to identify cognitive function‐associated genetic loci in elderly individuals of Japanese ancestry. Herein, 2571 elderly participants from the Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study were included. Their cognitive function was assessed using the Japanese version of the Mini‐Mental State Examination (MMSE), and both binary and continuous MMSE scores were analysed. Genotyping was performed using the Affymetrix Axiom Japonica Array v2, and imputation was conducted with 3.5KJPNv2 and 1KGP3. Statistical analyses were performed using FastGWA‐GLMM and FastGWA for binary and continuous MMSE scores, respectively. Although no genome‐wide significant loci were identified using binary MMSE values, the following two were detected using continuous MMSE values: rs77877360 (20p12.1) near BANF2 and SNX5 and rs9460729 (6p22.3) near PRL and HDGFL1. Additionally, functional annotation suggested the involvement of these loci in pathways related to cognitive function, including chromatin structure regulation, neuroinflammation, and iron metabolism. Notably, SNX5, identified through chromatin‐interaction mapping, has been implicated in neurodegenerative processes, particularly in Parkinson's disease. The findings of this study provide preliminary genome‐wide evidence suggesting a genetic predisposition to impaired cognitive function in elderly Japanese individuals.

Previous work has suggested that genetic confounding is a persistent issue in studies of environmental predictors of executive function (EF). This is largely because controlling for genetic confounding typically requires specialized samples such as twins or adoptees, which are more difficult to recruit. Polygenic scores provide a potential alternative control, scalable to smaller samples and not requiring specialized sample features. The purpose of this study was to determine if polygenic scores of EF could be used to replicate the findings of other genetic confounding studies in a less specialized sample. Confounding models showed evidence for genetic confounding in maternal education, although it was far weaker in magnitude than in other genetically informed studies. However, consistent with previous research, there were no detectable influences of indirect genetic effects on the EF polygenic score, indicating that the detected genetic confounding was likely a true genetic effect. Finally, while environmental factors other than maternal education seemed predictive of EF, confounding models showed that this was best explained by their association with maternal education. Other predictors of EF may thus be confounded environmentally, not just genetically. While polygenic scores are a promising method with a multitude of applications, in their current state they do not replicate the findings of other genetically informed studies of EF. Caution should thus be used when employing them to study genetic confounding in EF.

The underlying mechanisms of early onset memory deficit remain poorly understood. We tested the hypothesis that environmental enrichment (EE) can attenuate early-onset cognitive decline in a novel genetic model, the Wistar Kyoto More Immobile (WMI) inbred rat strain, which manifests the risk factors of enhanced stress reactivity and depression-like behavior compared to its nearly isogenic control, the Wistar Kyoto Less Immobile strain (WLI). Middle-aged (12 months) WMI females exhibited dramatically diminished fear and spatial memory in the contextual fear conditioning and Morris Water Maze paradigms, respectively, compared to young females of both strains and to middle-aged WLI females. Middle-aged WMI males showed a lesser, but significant, age-induced deficit. EE from 6 to 12 months of age completely reversed the memory deficits in middle-aged WMI females and reversed age-induced decreases in plasma levels of estradiol. RNA sequencing from female hippocampi revealed significant strain, age, and enrichment-induced differentially expressed genes. Among these, solute carrier family 35, member A4 (Slc35a4) and potassium inwardly rectifying channel, subfamily J, member 2 (Kcnj2) were confirmed to show hippocampal expression changes parallel to that of memory in the WMI. These genes have critical roles in the integrated stress response, cellular metabolism, and the effects of stress on neurovascular coupling, respectively. Pathway analyses revealed the involvement of oxidative phosphorylation and mitochondrial dysfunction in the hippocampal processes of aging and EE-induced reversal. These findings underscore the critical involvement of molecular stress responses in early-onset memory decline and suggest potential therapeutic targets for age-related cognitive impairment.

Higher delay discounting (DD) (i.e., propensity to devalue larger, delayed rewards over immediate, smaller rewards) is a transdiagnostic marker underpinning multiple health behaviors. Although genetic influences account for some of the variability in DD among adults, less is known about the genetic contributors to DD among preadolescents. We examined whether polygenic scores (PGS) for DD, educational attainment, and behavioral traits (i.e., impulsivity, inhibition, and externalizing behavior) were associated with phenotypic DD among preadolescents. Participants included youth (N = 8982, 53% male) from the Adolescent Brain Cognitive Development Study who completed an Adjusting Delay Discounting Task at the 1-year follow-up and had valid genetic data. PGS for DD, educational attainment, impulsivity, inhibition, and externalizing behaviors were created based on the largest GWAS available. Separate linear mixed effects models were conducted in individuals most genetically similar to European (EUR; n = 4972), African (AFR; n = 1769), and Admixed American (AMR; n = 2241) reference panels. After adjusting for age, sex, income, and the top ten genetic ancestry principal components, greater PGS for DD and lower educational attainment (but not impulsivity, inhibition, or externalizing) were associated with higher rates of DD (i.e., preference for sooner, smaller rewards) in participants most genetically similar to EUR reference panels. Findings provide insight into the influence of genetic propensity for DD and educational attainment on the discounting tendencies of preadolescents, particularly those most genetically similar to European reference samples, thereby advancing our understanding of the etiology of choice behaviors in this population.

Human microbiota-associated murine models, using fecal microbiota transplantation (FMT) from human donors, help explore the microbiome's role in diseases like Alzheimer's disease (AD). This study examines how gut bacteria from donors with protective factors against AD influence behavior and brain pathology in an AD mouse model. Female 3xTgAD mice received weekly FMT for 2 months from (i) an 80-year-old AD patient (AD-FMT), (ii) a cognitively healthy 73-year-old with the protective APOEe2 allele (APOEe2-FMT), (iii) a 22-year-old healthy donor (Young-FMT), and (iv) untreated mice (Mice-FMT). Behavioral assessments included novel object recognition (NOR), Y-maze, open-field, and elevated plus maze tests; brain pathology (amyloid and tau), neuroinflammation (in situ autoradiography of the 18 kDa translocator protein in the hippocampus); and gut microbiota were analyzed. APOEe2-FMT improved short-term memory in the NOR test compared to AD-FMT, without significant changes in other behavioral tests. This was associated with increased neuroinflammation in the hippocampus, but no effect was detected on brain amyloidosis and tauopathy. Specific genera, such as Parabacteroides and Prevotellaceae_UGC001, were enriched in the APOEe2-FMT group and associated with neuroinflammation, while genera like Desulfovibrio were reduced and linked to decreased neuroinflammation. Gut microbiota from a donor with a protective factor against AD improved short-term memory and induced neuroinflammation in regions strategic to AD. The association of several genera with neuroinflammation in the APOEe2-FMT group suggests a collegial effect of the transplanted microbiome rather than a single-microbe driver effect. These data support an association between gut bacteria, glial cell activation, and cognitive function in AD.

Schizophrenia is a frequent and disabling disease. The persistence of the disorder despite its harmful consequences represents an evolutionary paradox. Based on recent discoveries in genetics, scientists have formulated the "price-to-pay" hypothesis: schizophrenia would be intimately related to human evolution, particularly to brain development and human-specific higher cognitive functions. The objective of the present work is to question scientific literature about the relationship between schizophrenia and human evolution from a genetic point of view. In the last two decades, research investigated the association between schizophrenia and a few genetic evolutionary markers: Human accelerated regions, segmental duplications, andhighly repetitive DNA such as the Olduvai domain. Other studies focused on the action of natural selection on schizophrenia-associated genetic variants, also thanks to the complete sequencing of archaic hominins' genomes (Neanderthal, Denisova). Results suggested that a connection between human evolution and schizophrenia may exist; nonetheless, much research is still needed, and it is possible that a definitive answer to the evolutionary paradox of schizophrenia will never be found.

Mutations in voltage-gated sodium (Nav) channels, which are essential for generating and propagating action potentials, can lead to serious neurological disorders, such as epilepsy. However, disease-causing Nav channel mutations do not always result in severe symptoms, suggesting that the disease conditions are significantly affected by other genetic factors and various environmental exposures, collectively known as the "exposome". Notably, recent research emphasizes the pivotal role of commensal bacteria in neural development and function. Although these bacteria typically benefit the nervous system under normal conditions, their impact during pathological states remains largely unknown. Here, we investigated the influence of commensal microbes on seizure-like phenotypes exhibited by paraShu-a gain-of-function mutant of the Drosophila Nav channel gene, paralytic. Remarkably, the elimination of endogenous bacteria considerably ameliorated neurological impairments in paraShu. Consistently, reintroducing bacteria, specifically from the Lactobacillus or Acetobacter genera, heightened the phenotypic severity in the bacteria-deprived mutants. These findings posit that particular native bacteria contribute to the severity of seizure-like phenotypes in paraShu. We further uncovered that treating paraShu with antibiotics boosted Nrf2 signaling in the gut, and that global Nrf2 activation mirrored the effects of removing bacteria from paraShu. This raises the possibility that the removal of commensal bacteria suppresses the seizure-like manifestations through augmented antioxidant responses. Since bacterial removal during development was critical for suppression of adult paraShu phenotypes, our research sets the stage for subsequent studies, aiming to elucidate the interplay between commensal bacteria and the developing nervous system in conditions predisposed to the hyperexcitable nervous system.

Aquaculturists use polyploid fish to maximize production albeit with some unintended consequences including compromised behaviors and physiological function. Given benefits of probiotic therapies (e.g., improved immune response, growth, and metabolism), we explored probiotic supplementation (mixture of Bifidobacterium, Lactobacillus, and Lactococcus), to overcome drawbacks. We first examined fish gut bacterial community composition using 16S metabarcoding (via principal coordinate analyses and PERMANOVA) and determined probiotics significantly impacted gut bacteria composition (p = 0.001). Secondly, we examined how a genomic disruptor (triploidy) and diet supplements (probiotics) impact gene transcription and behavioral profiles of hatchery-reared Chinook salmon (Oncorhynchus tshawytscha). Juveniles from four treatment groups (diploid-regular feed, diploid-probiotic feed, triploid-regular feed, and triploid-probiotic feed; n = 360) underwent behavioral assays to test activity, exploration, neophobia, predator evasion, aggression/sociality, behavioral sensitivity, and flexibility. In these fish, transcriptional profiles for genes associated with neural functions (neurogenesis/synaptic plasticity) and biomarkers for stress response and development (growth/appetite) were (i) examined across treatments and (ii) used to describe behavioral phenotypes via principal component analyses and general linear mixed models. Triploids exhibited a more active behavioral profile (p = 0.002), and those on a regular diet had greater Neuropeptide Y transcription (p = 0.02). A growth gene (early growth response protein 1, p = 0.02) and long-term neural development genes (neurogenic differentiation factor, p = 0.003 and synaptysomal-associated protein 25-a, p = 0.005) impacted activity and reactionary profiles, respectively. Overall, our probiotic treatment did not compensate for triploidy. Our research highlights novel applications of behavioral transcriptomics for identifying candidate genes and dynamic, mechanistic associations with complex behavioral repertoires.