Biology subjects

Nambu, A.

Publications and source records attributed to Nambu, A..

12 recordsLinked to original sources

bioRxiv2026

A multimodal dataset for reconstructing common marmoset body-environment interactions in a 3D digital-twin framework

The common marmoset (Callithrix jacchus) is an important non-human primate model in neuroscience and biomedical research. However, existing 3D resources for this species have mainly focused on brain atlases or keypoint-based pose estimation, and reusable data resources that jointly describe the body surface, fur, articulated structure, and experimental environment remain limited. Here, we present a multimodal dataset designed to reconstruct body- environment interactions of common marmosets in three dimensions. The dataset includes a whole-body surface mesh derived from computed tomography (CT) images, fur representations based on photographic references, a rigged 3D model for pose-driven animation, synchronized behavioral videos from three individuals recorded for approximately 90 hours from eight view-points, 2D and 3D keypoint estimation data, 3D models of the experimental environment constructed from blueprint information, and rendered pseudo-egocentric views generated by integrating pose estimation results with the 3D body and environment models. Technical validation assessed the geometric agreement between the CT-derived mesh and the surface model, the accuracy of 2D and 3D keypoint estimation, the dimensional accuracy of the environment model, and the structural similarity between real and rendered images. This dataset provides a foundation for treating marmoset natural behavior not only as point trajectories but also as a three-dimensional phenomenon involving body shape and its spatial relationship with the environment, thereby enabling applications in behavioral analysis, visualization, synthetic-data generation, and future digital-twin studies.

animal behavior and cognition↗

bioRxiv2026

Forward processing of spatiotemporal maps across hippocampal subfields in common marmosets

Episodic memory requires distinguishing similar events occurring at the same location but at different times. While the hippocampus integrates "where" and "when," the specific roles of the primate dentate gyrus (DG) and CA3 remain elusive. We recorded single-unit activity from freely moving marmosets navigating a spatial maze in a visually impoverished environment. Both hippocampal subfields robustly encoded self-position via neurons selective for stationary epochs at platforms and movement along trajectories, whereas gaze-related coding was minimal. While DG signaled stationary and dynamic self-positions independently, CA3 integrated these elements into conjunctive representations. Critically, only CA3 neurons exhibited strong temporal-order modulation. These findings reveal a feedforward disambiguation process in which CA3 transforms discrete spatial inputs from DG into the integrated spatiotemporal maps essential for episodic memory.

neuroscience↗

bioRxiv2026

Left-right asymmetry of the microminipig brain.

Left-right asymmetry of the brain is well recognized in various animals including C. elegans, drosophila and zebrafish. In primates, most of the brain studies describe side of the brain. However, in spite of huge amounts of accumulating rodent studies on neuroscience, most of rodent studies do not distinguish the brain side. The pig brain is considered to occupy an intermediate position between primates and rodents in terms of structural complexity and brain function. Moreover, the numbers of studies using genetic manipulation of pigs are drastically increasing. So, we investigated microminipig (MMP) brain mesoscopic anatomy focusing on left-right differences of its morphology. Here, we show the anterior cingulate cortex, perirhinal cortex, and cerebellum of male and female MMPs, are structurally asymmetrical. The cerebellar vermis, paravermis is tilted from the midline and the consequently the cerebellar cortex exhibits asymmetrical morphology. The anterior cingulate gurus exhibited protrusion and invagination toward the midline on the right and left side, respectively. The left perirhinal lobe exhibited distinct patterns of cortical gyration between left and right side. These data demonstrate that MMPs are one of the suitable model animals for investigating cerebral and cerebellar asymmetry.

neuroscience↗

bioRxiv2024

Distinct roles of two thalamostriatal systems in learning processes of visual discrimination in common marmosets

The thalamostriatal projections arising from the intralaminar thalamic nuclei (ILN) constitute the principal source of input information to specified subregions of the striatum, a key structure of the cortico-basal ganglia circuitry. However, the roles of primate ILN in cortico-basal ganglia circuit functions remain unclear. Here, we performed immunotoxin-induced selective targeting of two representative structures of the ILN, the parafascicular nucleus (Pf) and centre median nucleus (CM) projecting to the caudate nucleus (Cd) and putamen (Pu), respectively, in common marmosets. Elimination of Pf-Cd neurons resulted in impaired reversal learning of a two-choice visual discrimination task, whereas removal of CM-Pu neurons disturbed the task acquisition. No marked impact of such manipulations was observed on either motor skill learning or spontaneous locomotor activity. Our findings reveal that the two thalamostriatal systems play distinct roles in the learning processes of external cue-dependent decision-making in nonhuman primates.

neuroscience↗

bioRxiv2023

Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth

Human silencers have been shown to exist and regulate developmental gene expression. However, the functional importance of human silencers needs to be elucidated, such as whether they can form "super-silencers" and whether they are linked to cancer progression. Here, through interrogating two putative silencer components of FGF18 gene, we found that two nearby silencers can cooperate via compensatory chromatin interactions to form a "super-silencer". Furthermore, double knockout of two silencers exhibited synergistic upregulation of FGF18 expression and changes of cell identity. To perturb the "super-silencers", we applied combinational treatment of an EZH2 inhibitor GSK343, and a REST inhibitor, X5050 ("GR"). We found that GR led to severe loss of TADs and loops, while the use of one inhibitor by itself only showed mild changes. Such changes in TADs and loops were associated with reduced CTCF and TOP2A mRNA levels. Moreover, GSK343 and X5050 synergistically upregulated super-silencer-controlled genes related to cell cycle, apoptosis and DNA damage, leading to anticancer effects both in vitro and in vivo. Overall, our data demonstrated the first example of a "super-silencer" and showed that combinational usage of GSK343 and X5050 to disrupt "super-silencers" could potentially lead to cancer ablation.

molecular biology↗

bioRxiv2023

Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia

Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist, L-DOPA, to treat Parkinsons disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we searched for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identified the enlarged axon terminals of striatal medium spiny neurons in both LID and TD model mice. The striatal overexpression of vesicular gamma-aminobutyric acid transporter (VGAT) was necessary and sufficient for modeling these structural changes; VGAT levels gated the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation, and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation. HighlightsO_LIEnhancement of GABAergic transmission is a shared mechanism between LID and TD. C_LIO_LIVGAT levels in MSNs govern the structure and function of MSN presynaptic terminals. C_LIO_LIGain and loss of VGAT function in MSNs exacerbates and ameliorates dyskinesia. C_LIO_LILowered D2 signaling with repetitive DA fluctuations causes VGAT overexpression. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/550763v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@15041b4org.highwire.dtl.DTLVardef@9bf41org.highwire.dtl.DTLVardef@1eb7ee4org.highwire.dtl.DTLVardef@1d7dae8_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Behavioral effects of zonisamide on L-DOPA-induced dyskinesia in Parkinson's disease model mice

Zonisamide (ZNS; 1,2-benzisoxazole-3-methanesulfonamide) was initially developed and is commonly used as an anticonvulsant drug. However, it has also shown beneficial effects on Parkinsons disease (PD), a progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the midbrain. Recent clinical studies have suggested that ZNS can also have beneficial effects on L-DOPA-induced dyskinesia (LID), which is a major side effects of long-term L-DOPA treatments for PD. In the present study, we examined the behavioral effects of ZNS on LID in PD model mice. Acute ZNS treatment did not have any observable behavioral effects on LID. Contrastingly, chronic ZNS treatment with L-DOPA delayed the peak of LID and reduced the severity of LID before the peak, but increased the duration of LID in a dose-dependent manner of ZNS, compared to PD model mice treated with L-DOPA alone. Thus, ZNS appears to have both beneficial and adverse effects on LID.

neuroscience↗

bioRxiv2022

The oral drug nitazoxanide restricts SARS-CoV-2 infection and attenuates disease pathogenesis in Syrian hamsters

A well-tolerated and cost-effective oral drug that blocks SARS-CoV-2 growth and dissemination would be a major advance in the global effort to reduce COVID-19 morbidity and mortality. Here, we show that the oral FDA-approved drug nitazoxanide (NTZ) significantly inhibits SARS-CoV-2 viral replication and infection in different primate and human cell models including stem cell-derived human alveolar epithelial type 2 cells. Furthermore, NTZ synergizes with remdesivir, and it broadly inhibits growth of SARS-CoV-2 variants B.1.351 (beta), P.1 (gamma), and B.1617.2 (delta) and viral syncytia formation driven by their spike proteins. Strikingly, oral NTZ treatment of Syrian hamsters significantly inhibits SARS-CoV-2-driven weight loss, inflammation, and viral dissemination and syncytia formation in the lungs. These studies show that NTZ is a novel host-directed therapeutic that broadly inhibits SARS-CoV-2 dissemination and pathogenesis in human and hamster physiological models, which supports further testing and optimization of NTZ-based therapy for SARS-CoV-2 infection alone and in combination with antiviral drugs.

immunology↗

bioRxiv2022

Super-silencers regulated by chromatin interactions control apoptotic genes

Human silencers have been shown to exist and regulate developmental gene expression. However, the functional importance of human silencers needs to be elucidated such as the working mechanism and whether they can form "super-silencers". Here, through interrogating two putative silencer components of FGF18 gene, we found that two silencers can cooperate via compensated chromatin interactions to form a "super-silencer". Furthermore, double knock-out of two silencers exhibited synergistic upregulation of FGF18 expression and changes of cell identity. To disturb the "super-silencers", we applied combinational treatment of an EZH2 inhibitor GSK343, and a REST inhibitor, X5050 ("GR"). We found that GR led to severe loss of TADs and loops, while the use of just one inhibitor by itself only showed mild changes. Such changes of TADs and loops may due to reduced CTCF protein level observed upon GR treatment. Moreover, GSK343 and X5050 worked together synergistically to upregulate the apoptotic genes controlled by super-silencers, and thus gave rise to antitumor effects including apoptosis, cell cycle arrest and tumor growth inhibition. Overall, our data demonstrated the first example of a "super-silencer" and showed that combinational usage of GSK343 and X5050 could potentially lead to cancer ablation through disruption of "super-silencers".

genomics↗

bioRxiv2021

Subthalamic nucleus stabilizes movements by reducing neural spike variability in monkey basal ganglia: chemogenetic study

AbstractsThe subthalamic nucleus (STN) projects to the external pallidum (GPe) and internal pallidum (GPi), the relay and output nuclei of the basal ganglia (BG), respectively, and plays an indispensable role in controlling voluntary movements. To elucidate the neural mechanism by which the STN controls GPe/GPi activity and movements, we utilized a chemogenetic method to reversibly suppress the motor subregion of the STN in three macaque monkeys (Macaca fuscata, both sexes) engaged in reaching tasks. Systemic administration of chemogenetic ligands prolonged movement time and increased spike train variability in the GPe/GPi, but only slightly affected firing rate modulations. Across-trial analyses revealed that the irregular discharge activity in the GPe/GPi coincided with prolonged movement time. STN suppression also induced excessive abnormal movements in the contralateral forelimbs, which was preceded by STN and GPe/GPi phasic activity changes. Our results suggest that the STN stabilizes spike trains in the BG and achieves stable movements.

neuroscience↗

bioRxiv2021

Transient response of basal ganglia network in healthy and low-dopamine state

The basal ganglia (BG) are crucial for a variety of motor and cognitive functions. Changes induced by persistent low-dopamine (e.g. in Parkinsons disease), result in aberrant changes in steady-state population activity ({beta}-band oscillations) and transient response of the BG. Typically, brief cortical stimulation results in a triphasic response in the substantia nigra pars reticulata (SNr, output of the BG). The properties of the triphasic responses are shaped by dopamine levels. While it is relatively well understood how changes in BG result in aberrant steady state activity, it is not clear which BG interactions are crucial for the aberrant transient responses in the BG. Moreover, it is also not clear whether the same or different mechanisms underlie the aberrant changes in steady-state activity and aberrant transient response. Here we used numerical simulations of a network model of BG to identify the key factors that determine the shape of the transient responses. We show that an aberrant transient response of the SNr in low-dopamine state, involves changes in both, the direct pathway and the recurrent interactions within the globus pallidus externa (GPe) and between GPe and sub-thalamic nucleus. We found that the connections from D2-type spiny projection neurons to GPe are most crucial in shaping the transient response and by restoring them to their healthy level, we could restore the shape of transient response even in low-dopamine state. Finally, we show that the changes in BG that result in aberrant transient response are also sufficient to generate pathological oscillatory activity. Significance statementTo understand how changes induced by low-dopamine (e.g. in Parkinsons disease, PD) affect basal ganglia (BG) function, we need to identify the factors that determine the shape of BG responses to brief cortical stimuli. We show that transient response of the BG is also affected by recurrent interactions within the subnuclei of the BG, and not just feedforward pathways. We found that input and local connectivity within the globus pallidus externa are crucial for shaping the transient response. We also show that the same network changes may underlie both, pathological {beta}-band oscillations and aberrant transient responses. Our results highlight the importance of the recurrent connectivity within the BG and provide a coherent view of emergence of pathological activity in PD.

neuroscience↗

bioRxiv2019

Forelimb movements evoked by optogenetic stimulation of the macaque motor cortex

Optogenetics has become an indispensable tool for investigating brain functions. Although non-human primates are particularly useful models for understanding the functions and dysfunctions of the human brain, application of optogenetics to non-human primates is still limited. In the present study, we generated an effective adeno-associated viral vector serotype DJ to express channelrhodopsin-2 (ChR2) under the control of a strong ubiquitous CAG promoter and injected into the somatotopically identified forelimb region of the primary motor cortex in macaque monkeys. ChR2 was strongly expressed around the injection sites, and optogenetic intracortical microstimulation (oICMS) through a homemade optrode induced prominent cortical activity: Even single-pulse, short duration oICMS evoked long-lasting repetitive firings of cortical neurons. In addition, oICMS elicited distinct forelimb movements and muscle activity, which were comparable to those elicited by conventional electrical ICMS. The present study removed obstacles to optogenetic manipulation of neuronal activity and behaviors in non-human primates.

neuroscience↗