Biology subjects

Mukai, Y.

Publications and source records attributed to Mukai, Y..

6 recordsLinked to original sources

bioRxiv2025

Tegmental atrophy in isolated REM sleep behaviour disorder: Ex vivo-informed in vivo imaging

Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is an early-stage synucleinopathy characterized by brainstem pathology. In rodents, the pontine tegmentum contains an REM sleep centre, the sublaterodorsal nucleus (SLD), which expresses corticotropin-releasing hormone binding protein (CRHBP). While the involvement of brainstem pathophysiology is thus implicated in iRBD, its solid evidence remains scarce in humans due to the difficulty in identifying small brainstem nuclei with conventional MRI technology alone. Here, we aimed to detect tegmental atrophy in iRBD with voxel-based morphometry (VBM) analysis combined with a novel human brainstem atlas. Structural MRIs from 98 patients with iRBD and 114 controls were analysed to investigate grey matter volume (GMV) using VBM. Our unique approach involved detailed assessments of the VBM results, guided by a high-resolution MRI-based atlas of the human brainstem. This brainstem atlas was founded on ex vivo MRI of 10 postmortem human specimens. We validated it with CRHBP immunostaining, which aided in identifying putative REM sleep-regulating nuclei in humans. We applied this brainstem atlas to identify atrophy in specific brainstem regions in iRBD and correlate their volumes with clinical measures, including autonomic functions. VBM revealed a focal cluster of grey matter atrophy in the dorsal pontine tegmentum of iRBD patients, including the laterodorsal tegmental nucleus, ventral part (LDTgV) and the pedunculopontine tegmental nucleus (PTg). Our atlas-based analysis confirmed the LDTgV as the site of most conspicuous atrophy, revealing a significant volume reduction in iRBD patients compared to controls with a moderate effect size (Cohens d = 0.46, Bonferroni-corrected p = 0.019). Furthermore, greater atrophy in the LDTgV and the PTg was associated with more severe autonomic dysfunction as measured by Scales for Outcomes in Parkinsons Disease-Autonomic dysfunction (SCOPA-AUT) scores (partial r = -0.237, p = 0.019 and partial r = -0.236, p = 0.019, respectively). Histological analysis confirmed that the LDTgV is selectively enriched with CRHBP-positive neurons, a putative marker for REM sleep-on neurons. We provided novel evidence for the involvement of LDTgV, the putative human homolog of the murine SLD, in iRBD. The present findings advance our understanding of the neuroanatomical basis of iRBD and will contribute to the development of early biomarkers for -synucleinopathies.

neuroscience↗

bioRxiv2023

Structure-based engineering of Tor complexes uncovers different roles of two types of yeast TORC1s

Certain proteins assemble into diverse complex states, each having a distinctive and unique function in the cell. The target of rapamycin complex 1 (TORC1) plays a central role in signaling pathways for cells to respond to their environment, such as nutritional status. TORC1 is widely recognised for its association with various diseases. The budding yeast Saccharomyces cerevisiae has two types of TORC1s comprising different constituent proteins, Tor1- and Tor2-containing TORC1s but are considered to have the same function. Here, we rationally redesigned the complex states by structure-based engineering and constructed a Tor2 mutant to form TORC2 but not TORC1. Functional analysis of the mutant revealed that the two types of TORC1s induced different phenotypes-rapamycin, caffeine and pH dependences of cell growth and replicative and chronological lifespans. These findings are expected to provide further insights into various fields such as molecular evolution and lifespan.

molecular biology↗

bioRxiv2022

Primary motor cortex drives expressive facial movements related to reward processing in mice

During reward-based learning tasks, animals make orofacial movements that globally influence brain activity at the timings of reward expectation and acquisition. These orofacial movements are not explicitly instructed and typically appear along with goal-directed behaviors. Here we show that reinforcing optogenetic stimulation of midbrain dopamine neurons (oDAS) in mice is sufficient to induce orofacial movements in the whiskers and nose without accompanying goal-directed behaviors. Pavlovian conditioning with a sensory cue and oDAS elicited cue-locked and oDAS aligned orofacial movements, which were distinguishable by a machine learning model. Inhibition or knock-out of dopamine D1 receptors in the nucleus accumbens inhibited oDAS-induced motion but spared cue-locked motion, suggesting differential neural regulation of these two types of orofacial motions. In contrast, inactivation of the whisker primary motor cortex (wM1) abolished both types of orofacial movements. We found specific neuronal populations in wM1 representing either oDAS-aligned or cue-locked whisker movements. Notably, optogenetic stimulation of wM1 neurons successfully replicated these two types of movements. Our results thus suggest that accumbal D1 receptor-dependent and -independent neuronal signals converge in the wM1 for facilitating uninstructed orofacial movements during a reward-based learning task.

neuroscience↗

bioRxiv2022

Unraveling the hidden diversity of endogenous bornavirus-like elements derived from ancient orthobornaviral X and P genes in mammalian genomes

Endogenous bornavirus-like elements (EBLs) are heritable sequences derived from bornaviruses in vertebrate genomes that originate from transcripts of ancient bornaviruses. EBLs have been detected using sequence similarity searches such as tBLASTn, whose technical limitations may hinder the detection of EBLs derived from small and/or rapidly evolving viral X and P genes. Indeed, no EBLs derived from the X and P genes of orthobornaviruses have been detected to date in vertebrate genomes. Here, we aimed to develop a novel strategy to detect such "hidden" EBLs. To this aim, we focused on the 1.9 kb read-through transcript of orthobornaviruses, which encodes a well-conserved N gene and small and rapidly evolving X and P genes. We show a series of evidence supporting the existence of EBLs derived from orthobornaviral X and P genes (EBLX/Ps) in mammalian genomes. Furthermore, we found that an EBLX/P is expressed as a fusion transcript with the cellular gene, ZNF451, which potentially encodes the ZNF451/EBLP fusion protein in miniopterid bat cells. This study contributes to a deeper understanding of ancient bornaviruses and co-evolution between bornaviruses and their hosts. Furthermore, our data suggest that endogenous viral elements detected thus far are just the tip of the iceberg, and further studies are required to understand ancient viruses more accurately.

microbiology↗

bioRxiv2022

The oxytocin system regulates tearing

Tears are an exocrine physiological fluid secreted onto the ocular surface from the lacrimal apparatus in all mammals. Limited research has been conducted on the functional neuronal circuitry of tear production. In particular, the neuronal mechanisms of emotional tearing, which is a physiological reaction harmonized with enhanced emotional arousal and assumed to be unique to humans, remain unclear. We identified that the oxytocin neurons in the paraventricular hypothalamus is functionally projected to the oxytocin receptor-expressing neurons in the lacrimation center of the superior salivatory nucleus. Optogenetic activation or inhibition of these neurons and/or receptors can modulate the superior salivatory nucleus dependent tear secretion mediated through oxytocin. Moreover, we identified that maternal behavior, nociceptive behavior stimulation, and aversive memory retrieval are linked to tearing in mice, and that these emotional linked tearing are suppressed by optogenetic inhibition of the corresponding oxytocin system. Thus, tearing could be regulated through functional connections between central oxytocin systems in the paraventricular hypothalamus and the superior salivatory nucleus.

animal behavior and cognition↗

bioRxiv2020

One hundred million years history of bornavirus infections hidden in vertebrate genomes

Although viruses have threatened our ancestors for millions of years, prehistoric epidemics of viruses are largely unknown. Endogenous bornavirus-like elements (EBLs) are ancient viral sequences that have been integrated into animal genomes. These elements can be used as molecular fossil records to trace past bornaviral infections. In this study, we systematically identified EBLs in vertebrate genomes and revealed the history of bornavirus infections over nearly 100 million years. We found that ancient bornaviral infections have occurred in diverse vertebrate lineages, especially in primate ancestors. Phylogenetic analyses indicated that primate ancestors had been infected with various bornaviral lineages during evolution. Moreover, EBLs in primate genomes formed clades according to their integration ages, suggesting that epidemic lineages of bornaviruses had changed chronologically. However, we found that some bornaviral lineages coexisted with primate ancestors and underwent repeated endogenizations for tens of millions of years. Furthermore, this viral lineage that coexisted with primate ancestors was also endogenized in some ancestral bats. Notably, the geographic distributions of these bat ancestors have been reported to overlap with the migration route of primate ancestors, suggesting that long-term virus-host coexistence could have expanded the geographic distributions of the viral lineage and might have spread their infections to new hosts. Thus, our findings describe hidden virus-host co-evolutionary history over geological timescales, including chronological change in epidemic bornaviral lineages, long-term virus-host coexistence, and expansion of viral infections.

microbiology↗