Biology subjects

Nishio, M.

Publications and source records attributed to Nishio, M..

15 recordsLinked to original sources

bioRxiv2026

Primary and higher-order thalamic nuclei make distinct contributions to cortical reorganization in congenital sensory loss

Early sensory loss transforms the functional organization of affected sensory systems, with regions that normally support vision or audition participating in noncanonical perceptual and cognitive functions. Such reorganization requires coordination across distributed networks. Higher-order thalamic nuclei are positioned to support these interactions through their widespread reciprocal cortical connectivity, yet studies of sensory-loss plasticity have focused primarily on cortex and first-order sensory pathways. Here, we combined structural and functional MRI in early blind and early deaf adults to test how reorganization after sensory loss is expressed across thalamocortical networks. In blindness, structural differences were concentrated along the primary input pathway, with reduced lateral geniculate nucleus volume that covaried with areal organization of primary visual cortex. Functional reorganization was more broadly distributed, with visual cortex showing greater similarity with higher-order (association) thalamic nuclei linked to cognitive control, paralleling a shift toward cognitive-control networks across cortex. This pattern was amplified during a nonvisual perceptual judgment task. Across visual cortex, cross-network functional differences were strongest in regions showing the largest structural effects. A related shift toward control-associated higher-order thalamus was observed in deafness, indicating that higher-order thalamic involvement generalizes across sensory modalities. Together, these results indicate that thalamocortical architecture shapes both the developmental consequences of early sensory loss and the capacity for distributed functional reorganization.

neuroscience↗

bioRxiv2026

Developmental links between play behavior and brain network integration

Play is a fundamental aspect of childhood and plays a crucial role in the development of creativity, yet its neural mechanisms remain poorly understood. We tested the hypothesis that more frequent play is associated with stronger functional integration among the default mode network (DMN), executive control network (CN), and salience network (SAL), as these cortical networks have been implicated in creativity in adults. In a preregistered study of infants and toddlers (Study 1; N = 143, 10 months-3 years, 67 boys, Baby Connectome Project), parent-reported play and imitation behaviors increased sharply from 1 to 2 years, and were associated with stronger within-DMN connectivity and DMN-CN coupling, controlling for age, sex, and head motion. In middle childhood (Study 2; N = 108, ages 4-11 years, 52 boys), parent-reported play frequency declined with age, as did cross-network coupling involving SAL. However, children who engaged more frequently in play showed higher DMN-SAL and CN-SAL connectivity. Finally, in a quasi-experimental comparison (Study 3; N = 45; ages 4-12 years, 20 boys), children enrolled in a curriculum that includes guided play (Montessori) showed higher DMN-SAL and DMN-CN connectivity than peers in traditional schools, suggesting that pedagogies that center child-led exploration might enable protracted brain network integration. Across these three studies, play was consistently associated with greater integration among DMN, SAL, and CN, a pattern previously linked to creativity in adults. Our findings offer a potential mechanism linking childhood play to later creativity through its role in supporting brain integration during development. Public Significant StatementO_LIPlay is widely believed to nurture childrens creativity, yet the brain mechanisms behind this link are not well understood. C_LIO_LIAcross three studies from infancy to middle childhood, we found that more frequent play was associated with stronger integration among brain networks tied to imagination, attention, and control. C_LIO_LIThese findings suggest that play may help build the neural foundation for later creative thinking. C_LI

neuroscience↗

bioRxiv2026

Cascading periods of language-related brain plasticity across early childhood

Language is thought to have multiple sensitive periods in early childhood, but the neural basis of these sensitive periods is less understood. We leverage advances in in-vivo neuroimaging of plasticity, measuring the neural inhibition across the brain via Hurst exponent. Using two large datasets with children ages 10 months to 18 years (Baby Connectome Project: 10m-3y6m, 458 observations across n=222 children; Human Connectome Project-Development: 5-18y, n=437), we characterize the development of the Hurst exponent in language-related brain regions. In early childhood, Hurst increases in temporal and frontal language areas, and posterior regions develop earlier than anterior regions. In contrast, thalamic Hurst plateaus earlier, perhaps underlying the earliest language-related sensitive periods. Children with higher language-related skills show slower increases in cortical Hurst in early childhood, suggesting protracted plasticity. Later in childhood, cortical Hurst plateaus around age 9, suggesting a potential neural mechanism for age-related declines syntax learning. These results highlight a potential neural basis for cascading language-related sensitive periods. Research highlightsO_LILanguage has multiple, cascading sensitive periods, but the neural basis of these sensitive periods is not well-understood. C_LIO_LIWe leverage advances in in-vivo neuroimaging to quantify plasticity in language-related brain regions across childhood via Hurst, a measure of inhibition. C_LIO_LIWe find that Hurst increases (plasticity decreases) in a graded fashion, with posterior regions maturing before anterior regions. C_LIO_LIThalamic hurst plateaus in the first year of life, while cortical Hurst plateaus at age 9, suggesting a neural basis for distinct language-related sensitive periods. C_LI

developmental biology↗

bioRxiv2025

Niche-targeted therapy via YAP/TAZ activation enhances hematopoietic regeneration

The distinctive milieu of the bone marrow (BM), known as the BM niche, supports hematopoietic stem cells (HSCs) and serves as a foundation for hematopoietic regeneration. Myeloablative stress disrupts not only hematopoietic stem and progenitor cells but also essential BM niche components, including endothelial cells (ECs) and mesenchymal stromal cells (MSCs); disruption of the latter impairs efficient hematopoietic recovery. However, therapeutic strategies targeting niche restoration remain largely underdeveloped. Here, we demonstrate that the Hippo pathway effectors YAP/TAZ are critical for enabling ECs and MSCs to respond to BM injury, and that YAP/TAZ activation accelerates BM niche recovery, thereby promoting hematopoietic regeneration. We found that YAP/TAZ are rapidly activated in both MSCs and ECs following myeloablative stress, maintaining MSC multipotency and orchestrating vascular remodeling. Mechanistically, YAP/TAZ function as transcriptional hubs in MSCs, regulating key transcriptional factors such as Ebf1 and Ebf3. This regulation preserves MSC identity by preventing osteogenic and fibrogenic differentiation while promoting the expression of hematopoietic factors such as Cxcl12 and angiogenic factors. In parallel, YAP/TAZ signaling in ECs facilitates pro-angiogenic responses and drives sinusoidal vessel remodeling after injury. These YAP/TAZ-mediated niche responses are essential for HSC retention and hematopoietic regeneration following diverse myelosuppressive therapies. Notably, pharmacological activation of YAP/TAZ enhances BM niche reorganization and augments hematopoietic regeneration following myeloablative therapies. These findings establish YAP/TAZ as central regulators of BM niche resilience, providing a rationale for niche-targeted therapeutic strategies to enhance hematopoietic regeneration. Key points{blacksquare} YAP/TAZ enable BM niche cells to sense injury and restore their structure and function, thereby promoting hematopoietic regeneration. {blacksquare}Pharmacological activation of YAP/TAZ enhances BM niche resilience and accelerates hematopoietic recovery after myelosuppressive therapies.

cell biology↗

bioRxiv2025

Alcohol impacts an fMRI marker of neural inhibition in humans and rodents.

Acute alcohol consumption leads to cognitive and behavioral disinhibition that increase health and social risks, such as traffic fatalities and violence. Although rodent studies have shown that alcohol affects inhibitory neuronal activity, its relevance to humans remains largely unexplored. Here, we used the Hurst exponent--an fMRI-based marker of neural inhibition--to examine alcohols effects in both rats and humans. In rats, acute alcohol administration significantly reduced the cortical Hurst exponent, suggesting a decrease in inhibitory neuronal activity. This reduction was strongly correlated with the spatial distribution of GABAA receptor expression, highlighting the key role of these receptors in mediating alcohols effects. Similarly, in humans, acute alcohol consumption reduced the cortical Hurst exponent, especially in brain regions with high GABAA receptor expression. Our findings provide cross-species in vivo evidence that acute alcohol consumption modulates neural inhibition, offering new insights into the neural mechanisms underlying alcohol-induced behavioral modulation.

neuroscience↗

bioRxiv2025

Myelination across cortical hierarchies and depths in humans and macaques

Myelination is fundamental to brain function, enabling rapid neural communication and supporting neuroplasticity throughout the lifespan. While hierarchical patterns of myelin maturation across the cortical surface are well-documented in humans, it remains unclear which features reflect evolutionarily conserved developmental processes versus human-characteristic adaptations. Moreover, the laminar development of myelin across the primate cortical surface, which shapes hierarchies and supports functions ranging from sensory integration to network communication, has been largely unexplored. Using neuroimaging to measure the T1-weighted/T2-weighted ratio in tissue contrast as a proxy for myelin content, we systematically compared depth-dependent trajectories of myelination across the cortical surface in humans and macaques. We identified a conserved "inside-out" pattern, with deeper layers exhibiting steeper increases in myelination and earlier plateaus than superficial layers. This depth-dependent organization followed a hierarchical gradient across the cortical surface, progressing from early maturation in sensorimotor regions to prolonged development in association areas. Humans exhibited a markedly extended timeline of myelination across both cortical regions and depths compared to macaques, allowing for prolonged postnatal plasticity across the entire cortical hierarchy -- from sensory and motor processing to higher-order association networks. This extended potential for plasticity may facilitate the shaping of cortical circuits through postnatal experience in ways that support human-characteristic perceptual and cognitive capabilities.

developmental biology↗

bioRxiv2024

The Hurst exponent as a marker of inhibition in the developing brain

The maturation of inhibitory neurons is crucial for regulating plasticity in developing brains. Previous work using computational models has suggested that the Hurst exponent, the decay in power over frequency, reflects inhibition, but empirical data supporting this link is sparse. Here, we took a cross-species approach to validating the Hurst exponent of fMRI as a marker of inhibition, then characterized the development of the Hurst exponent in childhood. We found significant spatial correlations between the Hurst exponent and ex vivo parvalbumin mRNA expression in human children and adults, and between the Hurst exponent and parvalbumin-positive cell counts in mice. We identified a plateau in the mRNA expression by late childhood, aligning with the Hurst exponent plateau in both humans and rats. In sum, this work suggests that the Hurst exponent can be used to study the development of inhibition in vivo, and in the future, to understand individual differences in plasticity.

neuroscience↗

bioRxiv2024

Transcriptome Analysis Identified SPP1+ Monocytes as a Key in Extracellular Matrix Formation in Thrombi

Thrombi follow various natural courses. They are known to become harder over time and may persist long-term; some of them can also undergo early spontaneous dissolution and disappearance. Hindering thrombus stability may contribute to the treatment of thrombosis and the prevention of embolisms. However, the detailed mechanisms underlying thrombus maturation remain unknown. Using RNA sequencing, we revealed the transcriptional landscape of thrombi retrieved from the cerebral vessels and identified SPP1 as a hub gene related to extracellular matrix formation. Immunohistochemistry confirmed the expression of osteopontin in monocytes/macrophages in the thrombi, particularly in older thrombi. Single-cell RNA sequencing of thrombi from the pulmonary artery revealed increased communication between SPP1-high monocytes/macrophages and fibroblasts. These data suggest that SPP1-high monocytes/macrophages play a crucial role in extracellular matrix formation in thrombi and provide a basis for new antithrombotic therapies targeting thrombus maturation. TeaserSPP1+ monocytes play a key role in thrombus maturation, which can be a potential target for novel antithrombotic therapies.

molecular biology↗

bioRxiv2024

The differential effect of optogenetic serotonergic manipulation on sustained motor actions and stationary waiting for future rewards in mice

Serotonin is an essential neuromodulator that affects behavioral and cognitive functions. Previous studies have shown that activation of serotonergic neurons in the dorsal raphe nucleus (DRN) promotes patience to wait for future rewards. However, it is still unclear whether serotonergic neurons also regulate persistence to act for future rewards. Here we used optogenetic activation and inhibition of DRN serotonergic neurons to examine their effects on sustained motor actions for future rewards. We trained mice to perform stationary waiting and repeated lever-pressing tasks with variable reward delays and tested effects of optogenetic activation and inhibition of DRN serotonergic neurons on task performance. Interestingly, in the lever-pressing task, mice tolerated longer delays as they repeatedly pressed a lever than in the stationary waiting task, suggesting that lever-pressing actions may not simply be costly, but may also be subjectively rewarding. Optogenetic activation of DRN serotonergic neurons prolonged waiting in the stationary waiting task, consistent with previous studies, but it did not affect lever pressing time or numbers. While optogenetic inhibition decreased waiting, it did not affect lever pressing time or numbers. In generalized linear model analysis that incorporated the time during each session and the number of sessions, however, optogenetic activation negatively affected the number and the speed of lever pressing. These results revealed that the necessity of motor actions may increase motivation for delayed rewards and that DRN serotonergic neurons more significantly promote stationary waiting rather than persistent motor actions for future rewards.

animal behavior and cognition↗

bioRxiv2024

Microevolution toward loss of photosynthesis: Mutations promoting dark-heterotrophic growth and suppressing photosynthetic growth in cyanobacteria

The prevalence of parasitic plants suggests frequent evolution of photosynthetic capacity loss in the natural environment. However, no studies have observed such evolutionary events as a loss of photosynthetic capacity. Herein, we report mutations that lead to a loss or decrease in photosynthetic growth capacity of dark-adapted variants of the cyanobacterium Leptolyngbya boryana, which can grow heterotrophically even in the dark. We isolated 28 dark-adapted variants through long-term cultivation (7-49 months) under dark-heterotrophic conditions. All variants showed significantly faster dark-heterotrophic growth than the parental strains, accompanied by the loss of photosynthetic growth capacity in 15 variants. Genome resequencing of the variants revealed that 19 of the 28 variants carried various mutations in a common single gene (LBDG_21500) encoding a protein phosphatase 2C (PP2C) RsbU that is involved in the partner switching system (PSS). Phenotypic and transcriptomic analyses of a LBDG_21500-knockout mutant suggested that the PSS, including LBDG_21500, is involved in the global transcriptional regulation of various genes under both photoautotrophic and dark-heterotrophic conditions. We propose the renaming of LBDG_21500 to phsP (phototrophic-heterotrophic switching phosphatase). Our results imply that mutations in the global transcriptional regulatory system serve as the first evolutionary step leading to the loss of photosynthetic capacity. ImportancePhotosynthetic organisms that grow using minimal resources: light, water, and CO2, support most heterotrophic organisms as producers on the Earth. When photosynthetic organisms thrive over long generations under environments where organic compounds are readily available, they may lose the photosynthetic capacity because of the relief of selective pressure to maintain photosynthesis. The prevalence of parasitic plants in the natural environment supports this idea. However, there have been no actual observations of evolutionary processes leading to a loss of photosynthetic growth capacity. The significance of our research is in observing microevolution of a cyanobacterium through a long-term cultivating under dark heterotrophic conditions. In particular, the high frequency of mutations to a gene involved in the global transcriptional regulatory system suggests that such mutations in regulatory systems are regarded as an example of the initial evolutionary processes toward complete loss of photosynthesis.

evolutionary biology↗

bioRxiv2024

Medial prefrontal cortex suppresses reward-seeking behavior with risk of positive punishment by reducing sensitivity to reward

Reward-seeking behavior is frequently associated with risk of punishment. There are two types of punishment: positive, resulting in an unpleasant outcome, and negative, resulting in omission of a reinforcing outcome. Although the medial prefrontal cortex (mPFC) is important in avoiding punishment, whether it is important for avoiding both positive and negative punishment and how it contributes to such avoidance are not clear. In this study, we trained male mice to perform decision-making tasks under the risks of positive (air-puff stimulus) and negative (reward omission) punishment. We found that pharmacological inactivation of mPFC enhanced the reward-seeking choice under the risk of positive, but not negative, punishment. In reinforcement learning models, this behavioral change was well-explained by hypersensitivity to the reward, rather than a decrease in the strength of aversion to punishment. Our results suggest that mPFC suppresses reward-seeking behavior by reducing sensitivity to reward under the risk of positive punishment.

animal behavior and cognition↗

bioRxiv2021

Heterozygous loss of ZBTB38 leads to early embryonic lethality in mice via suppressing Nanog and Sox2

Mammalian DNA methylation is an epigenetic modification which is involved in various biological processes, including gene expression regulation. In mice, methyltransferases are responsible for DNA methylation, which are critical for early embryogenesis. However, the significance of methyl-CpG binding proteins (MBPs) that bind methylated CpG remains largely unknown. We previously demonstrated that ZBTB38/CIBZ-a zinc finger type of MBP-is required for ES cell proliferation by positively regulating Nanog expression. However, the physiological function of ZBTB38 remains unclear. In this study, we generated conditional ZBTB38 knockout mice using Cre-loxP technology. Unexpectedly, our results showed that germline loss of the ZBTB38 single allele resulted in decreased epiblast cell proliferation and increased apoptosis shortly after implantation, leading to early embryonic lethality. We found that heterozygous loss of ZBTB38 reduced the expression of Nanog, Sox2, and the genes responsible for epiblast proliferation, differentiation, and cell viability. Despite this lethal phenotype, ZBTB38 is dispensable for ES cell establishment and identity. Together, these findings indicate that ZBTB38 is essential for early embryonic development, providing new insights into the roles of MBP in implantation.

developmental biology↗

bioRxiv2020

Human iPSC-derived hypertrophic chondrocytes reveal a mutation-specific unfolded protein response in chondrodysplasias

Chondrodysplasias are hereditary diseases caused by mutations in the components of growth cartilage. Although the unfolded protein response (UPR) has been identified as a key disease mechanism in mouse models, no suitable in vitro system has been reported to analyze the pathology in humans. Here, utilizing human chondrodysplasia-specific iPSCs, we examined the UPR caused by mutations in MATN3 or COL10A1. In growth plate-like structures formed from iPSC-derived sclerotome in vivo, the hypertrophic zone was disrupted, and induced hypertrophic chondrocytes in vitro showed varying levels of ER stress depending on the mutation. Autophagy inducers and chemical chaperones succeeded in reducing ER stress only in some mutants, while transcriptome analysis revealed many mutation-specific changes in genes involved in apoptosis, metabolism, and protein trafficking. In this way, our system has allowed the precise evaluation of the UPR caused by each mutation, opening up new avenues for treatment of individual chondrodysplasia patients.

cell biology↗

bioRxiv2019

Tunings for leapfrog integration of Hamiltonian Monte Carlo for estimating genetic parameters

A Hamiltonian Monte Carlo algorithm is a Markov Chain Monte Carlo method that is considered more effective than the conventional Gibbs sampling method. Hamiltonian Monte Carlo is based on Hamiltonian dynamics, and it follows Hamiltons equations, which are expressed as two differential equations. In the sampling process of Hamiltonian Monte Carlo, a numerical integration method called leapfrog integration is used to approximately solve Hamiltons equations, and the integration is required to set the number of discrete time steps and the integration stepsize. These two parameters require some amount of tuning and calibration for effective sampling. In this study, we applied the Hamiltonian Monte Carlo method to animal breeding data and identified the optimal tunings of leapfrog integration for normal and inverse chi-square distributions. Then, using real pig data, we revealed the properties of the Hamiltonian Monte Carlo method with the optimal tuning by applying models including variance explained by pedigree information or genomic information. Compared with the Gibbs sampling method, the Hamiltonian Monte Carlo method had superior performance in both models. We have provided the source codes of this method written in the R language.

genetics↗

bioRxiv2019

Modeling the Human Segmentation Clock with Pluripotent Stem Cells

Pluripotent stem cells (PSCs) have increasingly been used to model different aspects of embryogenesis and organ formation1. Despite recent advances in the in vitro induction of major mesodermal lineages and mesoderm-derived cell types2,3, experimental model systems that can recapitulate more complex biological features of human mesoderm development and patterning are largely missing. Here, we utilized induced pluripotent stem cells (iPSCs) for the stepwise in vitro induction of presomitic mesoderm (PSM) and its derivatives to model distinct aspects of human somitogenesis. We focused initially on modeling the human segmentation clock, a major biological concept believed to underlie the rhythmic and controlled emergence of somites, which give rise to the segmental pattern of the vertebrate axial skeleton. We succeeded to observe oscillatory expression of core segmentation clock genes, including HES7 and DKK1, and identified novel oscillatory genes in human iPSC-derived PSM. We furthermore determined the period of the human segmentation clock to be around five hours and showed the presence of dynamic traveling wave-like gene expression within in vitro induced human PSM. Utilizing CRISPR/Cas9-based genome editing technology, we then targeted genes, for which mutations in patients with abnormal axial skeletal development such as spondylocostal dysostosis (SCD) (HES7, LFNG and DLL3) or spondylothoracic dysostosis (STD) (MESP2) have been reported. Subsequent analysis of patient-like iPSC knock-out lines as well as patient-derived iPSCs together with their genetically corrected isogenic controls revealed gene-specific alterations in oscillation, synchronization or differentiation properties, validating the overall utility of our model system, to recapitulate not only key features of human somitogenesis but also to provide novel insights into diseases associated with the formation and patterning of the human axial skeleton.

developmental biology↗