Biology subjects

Shimura, A.

Publications and source records attributed to Shimura, A..

7 recordsLinked to original sources

bioRxiv2026

Zuranolone mitigates delirium-like bispectral EEG changes, behavioral deficits, and neuroinflammation across surgical and inflammatory mouse models and age groups

Delirium is an acute, fluctuating brain dysfunction that commonly follows surgery and systemic inflammation, disproportionately affects older adults, and remains difficult to quantify continuously over time and treat pharmacologically. Here, we tested whether the neuroactive steroid zuranolone, a positive allosteric modulator of synaptic and extrasynaptic GABA_A receptors, mitigates delirium-like abnormalities across two complementary murine delirium models, a lipopolysaccharide-induced systemic inflammation (LPS) model and a postoperative delirium (POD) model, primarily in young and aged mice, with selected analyses in super-aged mice. Using continuous EEG with a validated bispectral EEG (BSEEG) metric, we found that zuranolone attenuated delirium-like EEG slowing in the LPS model in young mice in a dose-dependent manner and retained efficacy in aged mice. In the POD model, prophylactic dosing provided limited benefit in young mice, whereas post-surgery treatment reduced postoperative BSEEG elevations. In aged mice, prophylactic dosing suppressed POD-associated BSEEG abnormalities, and in super-aged mice, prophylactic zuranolone improved survival after POD induction. In parallel, zuranolone reduced microglial density and activation markers (IBA1 and CD68 immunoreactivity) at 24 h after POD surgery and after LPS challenge, with effects that were particularly evident in peri-screw site tissue in young POD mice and more broadly distributed across regions in aged mice. Finally, in young mice, zuranolone improved a composite behavioral severity score in the LPS model, whereas behavioral effects in the POD model were modest and domain-specific. Together, these findings support zuranolone as a candidate strategy to reduce delirium-like electrophysiological and neuroimmune abnormalities, with the strongest effects in inflammation-driven and age-vulnerable contexts.

neuroscience↗

bioRxiv2026

Gut microbiome composition and predicted functions relate to growth and behavior in a Japanese preschool cohort

Early childhood is a period of rapid brain maturation and gut microbiome assembly, when emerging behavioral difficulties can shape later mental health and learning trajectories. Microbiota-gut-brain communication has been implicated in neurodevelopment through microbial metabolites and immune signaling. However, most pediatric evidence comes from high-risk or clinically referred cohorts, and gut microbiome-related correlates of typical behavioral variation in community-based preschool children remain poorly defined. In a cross-sectional sample of typically developing Japanese preschool children, here we show that behavioral variation within normative ranges is associated with distinct microbiome configurations: internalizing domains cluster with signatures consistent with higher inflammatory potential and elevated nucleotide biosynthesis, whereas somatic complaints and withdrawn behavior associate with reduced respiratory and fermentative activity. Sleep-related difficulties show the broadest predicted functional footprint, including enrichment of pathways related to methyl-donor and heme biosynthesis, while externalizing domains associate with pathways involved in cell-envelope and carbohydrate remodeling. In contrast, age, height, and weight track canonical maturation of gut microbiome composition, indicating that behavioral associations are not simple proxies of growth. Together, these findings extend early-life microbiome research by resolving domain-specific associations in a low-risk Asian community sample and highlighting pathway-level candidates that may interface with neurodevelopment.

microbiology↗

bioRxiv2025

Epigenetic markers of middle-age: non-linear DNA methylation changes with aging in humans

BackgroundHuman DNA is known to exhibit an overall tendency toward demethylation with aging. However, assuming a simple linear relationship between DNA methylation and age does not align with the phenotype of human development and the aging process. This study aimed to investigate the existence of DNA methylation patterns with peaks or troughs at specific ages in addition to simple linear changes. MethodsA large-scale dataset of genome-wide DNA methylation data from 10,420 individuals was analyzed. Hierarchical multiple regression models were applied to detect patterns of the association between age and DNA methylation: linear increase, linear decrease, U-shaped curve, and inverse U-shaped curve. ResultsAmong the 864,627 CpG sites analyzed, 8.4% exhibited an increase in DNA methylation with age, 23.9% showed a decrease, and 5.5% were better explained by a quadratic model (P < 5.7815x10 ). Within the non-linear subset, inverse U-shaped CpG sites peaking in methylation during middle age were predominant. Genes exhibiting quadratic association patterns between DNA methylation and age, and those linked to diseases with common onset during middle age, were also detected. ConclusionsNon-linear age-related DNA methylation patterns, with peaks or troughs occurring at specific ages, were detected. This suggests that humans do not simply age linearly, but that programmed mechanisms or cascade-like processes may exist to promote or suppress the expression of specific genes at certain ages, contributing onset of certain diseases at specific timings.

genomics↗

bioRxiv2025

Non-linear Age-related Change in Human Interleukin-11 and the receptor subunit alpha DNA Methylation

IntroductionInterleukin-11 (IL-11) is a cytokine involved in inflammatory processes and a previous study showed that blocking or knocking down IL11 in mice prolongs a healthy lifespan. This study investigates DNA methylation (DNAm) changes in the IL11 and IL-11 receptor subunit alpha (IL-11RA) gene across ages to reveal how aging might influence IL-11 production and sensitivity. MethodsA genome-wide DNAm database focusing on Cytosine-phosphate-Guanine (CpG) sites within the IL11 and IL11RA was analyzed. Hierarchical regression analyses examined the relationship between DNAm, age, and the squared age term for quadratic associations. ResultsThe database comprised 10,297 samples (5,156 males and 5,141 females) with a mean age of 53.9 years (SD = 14.1 years). The majority of IL11 and IL11RA CpG sites in the TSS1500 and 3UTR regions exhibited significant inverse U-shaped associations with age. DNAm levels were low during youth, increased in middle age (40s-50s), and decreased again in older age. ConclusionThe observed inverse U-shaped DNAm patterns in the IL11 and IL11RA suggest n non-linear, age-related regulation of IL-11 expression and sensitivity. These findings indicate that IL-11 may have different roles across life stages and suggest that therapeutic interventions targeting IL-11 should consider age-specific effects.

genetics↗

bioRxiv2025

Glial Contribution to the Pathogenesis of Post-Operative Delirium Revealed by Multi-omic Analysis of Brain Tissue from Neurosurgery Patients

Post-operative delirium (POD) is a common complication after surgery especially in elderly patients, characterized by acute disturbances in consciousness and cognition, which negatively impacts long-term outcomes. Effective treatments remain elusive due to the unclear pathophysiology of POD. To address the knowledge gap, we investigated DNA methylation profiles and gene expression changes in brain cells from POD and non-POD patients who underwent brain resection surgery for medication refractory epilepsy. DNA methylation analysis revealed alteration in epigenetic status of immune and inflammation-related genes. Single-nucleus RNA sequencing (snRNAseq) identified POD-specific glial cell alterations, particularly in microglia, where neuroinflammation was strongly enhanced, consistent with epigenetic findings. Astrocytes exhibited changes in synapse-related functions and migration. Furthermore, downstream analysis indicated similarities between POD-associated glial cell states and pathologies such as encephalitis and dementia. Overall, this study--the first multi-omics analysis of brain tissue from POD patients--provides direct evidence of glial cell contributions to POD pathogenesis, and highlights potential therapeutic targets.

neuroscience↗

bioRxiv2025

The age-related susceptibility to postoperative delirium quantified by bispectral electroencephalography (BSEEG) correlates with postoperative delirium-like behavior in mice

Postoperative delirium (POD) is a severe neuropsychiatric state characterized by acute fluctuating various mental symptoms. Despite its prevalence, the underlying mechanisms of POD remain largely unknown, and effective biomarkers for its detection are lacking. We have successfully developed a novel delirium detection method, the bispectral electroencephalography (BSEEG) method, which has shown excellent performance in delirium detection and outcome prediction. From there, similar to the clinical situation, we hypothesize that BSEEG scores can serve as indicators of POD-like states in mice. This study investigated the correlation between POD-like behavior and BSEEG score in a mouse model following EEG head mount implantation surgery. 2-3 and 22-23 month-old male C57BL/6J mice underwent EEG head-mount implantation surgery, followed by EEG monitoring and a battery of behavioral tests, including Buried Food Test, Open Field Test, and Y-maze, to assess POD-like behavior. We measured BSEEG scores and analyzed the correlation between these scores and the behavior measurements. The results showed that BSEEG scores correlated with attention deficit and decreases in locomotor activity in young mice, whilst BSEEG scores only correlated with a decrease in locomotor activity in aged mice. Notably, composite Z scores representing delirium severity also showed a correlation with BSEEG scores in young mice. Our findings indicate that the BSEEG method can be an indicator of POD-like states consistent with those measured by behavior tests. This study provides a novel preclinical framework for understanding the pathophysiology of POD and underscores the potential of BSEEG as a valuable tool for delirium detection and severity assessment.

animal behavior and cognition↗

bioRxiv2024

LPS-induced delirium-like behavior and microglial activation in mice correlate with bispectral electroencephalography (BSEEG)

Delirium is a multifactorial medical condition characterized by impairment across various mental functions and is one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Research focused on delirium has proven to be challenging due to a lack of objective measures for diagnosing patients, and few laboratory models have been validated. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes. We applied BSEEG to validate a lipopolysaccharide (LPS)-induced mouse model of delirium. Moreover, we investigated the relationship between BSEEG score, delirium-like behaviors, and microglia activation in hippocampal dentate gyrus and cortex regions in young and aged mice. There was a significant correlation between BSEEG score and impairment of attention in young mice. Additionally, there was a significant correlation between BSEEG score and microglial activation in hippocampal dentate gyrus and cortex regions in young and aged mice. We have successfully validated the BSEEG method by showing its associations with a level of behavioral change and microglial activation in an LPS-induced mouse model of delirium. In addition, the BSEEG method was able to sensitively capture an LPS-induced delirium-like condition that behavioral tests could not capture because of a hypoactive state.

neuroscience↗