Biology subjects

Hashimoto, H.

Publications and source records attributed to Hashimoto, H..

At least 19 recordsLinked to original sources

bioRxiv2026

The vagus nerve drives cognitive function through the default mode network

The afferent vagus nerve transmits interoceptive signals to the brain but a systematic understanding of how vagal signals affect brain-wide neuronal dynamics remains elusive. Here, comprehensive spatiotemporal analyses across the entire mouse brain revealed that vagus nerve stimulation activated neuronal ensembles within the default mode network (DMN). In contrast, vagal-independent mechanisms predominantly affected the salience network. The vagal-DMN association was mediated by locus coeruleus neuronal subpopulations. Selective activation or silencing of vagal-responsive DMN neuronal ensembles replicated or abolished VNS-induced enhancement of cognitive behaviors and progressive problem-solving behaviors. These findings establish a unifying framework for how the vagus nerve drives cognitive functions by engaging the DMN.

neuroscience↗

bioRxiv2026

Allele-Resolved Hybrid Embryos Reveal the Fates of Regulatory Divergence

Developmental programs can remain conserved despite extensive regulatory divergence, but how evolved regulatory differences are transmitted through embryonic lineages remains unclear. Here we generate a time resolved, allele resolved single-cell atlas of hybrid embryogenesis between Ciona intestinalis and Ciona savignyi, enabling regulatory differences accumulated between species to be followed across defined developmental lineages. We find that allelic differences are maintained or remodeled in lineage specific ways, with their outcomes associated with regulatory origin and allele specific chromatin accessibility. Across multiple tissues, allelic divergence increases along gene regulatory network (GRN) hierarchy from upstream regulators toward downstream regulators and effector genes. In the cardiopharyngeal lineage, Foxf illustrates how allelic dominance provides partial compensation for highly divergent regulatory sequences and thereby contributes to developmental system drift. Together, our results reveal that regulatory divergence is dynamically sorted during development according to lineage context and GRN hierarchy. This lineage resolved framework provides a developmental basis for understanding how extensive regulatory evolution can accumulate while conserved embryonic programs are maintained.

developmental biology↗

bioRxiv2026

Sequence-intrinsic barriers define a class of translation-restricted uORFs in the human genome

Ribosome profiling has revealed widespread translation of upstream open reading frames (uORFs) within the human 5' untranslated region, greatly expanding the apparent coding potential of the genome. However, despite pervasive translational activity, uORF-encoded proteins (uORFps) are only rarely detected by proteomic approaches, creating a major unresolved discrepancy between translation and protein accumulation. Here, we systematically quantified the intracellular accumulation of 111 evolutionarily conserved human uORFps using a unified reporter platform. Although we found that most conserved uORFps accumulated at extremely low levels despite robust transcript expression, protein length emerged as the strongest baseline predictor of this low accumulation. Intriguingly, a subset of conserved uORFs remained poorly accumulated even after experimental extension with a C-terminal EGFP tag, defining a distinct class of translation-restricted uORFs. Sequence and structural analysis of these translation-restricted uORFs revealed a cooperative enrichment of basic amino acids and stable local RNA secondary structures. Synonymous substitutions designed to disrupt these RNA structures substantially restored protein accumulation, demonstrating a major contribution of local transcript stratification to this translation-restricted phenotype. Using these identified rules, we developed a multivariable predictive model that classified 1,432 translation-restricted uORFs across the human transcriptome. Genes harboring these predicted translation-restricted uORFs exhibited significantly reduced downstream translation efficiency and elevated sequence conservation, demonstrating that these sequence-encoded barriers are under purifying selection to act as cis-regulatory elements scattered across the human transcriptome. Together, our findings identify a conserved class of human uORFs that encode intrinsic barriers to productive translation and provide a rigorous framework for understanding how noncanonical coding sequences shape the human proteome.

genetics↗

bioRxiv2026

Learning-related population dynamics in right and left dorsal premotor cortex during typing skill acquisition

Advances in intracortical brain-computer interface (BCI) technology have enabled increasingly sophisticated communication paradigms, including for decoding intended speech and touch typing. However, the methods by which intracortical neural population dynamics are engaged during practice-related skill acquisition in humans remain poorly understood. Here, we examined learning-related changes in neural activity during motor skill acquisition in a right-handed BCI clinical trial participant with tetraplegia, with intracortical microelectrode arrays placed in the bilateral dorsal precentral gyri (Brodmann area 6d), who learned how to type using a BCI-enabled typing interface. While decoder performance remained stable across sessions, typing speed improved with practice, indicating practice-related skill acquisition. Over weeks, low-dimensional neural population activity became progressively more compact, and this compaction was strongly associated with faster typing, independent of decoder accuracy. Although this compaction was observed bilaterally in 6d, firing-rate modulation and cross-session generalization were selectively enhanced in left 6d. Moreover, neural population changes across sessions were largely accounted for by canonical correlation analysis in right 6d, but only partially accounted for in left 6d. Together, these findings demonstrate that human intracortical neuro-motor skill acquisition related to intended typing engages shared bilateral population-level dynamics, with additional learning-related changes selectively expressed in dominant dorsal premotor cortex.

neuroscience↗

bioRxiv2025

Decoding intended speech with an intracortical brain-computer interface in a person with longstanding anarthria and locked-in syndrome

Intracortical brain-computer interfaces (iBCIs) for decoding intended speech have provided individuals with ALS and severe dysarthria an intuitive method for high-throughput communication. These advances have been demonstrated in individuals who are still able to vocalize and move speech articulators. Here, we decoded intended speech from an individual with longstanding anarthria, locked-in syndrome, and ventilator dependence due to advanced symptoms of ALS. We found that phonemes, words, and higher-order language units could be decoded well above chance. While sentence decoding accuracy was below that of demonstrations in participants with dysarthria, we are able to attain an extensive characterization of the neural signals underlying speech in a person with locked-in syndrome and through our results identify several directions for future improvement. These include closed-loop speech imagery training and decoding linguistic (rather than phonemic) units from neural signals in middle precentral gyrus. Overall, these results demonstrate that speech decoding from motor cortex may be feasible in people with anarthria and ventilator dependence. For individuals with longstanding anarthria, a purely phoneme-based decoding approach may lack the accuracy necessary to support independent use as a primary means of communication; however, additional linguistic information embedded within neural signals may provide a route to augment the performance of speech decoders.

neuroscience↗

bioRxiv2025

Noradrenergic efferent subsystems that gate traumatic social learning

Individuals experience varying magnitudes of stress in their daily lives. Although stress responses facilitate adaptive processes to cope with changing environments, severe stress can lead to traumatic learning and anxiety disorders. However, the neuronal mechanisms underlying the influence of stress severity on these processes remain unclear. Here, we show that traumatic social stress engages anatomically distinct locus coeruleus noradrenergic (LCNA) subpopulations that exhibit dynamic responses scaled to aversive salience. Using whole-brain activity and axonal projection mappings, we identified projectome subtypes of LCNA neurons, which are differentially recruited by single versus consecutive aversive social experiences. While hippocampus-projecting LCNA neurons responded to general social contacts, thalamus-projecting LCNA neurons tracked the aversive salience of social stimuli. Functional manipulations revealed a bidirectional role of thalamus-projecting LCNA neurons in social avoidance learning. These findings reveal the functional architecture of LCNA subsystems that regulate traumatic social learning via dynamic scaling to aversive salience.

neuroscience↗

bioRxiv2023

Endothelial-fibroblast interactions during Scarb1 accelerate heart failure

Endothelial cells (ECs) maintain cardiac homeostasis and EC dysfunction causes heart failure progression. Moreover, pathological changes occur via interactions between multiple cells, including ECs. Here, we conducted single-cell RNA-seq analysis of non-cardiomyocytes in mouse hearts during heart failure progression to elucidate the pathological changes in ECs and fibroblasts (FBs) mediated by cell-cell interactions. We show that capillary and arterial ECs exhibit mesenchymal gene expression changes with heart failure progression, indicating that endothelial-to-mesenchymal transition (EndMT) is a major pathological alteration in ECs. We also found that the interaction between ECs and FBs was enriched during heart failure, particularly when involving Scavenger Receptor Class B Member 1 (Scarb1) in ECs. FBs induce mesenchymal gene alterations in ECs in the EC-FB co-culture system, which is inhibited by blocking SCARB1. RNA-seq analysis showed that administration of a SCARB1 inhibitor blocked mesenchymal gene expression, and inflammatory changes, suggesting that the EC-FB interaction via Scarb1 is important for EndMT induction in ECs. Systemic administration of a SCARB1 inhibitor attenuated heart failure progression and cardiac fibrosis. EC-specific Scarb1 knockout mouse showed improved cardiac function, suggesting a crucial role of Scarb1 in heart failure progression. Our results suggest that Scarb1 is a promising candidate for novel heart failure treatments that target ECs.

molecular biology↗

bioRxiv2023

Volumetric trans-scale imaging of massive quantity of heterogeneous cell populations in centimeter-wide tissue and embryo

We established a volumetric trans-scale imaging system with an ultra-large field-of-view (FOV) that enables simultaneous observation of millions of cellular dynamics in centimeter-wide three-dimensional (3D) tissues and embryos. Using a custom-made giant lens system with a magnification of 2x and a numerical aperture (NA) of 0.25, and a CMOS camera with more than 100 megapixels, we built a trans-scale scope AMATERAS-2, and realized fluorescence imaging with a transverse spatial resolution of approximately 1.1 {micro}m across an FOV of approximately 1.5 x 1.0 cm2. The 3D resolving capability was realized through a combination of optical and computational sectioning techniques tailored for our low-power imaging system. We applied the imaging technique to 1.2 cm-wide section of mouse brain, and successfully observed various regions of the brain with sub-cellular resolution in a single FOV. We also performed time-lapse imaging of a 1-cm-wide vascular network during quail embryo development for over 24 hours, visualizing the movement of over 4.0 x 105 vascular endothelial cells and quantitatively analyzing their dynamics. Our results demonstrate the potential of this technique in accelerating production of comprehensive reference maps of all cells in organisms and tissues, which contributes to understanding developmental processes, brain functions, and pathogenesis of disease, as well as high-throughput quality check of tissues used for transplantation medicine.

developmental biology↗

bioRxiv2023

Pax3 and Pax7 function in combination with Mitf to generate melanophores and xanthophores in medaka and zebrafish

Neural crest cells generate numerous derivatives, including pigment cells, and are a model for studying how fate specification from multipotent progenitors is controlled. In mammals, the core gene regulatory network (GRN) for melanocytes (their only pigment cell-type) contains three transcription factors Sox10, Pax3 and Mitf, with the latter considered a master regulator of melanocyte development. In teleosts, which have three to four pigment cell types (melanophores, iridophores and xanthophores, plus leucophores e.g. in medaka), GRNs governing fate specification are poorly understood, although Mitf function is considered conserved. Here, we show that the regulatory relationships between Sox10, Pax3 and Mitf are conserved in zebrafish, but the role for Mitf is more complex than previously emphasised, affecting xanthophore development too. Similarly, medaka Mitf is necessary for melanophore, xanthophore and leucophore formation. Furthermore, expression patterns and mutant phenotypes of pax3 and pax7 suggest that Pax3 and Pax7 act sequentially, activating mitf expression. Pax7 modulates Mitf function, driving co-expressing cells to differentiate as xanthophores and leucophores rather than melanophores. We propose that pigment cell fate specification is better considered as resulting from the combinatorial activity of Mitf with other transcription factors.

developmental biology↗

bioRxiv2022

Structure of the pre-mRNA leakage 39-kDa proteinreveals a single domain of integrated zf-C3HC and Rsm1 modules

In Saccharomyces cerevisiae, the pre-mRNA leakage 39-kDa protein (ScPml39) was reported to retain unspliced pre-mRNA prior to export through nuclear pore complexes (NPCs). Pml39 homologs outside the Saccharomycetaceae family are currently unknown, and mechanistic insight into Pml39 function is lacking. Here we determined the crystal structure of ScPml39 at 2.5 [A] resolution to facilitate the discovery of orthologs beyond Saccharomycetaceae, e.g. in Schizosaccharomyces pombe or human. The crystal structure revealed integrated zf-C3HC and Rsm1 modules, which are tightly associated through a hydrophobic interface to form a single domain. Both zf-C3HC and Rsm1 modules belong to the Zn-containing BIR (Baculovirus IAP repeat)-like super family, with key residues of the canonical BIR domain being conserved. Features unique to the Pml39 modules refer to the spacing between the Zn-coordinating residues, giving rise to a substantially tilted helix aC in the zf-C3HC and Rsm1 modules, and an extra helix AB in the Rsm1 module. Conservation of key residues responsible for its distinct features identifies S. pombe Rsm1 and Homo sapiens NIPA/ZC3HC1 as structural orthologs of ScPml39. Based on the recent functional characterization of NIPA/ZC3HC1 as a scaffold protein that stabilizes the nuclear basket of the NPC, our data suggest an analogous function of ScPml39 in S. cerevisiae.

biochemistry↗

bioRxiv2021

Frequency band coupling with high-frequency activities during seizures shifts from θ band in tonic phase to δ band in clonic phase

ObjectiveTo clarify variations in the relationship between high-frequency activities (HFAs) and low-frequency bands from the tonic to the clonic phase in focal to bilateral tonic-clonic seizures (FBTCS), using phase-amplitude coupling. MethodsThis retrospective study enrolled six patients with drug-resistant focal epilepsy who underwent intracranial electrode placement for presurgical invasive electroencephalography at Osaka University Hospital (July 2018-July 2019). We used intracranial electrodes to record seizures in focal epilepsy (11 FBTCS). The magnitude of synchronization index (SIm) and receiver-operating characteristic (ROC) analysis were used to analyze the coupling between HFA amplitude (80-250 Hz) and lower frequencies phase. ResultsThe {theta} (4-8 Hz)-HFA SIm peaked in the tonic phase, whereas the {delta} (2-4 Hz)-HFA SIm peaked in the clonic phase. ROC analysis indicated that the {delta}-HFA SIm discriminated well the clonic from the tonic phase. ConclusionsThe main low-frequency band modulating the HFA shifted from the {theta} band in the tonic phase to the {delta} band in the clonic phase. SignificanceIn FBTCS, low-frequency band coupling with HFA amplitude varies temporally. Especially, the {delta} band is specific to the clonic phase. These results suggest dynamically neurophysiological changes in the thalamus or basal ganglia throughout FBTCS. HighlightsO_LIThe {theta} band (4-8 Hz) was mainly coupled with high-frequency activity (HFA) in the tonic phase of focal to bilateral tonic-clonic seizures (FBTCS). C_LIO_LIThe {delta} band (2-4 Hz) was mainly coupled with HFA in the clonic phase of FBTCS. C_LIO_LIThe magnitude of the synchronization index related to {delta}-HFA phase-amplitude coupling discriminated well the clonic from the tonic phase. C_LI

physiology↗

bioRxiv2021

Optical and computational dissection of emergent prefrontal rewiring to encode fear memory

Associative learning is crucial for adapting to environmental changes. The encoding of associative learning involves the dorso-medial prefrontal cortex (dmPFC), and is underpinned by interactions within the resident neuronal population. However, the nature of this population coding is poorly understood. Here we developed a pipeline for computational dissection and longitudinal two-photon imaging of neural population activities in the mouse dmPFC during fear-conditioning procedures, enabling us to detect learning-dependent changes in the dmPFC topology. Through regularized regression methods and graphical modeling, we found fear conditioning organized neuronal ensembles encoding conditioned responses (CR), with enhancing their coactivity, functional connectivity, and association with conditioned stimuli (CS). This suggests that fear conditioning drives dmPFC reorganization to generate novel associative circuits for CS-to-CR transformation. Importantly, neurons strongly responding to unconditioned stimuli (US) during conditioning anterogradely became a hub of the CR ensemble. Altogether, we demonstrate learning-dependent dynamic modulation of population coding structured on an activity-dependent hub-network formation within the dmPFC. TeaserOptical and computational dissection uncovered how prefrontal cortical networks are rewired to encode new associative memory Significance statementAnimals learn to adapt to changing environments. Associative learning is one of the simplest types of learning that has been intensively studied over the past century. Recent development in molecular, genetic, and optogenetic methods has enabled the identification of a neural population encoding the associative memory in the brain. However, it remains unclear how information is stored and processed by the neural population to encode and retrieve the associative memory. To investigate the nature of this population coding, we developed an optical and computational dissection method, demonstrating how associative learning drives reorganization of the neural network in the dorso-medial prefrontal cortex and generates novel circuits for associative memory and signal transformation.

neuroscience↗

bioRxiv2021

Functional cortical localization of the tongue using corticokinematic coherence with a deep learning-assisted motion capture system

Measuring the corticokinematic coherence (CKC) between magnetoencephalographic and movement signals using an accelerometer can evaluate the functional localization of the primary sensorimotor cortex (SM1) of the upper limbs. However, it is difficult to determine the tongue CKC because an accelerometer yields excessive magnetic artifacts. We introduce and validate a novel approach for measuring the tongue CKC using a deep learning-assisted motion capture system with videography, and compare it with an accelerometer in a control task measuring finger movement. Twelve healthy volunteers performed rhythmical side-to-side tongue movements in the whole-head magnetoencephalographic system, which were simultaneously recorded using a video camera and examined offline using a deep learning-assisted motion capture system. In the control task, right finger CKC measurements were simultaneously evaluated via motion capture and an accelerometer. The right finger CKC with motion capture was significant at the movement frequency peaks or its harmonics over the contralateral hemisphere; the motion-captured CKC was 84.9% similar to that with the accelerometer. The tongue CKC was significant at the movement frequency peaks or its harmonics over both hemispheres, with no difference between the left and right hemispheres. The CKC sources of the tongue were considerably lateral and inferior to those of the finger. Thus, the CKC based on deep learning-assisted motion capture can evaluate the functional localization of the tongue SM1. In this approach, because no devices are placed on the tongue, magnetic noise, disturbances due to tongue movements, risk of aspiration of the device, and risk of infection to the experimenter are eliminated.

neuroscience↗

bioRxiv2021

Serotonergic neural network related to behavioral inhibition system

Rationale The tendency to avoid punishment, called behavioral inhibition system, is an essential aspect of motivational behavior. Behavioral inhibition system is related to negative affect, such as anxiety, depression and pain, but its neural basis has not yet been clarified. Objectives To clarify the association between individual variations in behavioral inhibition system and brain 5-HT2A receptor availability and specify which brain networks were involved in healthy male subjects, using [18F]altanserin positron emission tomography and resting-state functional magnetic resonance imaging. Results Behavioral inhibition system score negatively correlated with 5-HT2A receptor availability in anterior cingulate cortex. A statistical model indicated that the behavioral inhibition system score was associated with 5-HT2A receptor availability, which was mediated by the functional connectivity between anterior cingulate cortex and left middle frontal gyrus, both of which involved in the cognitive control of negative information processing. Conclusions Individuals with high behavioral inhibition system displays low 5-HT2A receptor availability in anterior cingulate cortex and this cognitive control network links with prefrontal-cingulate integrity. These findings have implications for underlying the serotonergic basis of physiologies in aversion.

neuroscience↗

bioRxiv2020

Swallowing-related neural oscillation: An intracranial EEG study

Swallowing is a unique movement due to the indispensable orchestration of voluntary and involuntary movement. The transition from voluntary to involuntary swallowing is executed on the order of milliseconds. We hypothesized that its neural mechanism is revealed by high frequency cortical activities. Eight epileptic participants fitted with intracranial electrodes over the orofacial cortex were asked to swallow a water bolus, and cortical oscillatory changes, including high {gamma} band (75-150 Hz) and {beta} band (13-30 Hz) were investigated at the time of mouth-opening, water-injection, and swallowing. High {gamma} power increases associated with mouth-opening were observed in the ventrolateral prefrontal cortex with water-injection in the lateral central sulcus and with swallowing in the region along the Sylvian fissure. Mouth-opening induced a {beta} power decrease, which continued until the completion of swallowing. The high {gamma} burst activity was focal and specific to swallowing, however, the {beta} activities were extensive and not specific to swallowing. At the boundary time between voluntary and involuntary swallowing, swallowing-related high {gamma} power achieved the peak, and subsequently, the power decreased. We demonstrated three distinct activities related to mouth-opening, water-injection, and swallowing induced at different timings, using high {gamma} activities. The peak of high {gamma} power related to swallowing suggests that during voluntary swallowing phases, the cortex is the main driving force for swallowing rather than the brain stem.

neuroscience↗

bioRxiv2020

Comprehensive characterization of migration profiles of murine cerebral cortical neurons during development using FlashTag labeling

In mammalian cerebral neocortex, different regions have different cytoarchitecture, neuronal birthdates and functions. In most regions, neuronal migratory profiles have been speculated similar to each other based on observations using thymidine analogues. Few reports investigated regional migratory differences from mitosis at the ventricular surface. Here, in mice, we applied FlashTag technology, in which dyes are injected intraventricularly, to describe migratory profiles. We revealed a mediolateral regional difference in migratory profiles of neurons that is dependent on the developmental stages, e.g., neurons labeled at E12.5-15.5 reached their destination earlier dorsomedially than dorsolaterally even where there were underlying ventricular surfaces, reflecting sojourning below the subplate. This difference was hardly recapitulated by thymidine analogues, which visualize neurogenic gradient, suggesting biological significance different from neurogenic gradient. These observations advance understanding of cortical development, portraying strength of FlashTag in studying migration, and are thus a resource for studies of normal and abnormal neurodevelopment.

neuroscience↗

bioRxiv2020

Visualization of Phase-Amplitude Coupling Using Rhythmic High-Frequency Activity

ObjectiveHigh-frequency activities (HFAs) and phase-amplitude coupling (PAC) are gaining attention as key neurophysiological biomarkers for studying human epilepsy. We aimed to clarify and visualize how HFAs are modulated by the phase of low-frequency bands during seizures. MethodsWe used intracranial electrodes to record seizures of symptomatic focal epilepsy (15 seizures in seven patients). Ripples (80-250 Hz), as representative of HFAs, were evaluated along with PAC. The synchronization index (SI), representing PAC, was used to analyze the coupling between the amplitude of ripples and the phase of lower frequencies. We created a video in which the intracranial electrode contacts were represented by circles that were scaled linearly to the power changes of ripple. ResultsThe main low frequency band modulating ictal-ripple activities was the {theta} band (4-8 Hz), and after completion of ictal-ripple burst, {delta} (1-4 Hz)-ripple PAC occurred. The video showed that fluctuation of the diameter of these circles indicated the rhythmic changes during significant high values of {theta}-ripple PAC. ConclusionsWe inferred that ripple activities occurring during seizure evolution were modulated by {theta} rhythm. In addition, we concluded that rhythmic circles fluctuation presented in the video represents the PAC phenomenon. Our video is thus a useful tool for understanding how ripple activity is modulated by the low-frequency phase in relation with PAC.

neuroscience↗

bioRxiv2020

Motor and Sensory Cortical Processing of Neural Oscillatory Activities revealed by Human Swallowing using Intracranial Electrodes

Swallowing, a unique movement, is attributed to the indispensable orchestration of motor-output and sensory-input. We hypothesized that swallowing can illustrate differences between motor and sensory neural processing. Eight epileptic participants fitted with intracranial electrodes over the orofacial cortex were asked to swallow a water bolus. Mouth-opening and swallowing were treated as motor tasks, while water-injection as sensory tasks. Phase-amplitude coupling between lower frequency and high {gamma} (HG) band (75-150 Hz) was investigated. An (10-16 Hz) -HG coupling appeared before motor-related HG power increase (burst), and a {theta} (5-9 Hz) -HG coupling appeared during sensory-related HG burst. The motor- and sensory-related HG amplitude were modulated at the trough of oscillations and peak of {theta} oscillations, respectively. These contrasting results acquired from the orofacial cortex can help to fully elucidate the sensory-motor function in the brain.

neuroscience↗