Genes Brain and Behavior最新文献

To optimize health, organisms must coordinate energy intake and expenditure and apportion related behaviors to appropriate times of day. In the fruit fly, Drosophila melanogaster, the SIFamide (SIFa) neuropeptide impacts multiple behavioral outputs important for energy regulation, including reproductive activity, sleep, and feeding. SIFa-expressing neurons receive convergent inputs from circadian and homeostatic brain regions and extend elaborate projections throughout the central nervous system. Consistent with this distribution pattern, the SIFa receptor (SIFaR) is widely expressed in the brain and ventral nerve cord, providing the anatomical substrate for SIFa signaling to influence a broad range of neuronal functions. To further explore the pleiotropic role of SIFa signaling in behavioral control, we have assessed survival, locomotor activity, sleep, and feeding in SIFaR mutant flies, as well as in flies with RNA interference-induced reduction of SIFaR expression. We find that loss of SIFaR has a complex effect on fly survival that is background- and allele-specific. However, outcrossed SIFaR mutant flies are viable, enabling monitoring of adult behavior. These flies exhibit elevated locomotor activity, reduced sleep, and increased feeding at specific times of day. We also find that SIFaR mutations drastically decrease starvation resistance. These results suggest a prominent role for SIFaR in integrating homeostatic and circadian information to coordinate the magnitude and timing of energy balance-related behaviors.

Cannabis use is a growing public health concern due to its neuropsychiatric consequences and potential epigenetic effects. This study investigated the methylation status of the DAT1 dopamine transporter gene in individuals with cannabis use disorder (CUD) and examined associations with personality traits. A total of 490 male participants (212 with CUD and 278 controls) were assessed using the NEO Five-Factor Inventory (NEO-FFI) and the State-Trait Anxiety Inventory (STAI). DNA methylation levels at 33 CpG sites within the DAT1 promoter region were quantified through methylation-specific PCR and sequencing. Although no significant group differences were found in overall methylation levels, logistic regression revealed significant associations between methylation status and personality dimensions. CUD was linked to higher neuroticism and openness, lower agreeableness and conscientiousness, and elevated anxiety scores. Importantly, reduced DAT1 methylation was a significant predictor of CUD. These findings underscore the interplay between personality, gene regulation, and addiction, supporting a role for epigenetic mechanisms in the development and maintenance of substance use disorders. Future research should explore site-specific CpG alterations and their longitudinal impact on neurobehavioral outcomes.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with both genetic and environmental contributions. Previous work identified a de novo mutation in the dopamine transporter (DAT T356M) in an autism proband that results in profound behavioral changes when expressed homozygously in mice. Since complex human genetics are more likely to be present as heterozygous (single allele) mutations, we characterized mice that were heterozygous for the mutation. Both male and female DAT T356M^+/− mice exhibited hyperactivity but normal habituation to novel environments. The difference in hyperactivity compared to wild-type littermates was dramatically smaller than previously reported in homozygous animals. Other behavioral alterations were sex-specific, with only male heterozygous mice exhibiting greater repetitive behaviors and impaired spatial learning in the Barnes maze. Sensorimotor gating measured by prepulse inhibition of the startle response was largely unchanged in both sexes. Motor performance on the rotarod showed opposing effects, with male heterozygotes showing decreased latency to fall while females demonstrated increased latency (i.e., enhanced performance). These findings suggest that even a single copy of the DAT T356M variant can impact behavior in a sex-specific manner. The identification of intermediate phenotypes makes these mice an appropriate model for future studies examining how environmental factors might interact with genetic susceptibility to influence autism-relevant behaviors, particularly in the context of dopaminergic dysfunction.

While observational studies have linked birth weight to developmental-behavioral disorders, establishing genetic correlations and causal relationships remains challenging due to potential confounding factors. In this study, we assessed genetic correlations between birth weight and developmental-behavioral disorders using linkage disequilibrium score regression (LDSC), identified pleiotropic loci and genes through Pleiotropy Analysis under Composite Null Hypothesis (PLACO), and investigated causal relationships via Mendelian randomization (MR) analysis. The results revealed significant negative genetic correlations between ADHD and birth weight (fetal: r_g = −0.087, 95% CI −0.134 to −0.040; maternal: r_g = −0.088, 95% CI −0.139 to −0.0337; maternal effect: r_g = −0.107, 95% CI −0.183 to −0.030). We identified 41 pleiotropic genes enriched in cardiovascular, brain, and liver tissues, and 122 pleiotropic loci through eQTL integration. However, MR analysis showed no causal associations between birth weight and developmental behavioral disorders. These analyses establish both shared genetic etiology and biological pleiotropy underlying birth weight and developmental-behavioral disorder associations.

Investigating the spatiotemporal patterns of gene expression in the brain is a critical step toward unraveling the molecular mechanisms underlying social behavior. While significant progress has been made in identifying neurogenomic states associated with diverse social contexts and their biological pathways, genomic studies often yield hundreds of candidate genes. This necessitates pinpointing key genes that drive behavior for more targeted research. In this study, we examine how the spatiotemporal expression of selected candidate genes varies between mating and social contexts. Building on insights from previous transcriptomic analyses, we identified promising gene candidates and examined their expression patterns in the female guppy brain (Poecilia reticulata). We evaluated these patterns within the brain's social decision-making network at 10 and 30 min post-exposure to either a mating or social stimulus. Genes such as gria1a, thap6, gria2, and agap3 exhibited the most pronounced differences in expression between mating and social contexts, suggesting their potential roles in regulating mating behavior. Employing a novel hierarchical coexpression network analysis, we captured the intricate gene expression changes underlying behavior. This approach allowed us to visualize distinct patterns of brain activity, revealing that the response to mating stimuli was localized to anterior nuclei, whereas the response to social stimuli was more evenly distributed across the social decision-making network. Additionally, we observed greater variability in gene expression between social and mating contexts at the 10-min time point.

Large-scale human genetic studies implicate multiple genes that regulate protein ubiquitination in autism spectrum disorder (ASD). De novo loss-of-function mutations in the gene CULLIN3 (CUL3) are implicated in autism and intellectual disability (ID). CUL3 is an essential component of an E3 ubiquitin ligase complex required for ubiquitination of substrates, often a signal for proteasomal degradation. Homozygous deletion of Cul3 is embryonically lethal. Recent studies show heterozygous deletion of Cul3 results in phenotypes with some face validity for autism in constitutive and conditional Cul3 heterozygotes. To understand the function of Cul3 in late postnatal development and function in the brain, we crossed mice expressing Cre-recombinase under the control of the CaMKIIα promoter with conditional (floxed) Cul3 mice that resulted in viable homozygotes. In this study, we demonstrate that delayed postnatal deletion of Cul3 in predominantly forebrain excitatory neurons leads to robust behavioral differences across multiple behaviors. Cul3 conditional homozygotes show repetitive jumping, reduced marble burying, increased locomotion, impaired motor coordination, and increased hindlimb clasping. We were successfully able to replicate most of these findings in an independent cohort. Our future studies are aimed at gaining mechanistic insights into Cul3 function in the adult brain.

Heritability 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.

The amygdala participates in the processing of stimulus signals from stimuli and the coordination of the physiological and behavioral responses. The sexually dimorphic structure of the amygdala also contributes to sex-specific molecular and functional profiles. The present study compares the response of the amygdala molecular mechanisms to different environmental stimuli between sexes. The amygdala of female and male pigs was profiled under control, immunostimulation, and the metabolic stimulus of fasting using RNA-sequencing. Differential expression analysis (False Discovery Rate -adjusted p value < 0.05) identified 958 genes affected by stimulus and 504 genes affected by sex within treatments. The functional categories presenting a predominance of differentially expressed genes included the synaptic vesicle cycle pathway, vascular smooth muscle contraction pathway, epithelial cell proliferation process, chemokine signaling, and apoptosis. Network analysis revealed hub genes, including Stx1a, Cplx1, Clam3, and Myh11, among the gene modules susceptible to stimuli. The regulatory element SUZ12 was associated with differential gene expression between stimuli in both sexes, whereas RELA and IRF1 were uniquely detected in males and females, respectively. The findings from the multifaceted approach provide genomic leads to investigating interventions that can mitigate the effects of stimuli on the amygdala function.

Major depressive disorder is a prevalent and debilitating psychiatric illness that produces significant disability. Clinical data suggest that the pathophysiology of depression is due, in part, to a dysregulation of inflammation and glutamate levels in the brain. The systemic administration of lipopolysaccharide (LPS) has been shown to induce depressive-like behaviors in mice. Dapagliflozin (DPG), a sodium-glucose cotransporter-2 inhibitor (SGLT2i), used to treat type 2 diabetes, has been reported to produce neuroprotective effects in various animal models. This study aimed to determine the efficacy of DPG (0.5 mg/kg) to decrease LPS-induced depressive-like behaviors in mice. Thirty-six male mice were divided into four groups (n = 9): Saline (normal saline, 1 mL/kg, i.p., for 14 days), LPS (saline for 7 days followed by 1 mg/kg of LPS, i.p.), DPG (0.5 mg/kg, oral gavage for 14 days), and LPS and DPG (DPG alone for 7 days, followed by LPS and DPG for another 7 days). The forced swim (FST) and tail suspension tests (TST), putative animal models of depression, were conducted at the end of the study. After euthanization, brain tissues and blood samples were collected. The expression of glutamate transporter 1 (GLT-1), solute carrier family 7-member 11 (SLC7A11), and nuclear factor kappa β (NF-κB) mRNA was determined using q-PCR. LPS induced depressive-like behavior and significantly increased mRNA levels of GLT-1, SLC7A11, and NF-κB. DPG alone also affected baseline performance in the TST. Furthermore, DPG significantly decreased the LPS-induced changes, suggesting that it may alleviate LPS-induced depressive behaviors by modulating glutamate homeostasis and inflammatory pathways.

Genetic variants of the SCN2A gene, encoding the Na_V1.2 sodium channel, cause a spectrum of neurodevelopmental and epileptic disorders, and are among those that show the strongest association with Autism Spectrum Disorder (ASD). ASD has a male-bias prevalence, but several studies have proposed that female prevalence may be underestimated due to different symptomatic expression compared with males. However, it is unclear whether this is related to actual different pathological features or to greater masking abilities in females. Studies on Scn2a^+/− mice, a model of SCN2A haploinsufficiency and ASD, have shown an age-dependent ASD-like phenotype attenuated at adulthood in males. However, little is known about the behavioral features of Scn2a^+/− female mice. We performed a battery of behavioral tests that are relevant for assessing ASD-like features, investigating juvenile and adult Scn2a^+/− female mice. Our results demonstrate that female Scn2a^+/− mice exhibit an overall milder phenotype than males, showing increased risk-taking in juveniles, hyper-reactivity to cold stimuli, and mild memory impairments in adults, abnormally increased sociability, and altered decision-making related behaviors in both juveniles and adults. Thus, this aligns with the male-biased prevalence of ASD and supports the existence of sex-specific phenotypic differences, potentially arising from distinct underlying pathophysiological mechanisms. Both sexes should be investigated in studies of mouse models of ASD.