Biology subjects

Ujihara, Y.

Publications and source records attributed to Ujihara, Y..

11 recordsLinked to original sources

bioRxiv2026

Sex Differences in Aortic Remodeling During Blood Pressure Reduction Following Gradual Hypertension Development in Spontaneously Hypertensive Rats

BackgroundCardiovascular disease risk is higher in men than in women. Although sex differences in aortic wall adaptation following antihypertensive treatment have been reported in acute hypertension models, the response after gradually developing hypertension, which mimics human essential hypertension, remains unclear. This study investigated sex differences in aortic wall adaptation following acute blood pressure reduction after gradually developing hypertension. MethodSeventeen-week-old spontaneously hypertensive rats (SHRs) were assigned to the Hypertensive group or the antihypertensive (Reversal) group (N = 5/sex each). The Reversal group received the antihypertensive drug captopril for 4 weeks to maintain systolic blood pressure below 130 mmHg. Age-matched Wistar Kyoto rats (N = 3/sex) served as normotensive (Normal) group. After the experimental period, arterial wall thickness, circumferential wall stress, smooth muscle cell phenotype, and histological changes were evaluated. ResultsAntihypertensive treatment significantly reduced systolic blood pressure in both sexes. Both male and female SHRs exhibited elevated circumferential wall stress during the gradual development of hypertension. In females, antihypertensive treatment significantly reduced medial thickness compared with the Hypertensive group, whereas males showed no reduction. Circumferential wall stress in female Reversal group did not differ significantly from either the Hypertensive or Normal group, whereas males exhibited a significant reduction in circumferential wall stress compared with the Hypertensive group. Furthermore, the reduced collagen area fraction in the Hypertensive group returned to the normotensive levels only in females following antihypertensive treatment. ConclusionThese findings indicate that vascular remodeling induced by gradually developing hypertension is more effectively reversed by antihypertensive treatment in females than in males.

bioengineering↗

bioRxiv2026

Increased Interstitial Flow and Elastic Lamina Degradation Precede Aortic Dissection

AimsTo elucidate the relationship between interstitial flow (IF) and structural changes in the aortic media during the development of aortic dissection (AD). MethodsApolipoprotein E-deficient (ApoE[-/-]) mice infused with angiotensin II (AngII) were used as an AD model, in which AD develops exclusively in the thoracoabdominal aorta but not in the thoracic aorta. To capture characteristics present prior to AD onset, the duration of AngII infusion was shortened to generate Pre-AD group. Normal C57BL/6 mice (Normal group) and ApoE(-/-) mice without AngII infusion (Control group) were also included for comparison. Thoracic and thoracoabdominal aortas were excised from all groups, and IF was measured in vitro in accordance with our previously established methods. ResultsIF velocity was generally smaller than 4 m/s across all groups; however, velocities exceeding 4 m/s was observed predominantly in the thoracoabdominal region of the Pre-AD group. Although mean IF velocity did not differ significantly among groups, the standard deviation differed significantly and was the highest in the thoracoabdominal region of the Pre-AD group. In this region, IF velocity tended to increase with more prolonged AngII administration, indicating acceleration of IF prior to AD onset. Three-dimensional internal structural microscopy revealed fragmentation of the elastic lamina (ELs) and a reduction in elastin density only in the thoracoabdominal region of the Pre-AD group. ConclusionsOur findings suggest that increased IF and EL degradation occur in parallel and together contribute to the initiation of AD.

bioengineering↗

bioRxiv2026

Dysregulated flow responses drive pathogenesis in a cellular model of Sturge-Weber syndrome

Vascular diseases comprise a broad spectrum of conditions associated with organ dysfunction, yet how endothelial responses to mechanical forces drive their pathogenesis remains unclear. Sturge-Weber syndrome (SWS), a flow-associated vascular malformation caused by somatic GNAQ mutations, provides a model to investigate this question. Here, using isogenic induced pluripotent stem cell-derived endothelial cells (ECs), perfusable vascular models, and simplified systems under defined flow conditions, we show that SWS ECs exhibited maladaptive responses to laminar flow, including impaired flow alignment, reduced CLDN5 expression, and decreased transendothelial electrical resistance. Importantly, three-dimensional acoustic microscopy uncovered disturbed surface changes in SWS ECs, potentially contributing to changes in mechanosensing signaling. Transcriptomic and chromatin accessibility analyses revealed dysregulated flow-responsive gene programs, some of which were validated in human SWS samples. These findings provide insights into flow-dependent endothelial dysfunction and a framework for therapeutic modulation in SWS and other vascular disorders.

cell biology↗

bioRxiv2026

Expanding and Decoding the Chemistry of Phospholipid Headgroup in Eukaryotes

Cellular membranes have diverse phospholipids, chemical differences in whose headgroups impact many biological processes. Phosphatidylcholine is an essential phospholipid for human health, but not universally required for life. The evolutionary mechanisms underlying phospholipid preferences remain poorly understood, due to the difficulty of investigating metabolite structure-activity relationships in a cellular context. Here, we developed a generalizable metabolic-rewiring method to manipulate phospholipid headgroups together and their biological effects. This approach utilizes synthetic media to hijack evolutionarily conserved phosphatidylcholine biosynthesis, leveraging xenobiotics as principal precursors for scalable headgroup transformations. By identifying over 100 artificial headgroups, we expanded the chemical diversity of xenobiotic phospholipids. Unexpectedly, we discovered that subtle headgroup alterations produced distinct mammalian cellular activities. We demonstrated that chemical headgroup modifications differentially elicited structure-dependent effects on phospholipid-protein interactions, calcium dynamics, transcriptomic profiles, and stem cell differentiation. Notably, cross-species comparison revealed that human and yeast cells have different headgroup preferences critical for cell life and death. As proof-of-concept, interactome analysis identified headgroup-sensitive human microproteins vital for mitochondrial respiration, but non-conserved in yeast. These results exemplify the evolutionary diversity of key phospholipid-protein interactions, illustrating why humans depend on phosphatidylcholine. Overall, our findings establish a programmable platform for elucidating and engineering phospholipid-driven cellular functions.

cell biology↗

bioRxiv2024

Systemic injection of scopolamine increased the variability of temporal prediction in head-fixed mice.

Several theories propose that interval timing and memory share common cognitive mechanisms. Pharmacological disruption of the cholinergic system using scopolamine, a muscarinic acetylcholine receptor antagonist, is widely used as a model of cognitive impairment. However, its effects on temporal prediction remain poorly understood. Previous timing studies in freely moving animals are difficult to interpret because motor activity may confound measures of interval timing. Here, we investigated the effects of systemic scopolamine administration on temporal prediction in mice using a head-fixed behavioral paradigm. Mice were trained on a fixed-time schedule task using a peak procedure, in which a 10% sucrose solution was delivered every 10 s through a spout positioned within licking distance. After training, mice developed anticipatory licking responses that peaked around the expected reward time, demonstrating temporal prediction of reward delivery. Systemic administration of scopolamine increased the variability of temporal prediction in a dose-dependent manner without altering the mean peak time. Trial-by-trial analysis further revealed that scopolamine reduced the duration of licking bouts while preserving the total number of licks during peak trials, suggesting impaired maintenance of reward-directed licking behavior rather than altered reward consumption. In a separate open-field assay, scopolamine increased spontaneous locomotor activity and reduced fecal output. These findings demonstrate that cholinergic blockade disrupts the precision of temporal prediction and alters behavioral organization in mice. The increased variability in timing behavior following scopolamine administration may reflect impaired regulation of transitions between behavioral states, providing new insights into the role of cholinergic signaling in temporal cognition.

neuroscience↗

bioRxiv2024

Disruption of ultrasonic vocalization with systemic administration of the non-competitive N-methyl-d-aspartate receptor antagonist MK-801 in adult male mice

Objective: Social behavior and communication, including ultrasonic vocalizations (USVs), are important for survival and reproductive success across species. N-methyl-D-aspartate (NMDA) receptors contribute to the neural mechanisms underlying social behavior, and pharmacological modulation of these receptors can alter both social behavior and USVs in rodents. However, the effects of NMDA receptor blockade on dyadic USVs and social approach during male-female interactions in mice remain incompletely understood. We therefore investigated the effects of systemic administration of MK-801, a noncompetitive NMDA receptor antagonist, on dyadic vocal activity, social approach, locomotor behavior, and excretory outcomes in adult male mice. Methods: Sexually experienced male mice were tested in male-female interaction and same-sex social-preference tasks. Using VocalMat, a machine-learning-based tool, we classified the USVs recorded during male-female interactions into 11 call categories and examined their temporal relationship to the proximity of the male subject to the female stimulus. Results: Administration of MK-801 to the male dose-dependently reduced the total number of USVs recorded from the male-female dyad, with a marked reduction at the highest dose, while leaving the treated male's proximity to the female stimulus unchanged. In the same-sex social-preference task, MK-801 reduced the time spent near the social stimulus at the highest dose, although preference for the social stimulus over the non-social object remained significant under all treatment conditions. MK-801 also increased locomotor activity and reduced fecal output and estimated urine output in the open-field task. These findings demonstrate that systemic NMDA receptor blockade differentially affects dyadic vocal communication, social approach, locomotor activity, and excretory outcomes. Conclusion: Systemic MK-801 administration to the male reduced the number of USVs recorded during male-female interactions and produced distinct effects on social approach, locomotor activity, and excretory outcomes. These findings indicate that NMDA receptor blockade differentially affects multiple behavioral domains, although the mechanisms underlying the reduction in USVs remain to be determined.

pharmacology and toxicology↗

bioRxiv2024

Monosynaptically-interconnected Network Module (MNM) Approach for High-Resolution Brain Sub-Network Analysis

We introduce the Monosynaptically-interconnected Network Module (MNM) approach, an innovative method designed for efficiently analyzing the anatomical structure and functional dynamics of specific brain network modules in vivo. Utilizing an Intein-mediated split-Cre system combined with bidirectional adeno-associated viruses, this technique precisely targets and manipulates monosynaptically interconnected modular subnetworks in freely moving animals. We demonstrate its utility through anatomical and functional mapping of a specific MNM encompassing the prefrontal cortex (PFC), basolateral amygdala (BLA), and intermediary hub regions. Specifically, the MNM approach with Cre-reporter mice visualizes detailed network architecture and enables the tracing of axonal connections among the nodes in the network. Furthermore, integration of the MNM approach with Cre-dependent Ca2+ indicator and multi-fiber photometry in freely moving mice reveals enhanced correlative network activities in social contexts. This versatile technique offers significant potential for advancing our understanding of network functions that underlie complex behaviors, providing a modular network perspective.

neuroscience↗

bioRxiv2022

Differential effects of oxytocin receptor antagonist on social rank and other social behavior in mice

Oxytocin receptor signaling has been implicated in diverse social behaviors, but whether its behavioral effects depend on social tasks and an individual's position within a hierarchy remains unclear. We examined the effects of systemic administration of L-368,899, a blood-brain barrier-penetrating oxytocin receptor antagonist, across four domains of social behavior in male C57BL/6J mice: social rank, sex preference, general social preference, and dyadic interaction. Following the establishment of stable hierarchies in the tube test, administration of L-368,899 (10 mg/kg, intraperitoneally) to first-ranked mice did not alter their hierarchical position. Rank fluctuations were observed more frequently when the antagonist was administered to second-ranked mice. In both rank conditions, the remaining cage mates received saline. In the sex-preference task, saline-treated males spent more time in the female stimulus zone than in the male stimulus zone, whereas this preference was not statistically detectable following treatment with L-368,899 (3 or 10 mg/kg). In contrast, L-368,899 did not significantly alter proximity-based preference for a novel male over a nonsocial object or affect contact duration and inter-individual distance during dyadic interactions between familiar male cage mates, in which both members of each pair received the same treatment. Thus, systemic oxytocin receptor blockade did not produce a generalized reduction in social approach. Instead, the observed behavioral patterns suggest that its effects depend on specific social behavioral tasks and hierarchical position. These findings provide a pharmacological basis for further investigation of the task- and rank-dependent contributions of oxytocin receptor signaling to social behavior.

neuroscience↗

bioRxiv2021

Novel method for clarifying faster interstitial flow in the intimal side of the aorta under intraluminal pressurization

Hypertension causes aortic thickening, especially on the intimal side. Although the production of the extracellular matrix is observed, the type of mechanical stress that produces this response remains unclear. In this study, we hypothesize that the interstitial flow causes the thickening. To validate this claim, we proposed a novel method to measure the velocity distribution in the radial direction in the aorta, which has been unclear. A fluorescent dye was introduced in the lumen of the mouse thoracic aorta ex vivo, intraluminal pressure was applied, and a time-lapse image in the radial-circumferential plane was acquired under a two-photon microscope. The flow of the fluorescent dye from the intimal to the adventitial sides in the aorta was successfully observed. The acquired image was converted to a radial-time image (i.e., kymograph), and the flow velocity was quantified by applying the one-dimensional advection-diffusion equation to the fluorescent images. The results revealed a higher interstitial flow velocity in the aortic walls under higher intraluminal pressure and a higher velocity on the more intimal side. Thus, the interstitial flow is a candidate for the mechanical stress causing hyperplasia of the aorta under hypertension.

biophysics↗

bioRxiv2021

Transient induction of cell cycle promoter Fam64a improves cardiac function through regulating Klf15-dependent cardiomyocyte differentiation in mice

The introduction of fetal or neonatal signatures such as cell cycle promoting genes into damaged adult hearts has been vigorously pursued as a promising strategy for stimulating proliferation and regeneration of adult cardiomyocytes, which normally cannot divide. However, cell division of cardiomyocytes requires preceding dedifferentiation with sarcomere disassembly and calcium dysregulation, which, in principle, compromises contractile function. To overcome this intrinsic dilemma, we explored the feasibility of optimizing the induction protocol of the cell cycle promoter in mice. As a model of this approach, we used Fam64a, a fetal-specific cardiomyocyte cell cycle promoter that we have recently identified. We first analyzed transgenic mice maintaining long-term cardiomyocyte-specific expression of Fam64a after birth, when endogenous expression was abolished. Despite having an enhanced proliferation of postnatal cardiomyocytes, these mice showed age-related cardiac dysfunction characterized by sustained cardiomyocyte dedifferentiation, which was reminiscent of the dilemma. Mechanistically, Fam64a inhibited glucocorticoid receptor-mediated transcriptional activation of Klf15, a key regulator that drives cardiomyocyte differentiation, thereby directing cardiomyocytes toward immature undifferentiated states. In contrast, transient induction of Fam64a in cryoinjured wildtype adult mice hearts improved functional recovery with augmented cell cycle activation of cardiomyocytes. These data indicate that optimizing the intensity and duration of the stimulant to avoid excessive cardiomyocyte dedifferentiation could pave the way toward developing efficient strategy for successful heart regeneration.

physiology↗

bioRxiv2020

Interceptive capturing in large-billed crows: Velocity-dependent weighing of prediction of future target location and visual feedback of current target location.

Interception of a moving target is a fundamental behaviour of predators and requires tight coupling between the sensory and motor systems. In the literature of foraging studies, feedback mechanisms based on current target position are frequently reported. However, there have also been recent reports of animals employing feedforward mechanisms, in which prediction of future target location plays an important role. In nature, coordination of these two mechanisms may contribute to intercepting evasive prey. However, how animals weigh these two mechanisms remain poorly understood. Here, we conducted a behavioural experiment involving crows (which show flexible sensorimotor coordination in various domains) capturing a moving target. We changed the velocity of the target to examine how the crows utilised prediction of the target location. The analysis of moment-to-moment head movements and computational simulations revealed that the crows used prediction of future target location when the target velocity was high. In contrast, their interception depended on the current momentary position of the target when the target velocity was slow. These results suggest that crows successfully intercept targets by weighing predictive and visual feedback mechanisms, depending on the target velocity.

animal behavior and cognition↗