Genes Brain and Behavior最新文献

Impulsivity, often operationalized as delay discounting (DD) and as impulsive personality traits via the UPPS-P scales, is a key transdiagnostic construct across psychiatric disorders. Recent genome-wide association studies (GWAS) have studied the genetic basis of impulsivity in adults, but it remains unclear how similar the genetic architecture of DD is in children. The present study conducted GWAS of DD and impulsivity traits in 5548 children (ages 9–10 years old) of genetically inferred European ancestry from the Adolescent Brain Cognitive Development (ABCD) Study. Heritability estimates for DD (h² = 0.20, S.E. = 0.10) and UPPS-P subscales (h² = 0.08–0.11 S.E. = 0.05) were comparable to adult estimates. Genetic correlations between adult and child impulsivity were modest (r_g = 0.28–0.46), with positive urgency showing the strongest correlation (r_g = 0.83). While no genome-wide significant associations were identified, the top associated variants were mapped to genes previously linked to smoking initiation (rs3820908; p = 6.5 × 10⁻⁸) and UPPS-P Lack of Premeditation (rs17292179; p = 4.2 × 10⁻⁷). Polygenic score (PGS) associations were used to compare the genetic signals in children with those reported in adults. Adult PGSs for DD and positive and negative urgency indicators explained small but significant variance in the respective child impulsivity phenotypes (0.36%–0.44%, p < 7.5 × 10⁻⁴). Additionally, UPPS-P indices were broadly associated with PGSs derived from adult externalizing (0.42%–1.02%) and ADHD (0.23%–0.79%). This first GWAS of impulsivity in children offers a developmentally informed comparison of genetic influences, revealing both similarities and differences by developmental stage.

Autism affects ~1 in 100 people and arises from the interplay between rare genetic changes and the environment. Diagnosis is based on social and communication difficulties, as well as the presence of restricted and repetitive behaviours. Autism aetiology is complex. However, the social motivation hypothesis proposes that an imbalance in the salience of social over non-social stimuli contributes over time to the autism phenotype. Accordingly, motivational dysfunction in autism is widespread, and human imaging data has identified broad impairments to reward processing. The R451C mutation of the neuroligin-3 gene is one such rare genetic change. Knock-in mice harbouring this mutation (NL3) exhibit a range of autism-related phenotypes, including impaired sociability and social motivation. However, no prior report has directly probed non-social motivation. Here, we explore conflicting results from the progressive ratio (PR) and conditioned place preference tasks of non-social motivation. Initial PR results were inconsistent, suggesting reduced, unaltered, and elevated non-social motivation, respectively. Utilising several experimental designs, we probed a range of confounders likely to influence task performance. Overall, reduced PR responding by NL3s likely arose from a combination of their superior ability to withhold responding during prior training and a short PR training schedule. Meanwhile, increased PR responding by NL3s was attributable to their heightened degree of habitual responding. The NL3 mouse model therefore likely best represents autistic individuals with intact non-social motivation but altered behavioural updating. Finally, we discuss the benefits and limitations of using heterogenous experimental designs to probe behavioural phenotypes and offer some general recommendations for PR.

Developmental processes emerge from both maturational and experience-dependent mechanisms. Experience at the proper maturational stage is essential for the acquisition of many complex cognitive and behavioral processes. A striking example of this is a critical period, a restricted developmental phase during which experience is required for both behavioral acquisition and period closure. Juvenile male zebra finches (Taeniopygia castanotis) possess a critical period for song learning; hearing an adult "tutor's" song between posthatch days 30-65 is necessary for each male to produce a socially functional adult song. However, if tutor song is not experienced in this age range, juveniles can still learn beyond posthatch day 65. Our broad objective is to decipher the neurogenomic mechanisms that promote or limit the ability to learn, leveraging the known parameters of the critical period in the male zebra finch's sensory song learning ontogeny. Here, we manipulated juvenile males' tutor exposure and provided song playback experience at two ages, at the beginning or end of the critical period. We probed the relationship between DNA methylation and transcriptional profiles from the same individual and tissue samples to enhance interpretation across different levels of biological organization. Our findings uncovered specific genes and processes that may regulate aspects of critical period learning, as well as aspects of DNA methylation dynamics and how they correspond to RNA measures. Because we distinguished effects of age and experience, outcomes provide insight into fundamental links between epigenetic and molecular properties as the developing brain shifts its ability to learn.

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.

To identify genes that regulate the response to the potentially addictive drug cocaine, we performed a control experiment using genome-wide association studies (GWASs) and RNA-Seq of a panel of inbred and recombinant inbred mice undergoing intravenous self-administration of saline. A linear mixed model increased statistical power for the analysis of the longitudinal behavioral data, which was acquired over 10 days. A total of 145 loci were identified for saline compared to 17 for the corresponding cocaine GWAS. Only one locus overlapped. Transcriptome-wide association studies (TWASs) using RNA-Seq data from the nucleus accumbens and medial frontal cortex identified 5031434O11Rik and Zfp60 as significant for saline self-administration. Two other genes, Myh4 and Npc1, were nominated based on proximity to loci for multiple endpoints or a cis locus regulating expression. All four genes have previously been implicated in locomotor activity, despite the absence of a strong relationship between saline taking and distance traveled in the open field. Our results indicate a distinct genetic basis for saline and cocaine self-administration, and suggest some common genes for saline self-administration and locomotor activity.

Excessive levels of alcohol consumption play a major role in numerous alcohol-related harms, including a heightened risk of developing problematic drinking behaviors. Those who develop alcohol use disorder (AUD) often struggle with persistent difficulties in controlling their drinking, experience withdrawal symptoms, and engage in risky behaviors that pose danger to themselves and others. Advances in treating AUD may be supported by identifying specific cognitive and emotional factors that drive excessive alcohol consumption. Recognizing reliable behavioral biomarkers is instrumental in assessing the risk of developing alcohol problems and preventative care strategies. This study investigates innate behavioral differences associated with genetic predisposition for alcohol use by comparing crossed high alcohol-preferring (cHAP) and low alcohol-preferring (LAP) mice. Since there have been links between heightened impulsivity and excessive alcohol use, we hypothesized that cHAP mice would exhibit higher levels of impulsivity compared to LAPs. No significant differences were found in impulsivity between the mouse lines or sexes. cHAPs adapted to shorter stimulus durations (SDs), whereas LAPs showed a marked decline in correct responses and an increase in omission rates as task difficulty increased. Significant sex differences within the cHAP line were found, with females demonstrating higher accuracy, lower correct latency, and increased perseveration. This behavior points to potential sex-specific neural activation in cognitive processing areas. Future studies should explore salient brain regions to understand their roles in behavioral regulation and sex-specific responses to challenges. This study provides a foundation for exploring the interaction of genetic predisposition, sex differences, and neural mechanisms in alcohol preference and behavior.

We have previously demonstrated that a transmembrane domain mutation in Adenylate cyclase 3 (Adcy3) causes increased adiposity and negative emotion-like behaviors in a rat model. We set out to replicate and expand upon our previous study by conducting comprehensive behavioral testing, and we also investigated the molecular changes that result from this mutation. Rats with a mutation in the second transmembrane helix of ADCY3 (Adcy3^mut/mut) and wild-type rats were fed a high-fat diet for 12 weeks. We measured body weight, body composition, and depression-like and anxiety-like behaviors using the following tests: sucrose splash test, sucrose preference test, forced swim test, open field test, elevated plus maze, successive alleys test, and novelty-suppressed feeding. We also measured serum leptin levels, hypothalamic cyclic AMP (cAMP) production, and membrane fraction ADCY3 content. Adcy3^mut/mut male and female rats had increased adiposity. Adcy3^mut/mut males showed increased despair- and anxiety-like behaviors, food seeking, and higher leptin levels relative to wild-type males. Adcy3^mut/mut females showed only mildly increased anxiety-like behaviors relative to wild-type females. Adcy3^mut/mut rats of both sexes had decreased cAMP production in the hypothalamus, with no changes in ADCY3 content in the membrane fraction. We conclude that the transmembrane domain of ADCY3 plays a critical role in regulating adiposity and behavior, as well as cAMP production. There were key differences between males and females for the observed phenotypes. This study supports the idea that Adcy3 contributes to emotion-like behaviors and potentially mental health disorders, and that the transmembrane domain of ADCY3 is important for protein function.

Posttraumatic stress disorder (PTSD) may develop following trauma exposure; however, not all trauma-exposed individuals develop PTSD, suggesting the presence of susceptibility and resilience factors. The gut microbiome and host genome, which are interconnected, have been implicated in the aetiology of PTSD. However, their interaction has yet to be investigated in a South African population. Using genome-wide genotype data and 16S rRNA (V4) gene amplicon sequencing data from 53 trauma-exposed controls and 74 PTSD cases, we observed no significant association between the host genome and summed abundance of Mitsuokella, Odoribacter, Catenibacterium and Olsenella, previously reported as associated with PTSD status in this cohort. However, PROM2 rs2278067 T-allele was significantly positively associated with the summed relative abundance of these genera, but only in individuals with PTSD and not trauma-exposed controls (p < 0.014). Polygenic risk scores generated using genome-wide association study summary statistics from the PGC-PTSD Overall Freeze 2 were not predictive of gut microbial composition in this cohort. These preliminary results suggest a potential role for the interaction between genetic variation and gut microbial composition in the context of PTSD, underscoring the need for further investigation.

Alzheimer's disease is a debilitating neurodegenerative condition characterized by amyloid beta plaques and tau neurofibrillary tangles, which leads to progressive cognitive decline. Several new mouse models of fast amyloid deposition have been generated with compound mutations, but how these affect high-level cognitive function is still not fully understood. Four cohorts of a second-generation amyloid precursor protein knock-in mouse model, App^{NL-G-F/NL-G-F}, which develops aggressive amyloidopathy, were compared with two different control groups that do not produce plaques (App^NL/NL and wildtype littermates), on touchscreen-based tests of learning and cognitive flexibility. App^{NL-G-F/NL-G-F} mice learned to discriminate between two visual stimuli during the pairwise visual discrimination (PVD) task but were impaired when the reward contingencies were reversed (the PVR task). Analyses of the correction trials indicated perseverative behavior. One cohort was further tested on the touchscreen Extinction test, which isolates the ability to withhold responding to a previously rewarded stimulus. The App^{NL-G-F/NL-G-F} mice extinguished their responding no differently than the App^NL/NL control group. These results indicate that compound mutations in App driving fast accumulation of plaques in this mouse model impair cognitive flexibility and may serve as a preclinical target for putative therapeutic drugs.