Biology subjects

Furuyashiki, T.

Publications and source records attributed to Furuyashiki, T..

5 recordsLinked to original sources

bioRxiv2026

Synaptic mitochondrial oxidative stress drives individual variability in age-related cognitive decline in mice

Aging leads to cognitive decline with considerable individual variability, yet the biological mechanisms remain unclear. Here we performed ultrastructural and proteomic analyses of the medial prefrontal cortex (mPFC) alongside behavioral assessments of attentional set shifting in mice across age groups. Although reduced synaptic density did not consistently lead to cognitive decline, proteomic analyses of synaptosomes and whole tissue revealed that the molecular signatures associated with individual variability in cognitive decline were distinct from those associated with chronological aging, and that synaptic mitochondria and their proteins were more abundant in aged mice with greater cognitive decline. Moreover, treatment with the mitochondria-targeted antioxidant MitoQ reduced the abundance of synaptic mitochondrial proteins, including pro-apoptotic proteins, and mitigated age-related cognitive decline. These findings demonstrate that synaptic mitochondrial oxidative stress in the mPFC, distinct from chronological age-related processes, contributes to individual variability in age-related cognitive decline and offers a potential target for prevention and intervention.

animal behavior and cognition↗

bioRxiv2026

Aging Converts Microglial Repopulation into Maladaptive Reprogramming that Exacerbates Cognitive Deficits

Background and PurposeAging has been associated with neuroinflammation and cognitive decline. Microglial repopulation after pharmacological depletion has been proposed as a strategy to alleviate microglia-driven neuropathology. However, the effects of microglial repopulation on age-related cognitive decline remain largely unexplored. In the present study, we examined how microglial repopulation affects the transcriptomic profiles of cortical microglia and the decline in prefrontal cortex-dependent cognitive function in aged mice. Experimental ApproachYoung and aged male C57BL/6J mice were used in this study. Microglial depletion was induced by treatment with PLX3397, a CSF1R inhibitor, followed by microglial repopulation after drug withdrawal. Microglia isolated from the entire cerebral cortex were subjected to bulk RNA-sequencing analysis. The visual discrimination test followed by the response direction test was conducted to assess sensory learning and attentional set shifting abilities, respectively. Key ResultsRepopulated cortical microglia in aged, but not young, mice exhibited aberrant gene expression patterns, including reduced expression of microglial identity genes, reprogramming of innate and adaptive immune-related gene expression, and derepression of neuronal gene expression. Furthermore, microglial repopulation selectively impaired visual discrimination learning and attentional set shifting in aged mice. Conclusion and ImplicationsThese findings demonstrate that aging converts microglial repopulation into maladaptive reprogramming that exacerbates cognitive decline, possibly through aberrant gene expression programs. Therefore, the therapeutic potential of this approach must be carefully evaluated with respect to specific behavioral domains and disease contexts, including aging.

neuroscience↗

bioRxiv2025

Lateralized vagal oxytocin signaling separately controls feeding and socioemotional functions via hypothalamic oxytocin signaling

Oxytocin neurons in the paraventricular hypothalamus (PVHOxt) regulate feeding, anxiety, and social behaviors. Activation of Oxt receptor (Oxtr) -expressing vagal sensory neurons engages these PVHOxt neurons and improves hyperphagic obesity; however, their roles in anxiety and sociability remain unclear. Here, we activated vagal Oxtr-expressing neurons in male mice using a single intraperitoneal (IP) Oxt injection or chemogenetics. IP Oxt reduced anxiety-like behavior, enhanced social interaction, and suppressed feeding while activating both vagal sensory neurons and PVHOxt neurons. These effects were abolished by chemogenetic inhibition of PVHOxt neurons or central Oxtr blockade. Subdiaphragmatic vagotomy revealed lateralized functions: right-side vagotomy eliminated anxiolytic and prosocial effects, whereas left-side vagotomy blocked feeding suppression. Consistently, chemogenetic activation of left-sided neurons suppressed feeding, while right-sided activation reduced anxiety and increased sociability. These findings identify Oxtr-expressing vagal sensory neurons as a major peripheral pathway in which left- and right-sided inputs differentially control feeding and socioemotional behaviors.

physiology↗

bioRxiv2023

Stress-induced vascular remodeling: novel insight into the role of omega-3 fatty acid metabolite, 4-oxoDHA

BackgroundStress has garnered significant attention as a prominent risk factor for inflammation-related diseases, particularly cardiovascular diseases (CVDs). However, the precise mechanisms underlying stress-driven CVDs remain elusive, thereby impeding the development of effective preventive and therapeutic strategies. MethodsTo explore the correlation between plasma lipid metabolites and depressive states, we conducted a study involving healthy volunteers (n=408). Liquid chromatography (LC)/mass spectrometry (MS)/MS-based lipidomics and the self-rating depression (SDS) scale questionnaire were employed for data collection. In addition, we utilized a mouse model by subjecting mice to restraint stress and investigating the impact of stress on plasma lipid metabolites and vascular remodeling following carotid ligation. In vitro functional and mechanistic studies were performed using macrophages, endothelial cells, and neutrophil cells. ResultsOur findings revealed a significant association between depressive state and reduced plasma levels of 4-oxoDHA, a specific omega-3 fatty acid metabolite regulated by 5-lipoxygenase (LO) in neutrophils in healthy volunteers. In mice, restraint stress led to decreased plasma 4-oxoDHA levels and exacerbated vascular remodeling. Moreover, 4-oxoDHA demonstrated the ability to enhance Nrf2-HO-1 pathways, exerting anti-inflammatory effects on endothelial cells and macrophages. Mechanistically, stress-induced noradrenaline triggered the degradation of 5-LO in neutrophils through the proteasome system, facilitated by dopamine D2-like receptor activation. The reduction in circulating 4-oxoDHA resulted in the downregulation of the Nrf2-HO-1 anti-inflammatory axis and an increase in ICAM-1 expression, vascular permeability, and remodeling. ConclusionsOur study unveiled a novel stress-induced pathway of vascular inflammation, mediated through the regulation of omega-3 fatty acid metabolites. Reduced levels of circulating 4-oxoDHA under stress conditions may serve as a promising biomarker for stress. This understanding of the interplay between neurobiology and lipid metabolism provides a potential avenue for the development of treatments aimed at preventing stress-induced systemic neuroinflammation. Highlights- Our study reveals that stress-induced reduction in circulating levels of a specific omega-3 fatty acid metabolite, 4-oxoDHA, contributes to vascular inflammation. - We have identified a novel pathway that explains how stress promotes systemic vascular inflammation by regulating omega-3 fatty acid metabolites in the circulation. - Our findings provide new evidence for the role of 4-oxoDHA in maintaining Nrf2-ARE-related anti-inflammatory functions in endothelial cells and macrophages.

biochemistry↗

bioRxiv2022

High salt induces cognitive impairment via the angiotensin II-AT1 and prostaglandin E2-EP1 systems

High salt (HS) intake is a known risk factor for hypertension and dementia. Clinical studies have shown that antihypertensive drugs can decrease the incidence of dementia. Accordingly, a strong relationship can be suggested between hypertension and cognitive impairment. It is well-known that angiotensin II (Ang II)-AT1 and prostaglandin E2 (PGE2)-EP1 systems are involved in hypertension and neurotoxicity. However, the involvement of these systems in HS-mediated hypertension and emotional and cognitive impairments remains unclear. Herein, we demonstrated that hypertension and impaired social behavior and object recognition memory following HS intake could be associated with tau hyperphosphorylation, decreased phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII), and postsynaptic density protein 95 (PSD95) expression in the prefrontal cortex and hippocampus of mice. These changes were blocked by pharmacological treatment with losartan, an Ang II receptor blocker (ARB), or EP1 gene knockout. Our findings suggest that Ang II-AT1 and PGE2-EP1 systems could be novel therapeutic targets for hypertension-induced dementia.

neuroscience↗