Biology subjects

Urushihata, T.

Publications and source records attributed to Urushihata, T..

5 recordsLinked to original sources

bioRxiv2026

Inosine Triphosphate Pyrophosphatase as a Candidate Associated with White Matter Abnormalities in Chronic Heart Failure

Background: White matter hyperintensities (WMHs) are common with normal brain aging and frequently observed also in chronic heart failure (CHF). However, the relationship between CHF and white matter abnormalities and the biological factors remain unclear. We investigated WMH and associated white matter microstructural changes, such as fractional anisotropy (FA), in CHF and explored candidate molecular factors. Methods: We conducted a longitudinal prospective observation including brain T2-FLAIR magnetic resonace imaging for 32 asymptomatic Stage B (mean age 63.3{+/-}10.5 years; 25% women) and 23 symptomatic Stage C CHF patients (mean age 67.3{+/-}7.1 years; 30% women). Plasma proteomics and Mendelian randomization (MR) were used to identify candidate proteins associated with both CHF and WMH. The association of candidate proteins was further investigated using complementary analyses in CHF rats, cultured cortical neurons, and community-based genetic data in UK Biobank. Results: Global WMH volume increased more in Stage C than Stage B patients, predominantly near the anterior periventricular white matter, despite comparable cardiac indices (4,717{+/-}5,335 mm3 vs. 2,116{+/-}3,134 mm3, P=0.027). SomaScan-based proteomic analysis of plasma samples from this patient cohort revealed that 44 proteins are significantly associated with both Stage C CHF and WMH progression (P<0.05). Of these 44 proteins, two-step Mendelian randomization analysis identified inosine triphosphate pyrophosphatase (ITPA) as the only candidate protein, further supported by an association between rare variants in ITPA and FA. In CHF rats, the anterior pericallosal cortex showed decreases in myelin basic protein density and FA and an increase in ITPA expression compared to sham rats. In cultured cortical neurons, recombinant ITPA exposure reduced total axonal length. Conclusions: Symptomatic CHF was associated with WMH and impaired white matter integrity. ITPA emerged as a candidate factor across human, animal, and cellular analyses. These findings provide a basis for investgating the biological pathways linking CHF and white matter injury.

neuroscience↗

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↗

bioRxiv2022

Distribution of intraperitoneally administered D2O in AQP4-knockout mouse brain after MCA occlusion

As the movement of water in the brain is known to be involved in neural activity and various brain pathologies, the ability to assess water dynamics in the brain will be important for the understanding of brain function and the diagnosis and treatment of brain diseases. Aquaporin-4 (AQP4) is a membrane channel protein that is highly expressed in brain astrocytes and is important for the movement of water molecules in the brain. In this study, we investigated the contribution of AQP4 to brain water dynamics by administering deuterium-labeled water (D2O) intraperitoneally to wild-type and AQP4 knockout (AQP4-ko) mice that had undergone surgical occlusion of the middle cerebral artery. Water dynamics in the infarct region and on either side of the anterior cerebral artery (ACA) was monitored with proton-density-weighted imaging (PDWI) performed on a 7T animal MRI. D2O caused a negative signal change quickly after administration. The AQP4-ko mice showed a delay of the time-to-minimum in both contralateral and ipsilateral ACA region compared to wild-type mice. Also, only the AQP4-ko mice showed a delay of the time-to-minimum in the ipsilateral ACA region compared to the contralateral side. In only the wild-type mice, the signal minimum in the ipsilateral ACA region was higher than that in the contralateral ACA region. In the infarct region, the signal attenuation was slower for the AQP4-ko mice in comparison to the wild-type mice. These results suggest that AQP4 loss affects water dynamics in the ACA region not only in the infarct region. Dynamic PDWI after D2O administration may be a useful tool for showing the effects of AQP4 in vivo. HighlightsO_LIThe measurement of brain water dynamics with D2O. C_LIO_LIIn vivo investigation of AQP4 loss and focal brain ischemia. C_LIO_LIAQP4 loss affects water dynamics in the ACA region not only in the infarct region. C_LI

physiology↗

bioRxiv2020

MRS-measured Glutamate versus GABA reflects excitatory versus inhibitory neural activities in awake mice

To assess if magnetic resonance spectroscopy (MRS)-measured Glutamate (Glu) and GABA reflect excitatory and inhibitory neural activities, respectively, we conducted MRS measurements along with two-photon mesoscopic imaging of calcium signals in excitatory and inhibitory neurons of living, unanesthetized mice. For monitoring stimulus-driven activations of a brain region, MRS signals and mesoscopic neural activities were measured during two consecutive sessions of 15-min prolonged sensory stimulations. In the first session, putative excitatory neuronal activities were increased, while inhibitory neuronal activities remained at the baseline level. In the second half, while excitatory neuronal activities remained elevated, inhibitory neuronal activities were significantly enhanced. We also assessed regional neurochemical and functional statuses related to spontaneous neural firing by measuring MRS signals and neuronal activities in a mouse model of Dravet syndrome under a resting condition. Mesoscopic assessments showed that activities of inhibitory neurons in the cortex were diminished relative to wild-type mice in contrast to spared activities of excitatory neurons. Consistent with these observations, the Dravet model exhibited lower concentrations of GABA than wild-type controls. Collectively, the current investigations demonstrate that the MRS-measured Glu and GABA can reflect spontaneous and stimulated activities of neurons producing and releasing these neurotransmitters in an awake condition.

neuroscience↗

bioRxiv2019

Deschloroclozapine: a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys

The chemogenetic technology Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) affords remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities, and potential off-target effects of CNO represent areas for improvement. Here we provide a new high affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 g/kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 g/kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents the most potent, selective, metabolically stable and fast-acting DREADD agonist reported with utility in both mice and non-human primates for a variety of applications.

neuroscience↗