Biology subjects

Uchida, H.

Publications and source records attributed to Uchida, H..

11 recordsLinked to original sources

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 preoptic circuit triggers rewarming from torpor

Torpor is an adaptive hypometabolic state that enables homeotherm to survive periods of energetic challenge. This strategy ranges from short bouts of daily torpor to prolonged hibernation. During torpor, animals markedly suppress metabolic rate, body temperature, heart rate, and respiration, while retaining the ability to rewarm. Torpor therefore comprises two critical transitions -entry into a hypometabolic state and active rewarming-both essential for organismal viability. Although neural mechanisms controlling torpor entry have begun to emerge, the circuits that initiate active rewarming and restore euthermia remain poorly defined. Here we identify corticotropin-releasing hormone (Crh)-expressing neurons in the anterodorsal preoptic area (ADP) as a key population for rewarming from fasting-induced torpor in mice. These neurons become active around natural rewarming and are selectively required to limit the depth and duration of torpor. Unlike pathways mediating acute cold defence, stress hyperthermia, or LPS-induced fever, this circuit is dedicated to promoting timely recovery to euthermia. Closed-loop optogenetic activation of ADPCrh neurons during torpor entry rapidly initiates rewarming, and thermographic recordings show that brown adipose tissue (BAT) thermogenesis precedes locomotor arousal. ADPCrh neurons are predominantly GABAergic and project monosynaptically to the lateral preoptic area, whose terminal activation is sufficient to increase body temperature and locomotor activity. Finally, we find robust activation of ADPCrh neurons during rewarming in a hibernator, suggesting conserved logic for exiting deep torpor. Together, our results define a discrete preoptic circuit that drives recovery from torpor and provide a framework for understanding and potentially controlling timely rewarming from profound hypothermia.

neuroscience↗

bioRxiv2025

Ascl3+ ionocytes in murine salivary gland ducts are innervated sensory cells that display unique calcium signaling characteristics and contribute to the composition of saliva

Ionocytes are distinct epithelial sensory cells scattered throughout the ductal system of the salivary glands. These cells are distinguished by their unusual morphology, as well as by a specific transcriptomic signature that includes expression of the Foxi1 and Ascl3 transcription factors. Currently, little is known about the biology or function of ionocytes in the salivary glands. To facilitate characterization of these cells, we generated an inducible Cre mouse allele driven by the Ascl3 promoter. This strain was crossed with a reporter to fluorescently label Ascl3+ ionocytes, highlighting that they are the site of enriched CFTR expression in the salivary glands, and demonstrating the proximity of these cells to neurons. Conditional Cre-mediated cell ablation, using diphtheria toxin (DTA), removed Ascl3+ ionocytes from the salivary glands and resulted in an altered pH of total saliva, supporting a function for ionocytes in transepithelial ion flow. Finally, Cre-mediated expression of the calcium indicator GCaMP6f revealed that Ascl3+ ionocytes exhibit unique properties not observed in acinar or surrounding duct cells, including elevated basal [Ca2+]I, spontaneous blinking in the absence of stimulation, and a rapid loss of [Ca2+]I following nerve stimulation. These unique properties distinguish ionocytes as a specialized subset of salivary gland duct cells.

physiology↗

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

Endothelial Sphingosine-1-Phosphate Receptor (S1PR) 1, a Functional S1PR in the Human Cerebrovascular Endothelium, Limits Blood Brain Barrier Permeability and Neuronal Injury following Subarachnoid Hemorrhage in Mice.

Hypoxia-induced blood-brain barrier (BBB) permeability has been identified as a key contributor to the progression of ischemic-hypoxic brain injury and neuronal dysfunction in stroke and other cerebrovascular diseases. Emerging clinical evidence highlights that the vasoprotective signaling properties of high-density lipoprotein (HDL), mediated through its bioactive lipid component sphingosine-1-phosphate (S1P), may be impaired in cardiovascular and inflammatory conditions. Nonetheless, the precise contributions and mechanistic roles of S1P signaling within the cerebral microvasculature remain insufficiently characterized. In this study, we aimed to elucidate the role of S1P signaling via its endothelial receptor S1PR1 in the pathophysiology of early brain injury following subarachnoid hemorrhage (SAH), a particularly severe form of stroke. Additionally, we sought to evaluate the relevance of the endothelial S1PR1 pathway in the human cerebrovascular endothelium, its functional role in hypoxia-induced cerebral endothelial barrier dysfunction, and its underlying molecular mechanisms. To address these objectives, we utilized endothelial-specific S1PR1 knockout mice subjected to the endovascular rupture model of aneurysmal SAH, performed mechanistic studies in primary human cerebral microvascular endothelial cells, and characterized S1PR1 expression in human brain tissue using validated protocols. Our findings reveal robust expression of S1PR1 in the cerebrovascular endothelium of both mice and humans. Functional analyses demonstrated that S1PR1 is critical for maintaining BBB integrity and mitigating neuronal injury in the context of SAH. Mechanistic in vitro studies indicated that S1PR1 exerts a vasoprotective effect by limiting hypoxia-induced BBB dysfunction in human primary brain microvascular endothelial cells through inhibition of Rho-associated kinase (ROCK)-mediated phosphorylation of myosin light chain (MLC), suppression of stress fiber formation and caveolin-1-dependent endosomal trafficking. These results highlight the pivotal role of endothelial S1PR1 signaling in preserving cerebral vascular integrity and provide a strong scientific foundation for developing novel therapeutic approaches targeting the S1P pathway in the endothelium to enhance neurovascular protection.

neuroscience↗

bioRxiv2024

Molecular and functional alterations in the cerebral microvasculature in an optimized mouse model of sepsis-associated cognitive dysfunction.

Systemic inflammation has been implicated in the development and progression of neurodegenerative conditions such as cognitive impairment and dementia. Recent clinical studies indicate an association between sepsis, endothelial dysfunction, and cognitive decline. However, the investigations of the role and therapeutic potential of the cerebral microvasculature in systemic inflammation-induced cognitive dysfunction have been limited by the lack of standardized experimental models for evaluating the alterations in the cerebral microvasculature and cognition induced by the systemic inflammatory response. Herein, we validated a mouse model of endotoxemia that recapitulates key pathophysiology related to sepsis-induced cognitive dysfunction, including the induction of an acute systemic hyperinflammatory response, blood-brain barrier (BBB) leakage, neurovascular inflammation, and memory impairment after recovery from the systemic inflammatory response. In the acute phase, we identified novel molecular (e.g. upregulation of plasmalemma vesicle associated protein, a driver of endothelial permeability, and the pro-coagulant plasminogen activator inhibitor-1, PAI-1) and functional perturbations (i.e., albumin and small molecule BBB leakage) in the cerebral microvasculature along with neuroinflammation. Remarkably, small molecule BBB permeability, elevated levels of PAI-1, intra/perivascular fibrin/fibrinogen deposition and microglial activation persisted 1 month after recovery from sepsis. We also highlight molecular neuronal alterations of potential clinical relevance following systemic inflammation including changes in neurofilament phosphorylation and decreases in postsynaptic density protein 95 and brain-derived neurotrophic factor suggesting diffuse axonal injury, synapse degeneration and impaired neurotrophism. Our study serves as a standardized model to support future mechanistic studies of sepsis-associated cognitive dysfunction and to identify novel endothelial therapeutic targets for this devastating condition. SIGNIFICANCEThe limited knowledge of how systemic inflammation contributes to cognitive decline is a major obstacle to the development of novel therapies for dementia and other neurodegenerative diseases. Clinical evidence supports a role for the cerebral microvasculature in sepsis-induced neurocognitive dysfunction, but the investigation of the underlying mechanisms has been limited by the lack of standardized experimental models. Herein, we optimized a mouse model that recapitulates important pathophysiological aspects of systemic inflammation-induced cognitive decline and identified key alterations in the cerebral microvasculature associated with cognitive dysfunction. Our study provides a reliable experimental model for mechanistic studies and therapeutic discovery of the impact of systemic inflammation on cerebral microvascular function and the development and progression of cognitive impairment.

neuroscience↗

bioRxiv2023

Brn3a controls the soma localization and axonal extension patterns of developing spinal dorsal horn neurons

The spinal dorsal horn comprises heterogeneous neuronal populations, that interconnect with one another to form neural circuits modulating various types of sensory information. Decades of evidence has revealed that transcription factors expressed in each neuronal progenitor subclass play pivotal roles in the cell fate specification of spinal dorsal horn neurons. However, the development of subtypes of these neurons is not fully understood in more detail as yet and warrants the investigation of additional transcription factors. In the present study, we examined the involvement of the POU domain-containing transcription factor Brn3a in the development of spinal dorsal horn neurons. Analyses of Brn3a expression in the developing spinal dorsal horn neurons in mice demonstrated that Brn3a was downregulated in majority of the Brn3a-lineage neurons during embryonic stages (Brn3a-transient neurons), whereas a limited population continued to express Brn3a after E18.5 (Brn3a-persistent neurons). Brn3a knockout disrupted the localization pattern of Brn3a-persistent neurons, indicating a critical role of this transcription factor in the development of these neurons. In contrast, Brn3a overexpression in Brn3a-transient neurons directed their localization in a manner similar to that in Brn3a-persistent neurons. Moreover, Brn3a-overexpressing neurons exhibited increased axonal extension to the ventral and ventrolateral funiculi, where the axonal tracts of Brn3a-persistent neurons reside. These results suggest that Brn3a controls the soma localization and axonal extension patterns of Brn3a-persistent spinal dorsal horn neurons.

neuroscience↗

bioRxiv2023

Vascular oxidative stress causes neutrophil arrest in brain capillaries, leading to decreased cerebral blood flow and contributing to memory impairment in a mouse model of Alzheimer's disease

INTRODUCTIONIn this study, we explore the role of oxidative stress produced by NOX2-containing NADPH oxidase as a molecular mechanism causing capillary stalling and cerebral blood flow deficits in the APP/PS1 mouse model of AD. METHODSWe inhibited NOX2 in APP/PS1 mice by administering a 10 mg/kg dose of the peptide inhibitor gp91-ds-tat i.p., for two weeks. We used in vivo two-photon imaging to measure capillary stalling, penetrating arteriole flow, and vascular inflammation. We also characterized short-term memory function and gene expression changes in cerebral microvessels. RESULTSWe found that after NOX2 inhibition capillary stalling, as well as parenchymal and vascular inflammation, were significantly reduced. In addition, we found a significant increase in penetrating arteriole flow, followed by an improvement in short-term memory, and downregulation of inflammatory gene expression pathways. DISCUSSIONOxidative stress is a major mechanism leading to microvascular dysfunction in AD, and represents an important therapeutic target.

neuroscience↗

bioRxiv2022

Short-term and bystander effects of radiation on murine submandibular glands

Many patients treated for head and neck cancers experience salivary gland hypofunction due to radiation damage. Understanding the mechanisms of cellular damage induced by radiation treatment is important in order to design methods of radioprotection. In addition, it is crucial to recognize the indirect effects of IR and the systemic responses that may alter saliva secretion. In this study, radiation was delivered to murine submandibular glands (SMG) bilaterally, using a 137Cs gamma ray irradiator, or unilaterally, using a small animal radiation research platform (SARRP). Analysis at 3, 24 and 48 hours showed dynamic changes in mRNA levels and protein abundance in SMG irradiated bilaterally. Unilateral irradiation using the SARRP caused similar changes in the irradiated SMG, as well as significant off-target, bystander effects in the non-irradiated contralateral SMG. Summary statementRapid changes in gene expression occur in irradiated salivary glands within hours of irradiation, and in non-irradiated contralateral glands, due to bystander effects.

cancer biology↗

bioRxiv2021

Structural basis for the absence of low-energy chlorophylls responsible for photoprotection from a primitive cyanobacterial PSI

Photosystem I (PSI) of photosynthetic organisms is a multi-subunit pigment-protein complex and functions in light harvesting and photochemical charge-separation reactions, followed by reduction of NADP to NADPH required for CO2 fixation. PSI from different photosynthetic organisms has a variety of chlorophylls (Chls), some of which are at lower-energy levels than its reaction center P700, a special pair of Chls, and are called low-energy Chls. However, the site of low-energy Chls is still under debate. Here, we solved a 2.04-[A] resolution structure of a PSI trimer by cryo-electron microscopy from a primitive cyanobacterium Gloeobacter violaceus PCC 7421, which has no low-energy Chls. The structure showed absence of some subunits commonly found in other cyanobacteria, confirming the primitive nature of this cyanobacterium. Comparison with the known structures of PSI from other cyanobacteria and eukaryotic organisms reveals that one dimeric and one trimeric Chls are lacking in the Gloeobacter PSI. The dimeric and trimeric Chls are named Low1 and Low2, respectively. Low2 does not exist in some cyanobacterial and eukaryotic PSIs, whereas Low1 is absent only in Gloeobacter. Since Gloeobacter is susceptible to light, this indicates that Low1 serves as a main photoprotection site in most oxyphototrophs, whereas Low2 is involved in either energy transfer or energy quenching in some of the oxyphototrophs. Thus, these findings provide insights into not only the functional significance of low-energy Chls in PSI, but also the evolutionary changes of low-energy Chls responsible for the photoprotection machinery from photosynthetic prokaryotes to eukaryotes.

plant biology↗

bioRxiv2019

Translationally relevant transcriptomic alterations in mouse ischemic cerebral microvessels

Increasing evidence implicates cerebral microvascular dysfunction in the pathophysiology of numerous central nervous system pathologies, including stroke. Understanding the molecular alterations in cerebral microvessels in these conditions will provide original opportunities for scientific investigation at the pre-clinical and clinical levels. In this study, we conducted a novel genome-wide transcriptomic analysis of microvessels in a mouse model of transient focal cerebral ischemia. Using a publicly available human ischemic stroke dataset, we identified shared alterations in our microvessel dataset with implications for human pathophysiology. From this unbiased analysis, we report predicted alterations in inter- and intra-cellular signaling, emphasizing perturbations in genes involved in blood brain barrier function, endothelial cell activation and metabolism. Furthermore, our study unveiled previously unreported gene expression changes associated with altered sphingolipid metabolism. Altogether, our results have identified microvessel-specific transcriptomic changes in a number of translationally relevant pathways that support the targeting of these pathways in preclinical studies. The data shared here provide a resource for future investigation of translationally relevant pathways in ischemic stroke.

neuroscience↗