Biology subjects

Nakajima, S.

Publications and source records attributed to Nakajima, S..

14 recordsLinked to original sources

bioRxiv2026

Dietary fructose promotes anxiety through impairment of microglia physiology

Excessive dietary fructose has been linked to metabolic and mood disorders but the underlying brain mechanisms remain unclear. In this study, we tested whether microglia, the brain resident immune cells, mediate fructose-induced anxiety. Adult C57BL/6J mice and mice knock-down for the fructose transporter Glut5 selectively in microglia (Slc2a5flox/flox:Tmem119-Cre-positive mice) were exposed to 25% fructose in drinking water for 8 weeks. We assessed metabolic parameters, anxiety- and depression-like behaviors using a battery of behavioral tests. We then performed RNA sequencing in several brain regions, including the hippocampus to characterize fructose-induced transcriptional changes. Microglial responsiveness to lipopolysaccharide (LPS) treatment was assessed in vitro and in vivo using immunohistochemistry (microglia morphology) and RT-qPCR (cytokine gene expression). Fructose feeding induced marked metabolic alterations and robust anxiety-like behavior in male mice, together with memory deficits, whereas females showed milder metabolic changes and memory impairment without clear emotional disturbances. RNA sequencing revealed that fructose alters microglial gene-expression profiles in the hippocampus. Microglial Glut5 knockdown prevented fructose-induced anxiety-like behavior in the novelty-suppressed feeding test, indicating that microglial fructose uptake is required for this effect. At the molecular level, physiological fructose exposure did not markedly increase microglial cytokine expression but blunted the cytokine response to lipopolysaccharide, consistent with a hypo-reactive microglial state. Overall, these findings identify microglia as a critical mediator of fructose-induced anxiety and suggest that chronic fructose exposure promotes a maladaptive microglial phenotype that disrupts brain circuit function, with potential implications for diet-related mental health risk.

neuroscience↗

bioRxiv2026

Postmortem Alterations of Metabotropic Glutamate Receptors across Neuropsychiatric Disorders: A Systematic Review

Metabotropic glutamate receptors (mGluRs) regulate glutamatergic transmission and have been implicated in diverse neuropsychiatric disorders, but human postmortem evidence remains fragmented. We aimed to map these findings across diagnoses, receptor subtypes, brain regions, and measurement modalities. Following PRISMA guidelines, we systematically searched MEDLINE, EMBASE, and Web of Science from inception to August 8, 2026, for studies assessing GRM transcripts, as well as mGluR protein abundance, localization, assembly, or receptor binding in human postmortem brain tissue. Of 532 records identified, 57 reports met eligibility criteria. Findings were synthesized narratively because of substantial heterogeneity in diagnoses, brain regions, receptor subtypes, and assays. Postmortem evidence was concentrated on mGluR5, mGluR2/3, and mGluR1, and on the prefrontal cortex, anterior cingulate cortex, and hippocampus. mGluR-related alterations were reported across disorders, including schizophrenia, major depressive disorder, Alzheimer disease, autism spectrum disorder, and alcohol use disorder. Although most analyses yielded null findings, the direction and magnitude of mGluR alterations varied across brain regions, receptor subtypes, and molecular endpoints. This inconsistency may partly reflect the distinct biological levels captured by transcript abundance, total protein, receptor assembly, localization, and ligand binding, together with regional, cell-type, disease-stage, and clinical heterogeneity. The available evidence therefore suggests context-dependent alterations in mGluR biology but not a uniform or disorder-specific molecular signature. Integration of postmortem findings with other approaches, including in vivo imaging, may clarify their biological and clinical significance.

neuroscience↗

bioRxiv2026

A senescent iCAF-like fibroblast state governs therapy resistance in rheumatoid arthritis

ObjectivesRheumatoid arthritis (RA) synovitis frequently persists despite cytokine-targeted therapies, suggesting the existence of pathogenic stromal programs that sustain chronic inflammation independently of canonical immune pathways. Although synovial fibroblasts (SF) are increasingly implicated in treatment resistance, the pathogenic fibroblast states driving refractory disease and their therapeutic vulnerabilities remain poorly defined. MethodsWe integrated multimodal single-cell and spatial profiling of synovial tissue from 54 patients with RA with prospective treatment-response data and functional studies in human fibroblasts and experimental arthritis models. ResultsWe identified a C-X-C motif chemokine 12 (CXCL12)hi Apolipoprotein C1 (APOC1)+ fibroblast population selectively enriched in treatment-refractory synovitis. Spatial analyses demonstrated that these fibroblasts establish CXCL12-dependent plasmablast niches within inflamed synovium, resembling inflammatory cancer-associated fibroblasts (iCAF) that orchestrate immune cell recruitment in the tumor microenvironment. CXCL12hi APOC1+ fibroblasts exhibited a senescence-associated iCAF-like transcriptional program characterized by STAT3-C/EBP activation and APOC1 expression and were associated with poor response to TNF and IL-6 pathway inhibition. Mechanistically, APOC1 knockdown in RA-SF attenuated invasive mesenchymal behavior and disrupted senescence-associated inflammatory programs, identifying APOC1 as a central regulator of pathogenic fibroblast reprogramming. Importantly, genetic or pharmacological elimination of senescent cells ameliorated experimental arthritis and enhanced the efficacy of TNF blockade. ConclusionsThese findings implicate iCAF-like fibroblasts with senescent properties as a mechanistic driver of refractory RA synovitis and highlight stromal senescence programs as preclinically actionable therapeutic targets beyond cytokine inhibition.

immunology↗

bioRxiv2025

Immunometabolic state modulation of sequential decision making in patch-foraging mice

Animals have evolved sophisticated behavioural and metabolic adaptations to respond to threats to homeostasis, including resource scarcity and infectious pathogens. Energy deficits associated with lack of food availability and sickness-associated anorexia elicit distinctive hypometabolic states, however how such states are integrated with higher-order cognition is largely unknown. Patch-foraging paradigms have proven useful for deciphering evolutionarily conserved and ethologically grounded insights into cost-benefit decision-making as animals continually deliberate between exploiting and exploring their environment. We developed and extensively validated a touchscreen-based patch-foraging task for mice in which food reward dynamically varied across trials, in a dataset comprising over 111,000 sequential decisions from 35 adult male mice. Contrary to predictions that emphasize the impact of inflammation to blunt effortful reward-driven behaviour, our results demonstrate that systemic lipopolysaccharides-induced inflammation promotes hyper-exploitation by attenuating exploratory choice behaviour in animals interacting with complex food environments. Such behaviour can be seen as a bias towards immediate outcomes, with impulsivity as a feature affecting the weighting of temporal factors. Given the ubiquity of systemic inflammation in numerous infectious, metabolic and psychiatric disorders featuring dysfunctional value- and cost-sensitive behaviour, these results provide insight into how immunometabolic states are linked to altered decision-making.

neuroscience↗

bioRxiv2025

MARK2 in glial cells suppresses inflammatory responses and mitigates tau toxicity

Neuroinflammation is a pathological hallmark of Alzheimers disease and related neurodegenerative diseases. However, signaling molecules that regulate glial activation status are not fully understood. Microtubule affinity-regulating kinase 2 (MARK2) has been implicated in both immune responses and AD pathology. Here, we report that MARK2 negatively regulates glial immune responses, which protects against neurodegeneration. We found that MARK2 knockdown in the BV2 murine microglial cell line enhanced IL-6 expression in response to LPS. MARK2 knockdown enhanced IL-6 expression induced by TLR7 agonist but not stimulation of RLR pathways and cGAS-STING. In the brains of PS19 tauopathy mice, MARK2 was elevated in homeostatic microglia but reduced in activated microglia. In Drosophila expressing human tau in the retina, expression of AMP downstream of the Toll pathway in the pigment glia enhances degeneration of photoreceptor neurons. Glial knockdown of Par-1, the Drosophila ortholog of MARK2, enhanced Toll-mediated AMP expression and neurodegeneration, whereas overexpression of Par-1 in the pigment glia suppressed them. These results suggest that MARK2/Par-1 in glia negatively regulates Toll pathway-driven inflammation and protects against tau-induced neurodegeneration. These findings provide insight into the molecular underpinnings of glial inflammation in neurodegenerative conditions and highlight MARK2 as a potential therapeutic target for modulating neuroinflammatory responses.

neuroscience↗

bioRxiv2025

Pleasure in groove is associated with neuromelanin levels in the substantia nigra of younger healthy individuals: A neuromelanin-sensitive MRI study

The pleasurable urge to move in response to music is called groove. Prior research has suggested a potential link between groove and dopamine function. However, no studies to date have directly investigated the relationship between the two. Here, we aimed to assess individual dopamine function in the substantia nigra of healthy individuals using neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a non-invasive method associated with dopamine function, and to investigate the relationship between the individual dopamine proxy index and sensitivity to the groove experience. In this study, 15 younger (< 48 years) and 16 older ([greater double equals]48 years) healthy individuals participated. Participants listened to ten musical excerpts and rated the groove experience based on "pleasure" and "wanting to move." To assess whether the groove experience is related to NM levels, type of musical excerpts, and sex, we analyzed with linear mixed-effects regression models. The results showed that higher NM levels (p = 0.032) and male sex (p = 0.034) were associated with higher pleasure ratings in the younger group. For the "urge to move" ratings, type of musical excerpts was associated with ratings in both groups (ps < 0.001), where high-groove music (Janata et al., 2012) receiving higher ratings. Taken together, these results suggest that the "pleasure" aspect of the groove experience in younger individuals was related to dopamine levels in the substantia nigra, but may not be associated with the "urge to move." Thus, pleasure and the urge to move are likely to involve distinct dopaminergic pathways and mechanisms, warranting further investigation.

neuroscience↗

bioRxiv2025

MARK4 enhances stress granule formation and increases tau accumulation

Stress granules (SGs) are membrane-less organelles that are formed in response to cellular stress. SG formation protects cells against stress; however, their dysregulation and longer persistence may disrupt proteostasis. Abnormal activity of Microtubule-affinity regulating kinase 4 (MARK4) has been linked to cancer and Alzheimers disease. Here, we report that MARK4 is a component of SGs and enhances SG formation. MARK4 is found in SGs in mammalian cultured cells and primary neurons with T-cell intracellular antigen 1 (TIA1). MARK4 expression enhances SG formation induced by hydrogen peroxide. The spacer domain of MARK4 mediates its localization to SGs, and its kinase activity is required for the enhancement of SG formation. MARK4 suppresses TIA1 dimerization induced by hydrogen peroxide. Furthermore, we found that MARK4 and TIA1 synergistically promoted tau accumulation in cultured cells, and knockdown of a fly TIA1 homolog suppressed tau toxicity in a Drosophila model. These results indicate that MARK4 regulates TIA1 and SG formation and suggest that MARK4 and TIA1 synergistically contribute to tau toxicity.

cell biology↗

bioRxiv2024

Microglial engulfing of glutamatergic inputs and diminished excitability of D1 medium spiny neurons of the nucleus accumbens by peripheral inflammatory insult

Neuroimmune responses to systemic inflammation can generate anxiodepressive behaviors and psychomotor slowing. The nucleus accumbens (NAc) is a neural hub encoding mood and motivation that contributes to the locomotor and mood dampening effects of neuroinflammation. Dopamine receptor 1 mediums spiny neurons (D1-MSNs) of the NAc regulate locomotor activity, motivated behavior and emotional states and are modulated by microglial reactivity. Here, we evaluated sickness- and anxiety-like behaviors along with D1-MSN activity and microglial responses in the NAc to systemic lipopolysaccharide (LPS) administration. LPS stimulated anxiety-like behavior, blunted locomotion and reduced cFos expression in D1-MSNs of the NAc core and shell of male mice. These effects associated with reduced excitatory inputs (EPSCs) onto D1-MSNs as measured by whole cell patch-clamp. To determine if microglia contribute to changes in MSN activity, Ca2+ imaging of primary cultures containing NAc neurons with or without primary NAc microglia was performed. The presence of microglia decreased the activity of LPS-treated MSNs in response to dopamine and glutamate application and LPS stimulated microglial phagocytosis of MSN processes in co-cultures. Immunohistochemical analyses revealed that in vivo LPS treatment enhanced morphological indices of microglia reactivity and engulfment of vesicular glutamate transporter 1 (VGLUT1) inputs in the NAc. Our results suggest that LPS reduces locomotion and stimulates anxiety via increasing microglia engulfment of excitatory inputs onto D1-MSNs, and highlight changes in NAc microglia phagocytic activity in the behavioral consequences of neuroinflammation.

neuroscience↗

bioRxiv2024

Glucose uptake in pigment glia suppresses tau-induced inflammation and photoreceptor degeneration in Drosophila

Brain inflammation contributes to the pathogenesis of neurodegenerative diseases such as Alzheimers disease (AD). Glucose hypometabolism and glial activation are pathological features seen in AD brains; however, the connection between the two is not fully understood. Using a Drosophila model of AD, we identified that glucose metabolism in glia plays a critical role in neuroinflammation under disease conditions. Expression of human Tau in the retinal cells, including photoreceptor neurons and pigment glia, causes photoreceptor degeneration accompanied by inclusion formation and swelling of the lamina cortex. We found that inclusions are formed by glial phagocytosis, and swelling of the laminal cortex correlates with the expression of antimicrobial peptides. Co-expression of human glucose transporter 3 (GLUT3) with Tau in the retina does not affect tau levels but suppresses these inflammatory responses and photoreceptor degeneration. We also found that expression of GLUT3, specifically in the pigment glia, is sufficient to suppress inflammatory phenotypes and mitigate photoreceptor degeneration in the tau-expressing retina. Our results suggest that glial glucose metabolism contributes to inflammatory responses and neurodegeneration in tauopathy. Summary StatementGlucose uptake into pigment glia suppresses inflammatory responses and photoreceptor degeneration in the fly model of tauopathy.

neuroscience↗

bioRxiv2023

Planar Amorphous Silicon Carbide Microelectrode Arrays for Chronic Recording in Rat Motor Cortex

Chronic implantation of intracortical microelectrode arrays (MEAs) capable of recording from individual neurons can be used for the development of brain-machine interfaces. However, these devices show reduced recording capabilities under chronic conditions due, at least in part, to the brains foreign body response. This creates a need for MEAs that can minimize the foreign body response to enable long-term recording. A potential approach to reduce the foreign body response is the use of ultrathin MEAs. Here, we fabricated ultrathin (cross-sectional area: 160 {micro}m2) amorphous silicon carbide (a-SiC) MEAs with sixteen electrode channels and implanted them into the motor cortex of seven female Sprague-Dawley rats. A-SiC was chosen as the fabrication base for its high chemical stability, good electrical insulation properties, and amenability to thin film fabrication techniques. Electrochemical analysis and neural recordings were performed weekly for 4 months. MEAs were characterized in vitro pre-implantation and in vivo using electrochemical impedance spectroscopy and cyclic voltammetry at 50 mV/s and 50,000 mV/s. Neural recordings were analyzed for single unit activity. At the end of the study, animals were sacrificed for immunohistochemistry analysis. We observed statistically significant, but small, increases in 1 and 30 kHz impedance values and 50,000 mV/s charge storage capacity over the 16-week implantation period. Slow sweep 50 mV/s CV and 1 Hz impedance did not significantly change over time. Impedance values increased from 11.6 M{Omega} to 13.5 M{Omega} at 1 Hz, 1.2 M{Omega} to 2.9 M{Omega} at 1 kHz, and 0.11 M{Omega} to 0.13 M{Omega} at 30 kHz over 16 weeks. The median charge storage capacity of the implanted electrodes at 50 mV/s were 58.1 mC/cm2 on week 1 and 55.9 mC/cm2 on week 16, and at 50,000 mV/s were 4.27 mC/cm2 on week 1 and 5.93 mC/cm2 on week 16. Devices were able to record neural activity from 92% of all active channels at the beginning of the study, At the study endpoint, a-SiC devices were still recording single-unit activity on 51% of electrochemically active electrode channels. In addition, we observed that the signal-to-noise ratio experienced a small decline of only -0.19 per week. We also classified the units as fast and slow spiking based on the trough-to-peak time. Although the overall presence of single units declined, fast and slow spiking units declined at a similar rate. Furthermore, immunohistochemistry showed minimal foreign body response to the a-SiC devices, as highlighted by statistically insignificant differences in activated glial cells between implanted brains slices and contralateral sham slices, as evidenced by GFAP staining. NeuN staining revealed the presence of neural cell bodies close to the implantation site, again statistically not different from a contralateral sham slice. These results support the use of ultrathin a-SiC MEAs for long-term implantation and use in brain-machine interfaces.

bioengineering↗

bioRxiv2022

Identification of inosine monophosphate dehydrogenase as a potential target for anti-monkeypox virus agents

Monkeypox virus (MPXV) is a neglected zoonotic pathogen that caused a worldwide outbreak in May 2022. Given the lack of an established therapy, the development of an anti-MPXV strategy is of vital importance. To identify drug targets for the development of anti-MPXV agents, we screened a chemical library using an MPXV infection cell assay and found that gemcitabine, trifluridine, and mycophenolic acid (MPA) inhibited MPXV propagation. These compounds showed broad-spectrum anti-orthopoxvirus activities and presented lower 90% inhibitory concentrations (0.032-1.40 M) than brincidofovir, an approved anti-smallpox agent. These three compounds have been suggested to target the post-entry step to reduce the intracellular production of virions. Knockdown of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme of guanosine biosynthesis and a target of MPA, dramatically reduced MPXV DNA production. Moreover, supplementation with guanosine recovered the anti-MPXV effect of MPA, suggesting that IMPDH and its guanosine biosynthetic pathway regulate MPXV replication. By targeting IMPDH, we identified a series of compounds with stronger anti-MPXV activity than MPA. These evidences propose that IMPDH is a potential target for the development of anti-MPXV agents. ImportanceMonkeypox is a zoonotic disease caused by infection with the monkeypox virus, and a worldwide outbreak occurred in May 2022. The smallpox vaccine has recently been approved for clinical use against monkeypox in the United States. Although brincidofovir and tecovirimat are drugs approved for the treatment of smallpox by the U.S. Food and Drug Administration, their efficacy against monkeypox has not been established. Moreover, these drugs may present negative side effects. Therefore, new anti-monkeypox virus agents are needed. This study revealed that gemcitabine, trifluridine, and mycophenolic acid inhibited monkeypox virus propagation, exhibited broad-spectrum anti-orthopoxvirus activities. We also suggested inosine monophosphate dehydrogenase as a potential target for the development of anti-monkeypox virus agents. By targeting this molecule, we identified a series of compounds with stronger anti-monkeypox virus activity than mycophenolic acid.

microbiology↗

bioRxiv2022

Potential anti-monkeypox virus activity of atovaquone, mefloquine, and molnupiravir, and their potential use as treatments

Monkeypox virus (MPXV) is a zoonotic orthopoxvirus that causes smallpox-like symptoms in humans and caused an outbreak in May 2022 that led the WHO to declare global health emergency. In this study, from a screening of approved-drug libraries using an MPXV infection cell system, atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 M, which is more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted post-entry process to impair intracellular virion accumulation. Inhibitors of dihydroorotate dehydrogenase, an atovaquones target enzyme, showed conserved anti-MPXV activities. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by seven days at clinically relevant drug concentrations. Moreover, atovaquone and molnupiravir exhibited pan-Orthopoxvirus activity against vaccinia and cowpox viruses. These data suggest that atovaquone would be potential candidates for treating monkeypox.

microbiology↗

bioRxiv2022

Inferring future changes in gene flow under climate change in riverscapes

Global climate change poses a significant threat to the habitat connectivity of cold-water-adapted organisms, leading to species extinctions. Because gene flow is itself a functional connectivity among wild populations, if gene flow is modeled by landscape variables, changes in population connectivity could be predicted. In this study, using a model-based riverscape genetics technique and a hydrological model to estimate water temperature, we inferred the determinants of and future changes in gene flow of the fluvial sculpin Cottus nozawae in the upstream section of the Sorachi River, Hokkaido, Japan. As a result of model selection, stream order, water temperature, slope, and distance were detected as landscape variables affecting the strength of gene flow in each stream section. In particular, the trend of greater gene flow in sections with higher stream order and lower temperature fluctuations or summer water temperatures was pronounced. The map from the model showed that gene flow is overall prevented in small tributaries in the southern area, where spring-fed environments are less prevalent. Estimating future changes in gene flow using future water temperature predictions, genetic connectivity was predicted to decrease dramatically until the end of the 21st century under IPCC representative concentration pathway scenario 8.5 (RCP8.5).

ecology↗

bioRxiv2021

A strategic sampling design revealed the local genetic structure of cold-water fluvial sculpin: a focus on groundwater-dependent water temperature heterogeneity

A key piece of information for ecosystem management is the relationship between the environment and population genetic structure. However, it is difficult to clearly quantify the effects of environmental factors on genetic differentiation because of spatial autocorrelation and analytical problems. In this study, we focused on stream ecosystems and the environmental heterogeneity caused by groundwater and constructed a sampling design in which geographic distance and environmental differences are not correlated. Using multiplexed ISSR genotyping by sequencing (MIG-seq) method, a fine-scale population genetics study was conducted in fluvial sculpin Cottus nozawae, for which summer water temperature is the determinant factor in distribution and survival. There was a clear genetic structure in the watershed. Although a significant isolation-by-distance pattern was detected in the watershed, there was no association between genetic differentiation and water temperature. Instead, asymmetric gene flow from relatively low-temperature streams to high-temperature streams was detected, indicating the importance of low-temperature streams and continuous habitats. The groundwater-focused sampling strategy yielded unexpected results and provided important insights for conservation.

ecology↗