Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer’s disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.

Maintenance of genetic variants susceptible to psychiatric disorders is one of the intriguing evolutionary enigmas. The present study detects three psychiatric disorder‐relevant genes (CLSTN2, FAT1, and SLC18A1) that have been under positive selection during the human evolution. In particular, SLC18A1 (vesicular monoamine transporter 1; VMAT1) gene has a human‐unique variant (rs1390938, Thr136Ile), which is associated with bipolar disorders and/or the anxiety‐related personality traits. 136Ile shows relatively high (20–61%) frequency in non‐African populations, and Tajima's D reports a significant peak around the Thr136Ile site, suggesting that this polymorphism has been positively maintained by balancing selection in non‐African populations. Moreover, Coalescent simulations predict that 136Ile originated around 100,000 years ago, the time being generally associated with the Out‐of‐Africa migration of modern humans. Our study sheds new light on a gene in monoamine pathway as a strong candidate contributing to human‐unique psychological traits.

Domestication has resulted in immense phenotypic changes in animals despite their relatively short evolutionary history. The European rabbit is one of the most recently domesticated animals, but exhibits distinct morphological, physiological, and behavioral differences from their wild conspecifics. A previous study revealed that sequence variants with striking allele frequency differences between wild and domestic rabbits were enriched in conserved noncoding regions, in the vicinity of genes involved in nervous system development. This suggests that a large proportion of the genetic changes targeted by selection during domestication might affect gene regulation. Here, we generated RNA-sequencing data for four brain regions (amygdala, hypothalamus, hippocampus, and parietal/temporal cortex) sampled at birth and revealed hundreds of differentially expressed genes (DEGs) between wild and domestic rabbits. DEGs in amygdala were significantly enriched for genes associated with dopaminergic function and all 12 DEGs in this category showed higher expression in domestic rabbits. DEGs in hippocampus were enriched for genes associated with ciliary function, all 21 genes in this category showed lower expression in domestic rabbits. These results indicate an important role of dopamine signaling and ciliary function in the evolution of tameness during rabbit domestication. Our study shows that gene expression in specific pathways has been profoundly altered during domestication, but that the majority of genes showing differential expression in this study have not been the direct targets of selection.

Biological invasion refers to the introduction, spread, and establishment of non-native species in a novel habitat. The ways in which invasive species successfully colonize new and different environments remain a fundamental topic of research in ecology and evolutionary biology. Here, we investigated the genomic and transcriptomic characteristics of the red swamp crayfish (Procambarus clarkii), a widespread invader in freshwater environments. Targeting a recently colonized population in Sapporo, Japan that appears to have acquired a high degree of cold tolerance, RNA-seq analysis revealed differentially expressed genes in response to cold exposure, and those involved in protease inhibitors and cuticle development were considered top candidates. We also found remarkable duplications for these gene families during evolution and their concerted expression patterns, suggesting functional amplification against low temperatures. Our study thus provides clues to the unique genetic characteristics of P. clarkii, possibly related to cold adaptation.

The underlying molecular mechanisms that determine long day versus short day breeders remain unknown in any organism. Atlantic herring provides a unique opportunity to examine the molecular mechanisms involved in reproduction timing, because both spring and autumn spawners exist within the same species. Although our previous whole genome comparisons revealed a strong association of TSHR alleles with spawning seasons, the functional consequences of these variants remain unknown. Here we examined the functional significance of six candidate TSHR mutations strongly associated with herring reproductive seasonality. We show that the L471M missense mutation in the spring-allele causes enhanced cAMP signaling. The best candidate non-coding mutation is a 5.2 kb retrotransposon insertion upstream of the TSHR transcription start site, near an open chromatin region, which is likely to affect TSHR expression. The insertion occurred prior to the split between Pacific and Atlantic herring and was lost in the autumn-allele. Our study shows that strongly associated coding and non-coding variants at the TSHR locus may both contribute to the regulation of seasonal reproduction in herring.

Collective behavior plays a vital role in detecting and evading predators, yet its neural and genetic underpinnings remain poorly understood. In Drosophila melanogaster, visual cues from conspecifics can alleviate freezing responses to threatening stimuli. Using a large-scale behavioral experiment combined with GWAS, we identify key loci, including Ptp99A and kirre, which are involved in visual neuron development and may influence visual responsiveness to conspecifics. Single-cell transcriptomics and functional assays confirm the modulatory roles of Ptp99A in gene expression in visual neurons and behavior. Furthermore, mixed-strain groups show enhanced freezing behavior compared to homogeneous groups, demonstrating a “diversity effect” where genetic diversity within groups induces flexible behavioral changes. Animal-computer interaction experiments using predatory spiders validate that variation in freezing durations among interactive individuals improves antipredator behavioral performance in fly groups. Agent-based simulations further support the hypothesis that behavioral synchronization among genetically diverse individuals improves group-level performance. We introduce genome-wide higher-level association study to find loci whose genetic diversity correlates with diversity effect, highlighting the potential roles of neuronal diversity. These findings demonstrate how genetic diversity fosters synergistic responses to threats, offering insights into the neural and genomic mechanisms underlying collective behavior in non-eusocial insects.