Rui Yamada, Hirotaka Nagai, Io Horikawa, Wenran Qiu, Yunhui Zhu, Kohei Ota and Tomoyuki Furuyashiki : C57BL/6J and C57BL/6N mice show distinct aging-associated behavioral alterations., Journal of Pharmacological Sciences, 157, 2, 124-129, 2025.
(要約)
Aging affects emotional, cognitive, and social functions, increasing susceptibility to neuropsychiatric conditions. C57BL/6 mice are commonly used to study aging mechanisms, yet differences between C57BL/6J and C57BL/6N substrains remain underexplored. This study compared aging-related behavioral changes in these substrains. Aging reduced exploratory activity and heightened anxiety in C57BL/6J, but not C57BL/6N, mice. Conversely, aging reduced social novelty preference in C57BL/6N, but not C57BL/6J, mice. Male mice of both substrains exhibited increased female urine sniffing with age. These findings highlight substrain-specific aging effects, underscoring the importance of substrain selection in behavioral studies of aged mice for drug development.
Io Horikawa, Hirotaka Nagai, Masayuki Taniguchi, Guowei Chen, Masakazu Shinohara, Tomohide Suzuki, Shinichi Ishii, Yoshio Katayama, Shiho Kitaoka and Tomoyuki Furuyashiki : Chronic stress alters lipid mediator profiles associated with immune-related gene expressions and cell compositions in mouse bone marrow and spleen., Journal of Pharmacological Sciences, 154, 4, 279-293, 2024.
(要約)
Despite the importance of lipid mediators in stress and depression and their link to inflammation, the influence of stress on these mediators and their role in inflammation is not fully understood. This study used RNA-seq, LC-MS/MS, and flow cytometry analyses in a mouse model subjected to chronic social defeat stress to explore the effects of acute and chronic stress on lipid mediators, gene expression, and cell population in the bone marrow and spleen. In the bone marrow, chronic stress induced a sustained transition from lymphoid to myeloid cells, accompanied by corresponding changes in gene expression. This change was associated with decreased levels of 15-deoxy-d12,14-prostaglandin J2, a lipid mediator that inhibits inflammation. In the spleen, chronic stress also induced a lymphoid-to-myeloid transition, albeit transiently, alongside gene expression changes indicative of extramedullary hematopoiesis. These changes were linked to lower levels of 12-HEPE and resolvins, both critical for inhibiting and resolving inflammation. Our findings highlight the significant role of anti-inflammatory and pro-resolving lipid mediators in the immune responses induced by chronic stress in the bone marrow and spleen. This study paves the way for understanding how these lipid mediators contribute to the immune mechanisms of stress and depression.
(キーワード)
ノックアウトマウス (knockout mice) / Animals / Spleen / Bone Marrow / Chromatography, Liquid / Tandem Mass Spectrometry / 炎症 (inflammation) / Lipids / 遺伝子発現 (gene expression)
Satoshi Akiyama, Hirotaka Nagai, Shota Oike, Io Horikawa, Masakazu Shinohara, Yabin Lu, Takashi Futamura, Ryota Shinohara, Shiho Kitaoka and Tomoyuki Furuyashiki : Chronic social defeat stress increases the amounts of 12-lipoxygenase lipid metabolites in the nucleus accumbens of stress-resilient mice., Scientific Reports, 12, 1, 2022.
(要約)
Severe and prolonged social stress induces mood and cognitive dysfunctions and precipitates major depression. Neuroinflammation has been associated with chronic stress and depression. Rodent studies showed crucial roles of a few inflammation-related lipid mediators for chronic stress-induced depressive-like behaviors. Despite an increasing number of lipid mediators identified, systematic analyses of synthetic pathways of lipid mediators in chronic stress models have not been performed. Using LC-MS/MS, here we examined the effects of chronic social defeat stress on multiple synthetic pathways of lipid mediators in brain regions associated with stress susceptibility in mice. Chronic social defeat stress increased the amounts of 12-lipoxygenase (LOX) metabolites, 12-HETE and 12-HEPE, specifically in the nucleus accumbens 1 week, but not immediately, after the last stress exposure. The increase was larger in stress-resilient mice than stress-susceptible mice. The S isomer of 12-HETE was selectively increased in amount, indicating the role of 12S-LOX activity. Among the enzymes known to have 12S-LOX activity, only Alox12 mRNA was reliably detected in the brain and enriched in brain endothelial cells. These findings suggest that chronic social stress induces a late increase in the amounts of 12S-LOX metabolites derived from the brain vasculature in the nucleus accumbens in a manner associated with stress resilience.
Hirofumi Hohjoh, Io Horikawa, Kimie Nakagawa, Eri Segi-Nishida and Hiroshi Hasegawa : Induced mRNA expression of matrix metalloproteinases Mmp-3, Mmp-12, and Mmp-13 in the infarct cerebral cortex of photothrombosis model mice., Neuroscience Letters, 739, 2020.
(要約)
A strong therapeutic target of ischemic stroke is controlling brain inflammation. Recent studies have implicated the critical role of C-C chemokine receptor 5 (CCR5) in neuroinflammation during ischemic stroke. It has been reported that the expression of the matrix metalloproteinases, MMP-3, MMP-12, and MMP-13, is controlled by CCR5; however, their expressional regulation in the infarct brain has not been clearly understood. This study investigated the mRNA expression of Mmp-3, -12, and -13 in the ischemic cerebral cortex of photothrombosis mouse model. The three Mmps were highly upregulated in the early stages of ischemic stroke and were expressed in different types of cells. Mmp-3 and Mmp-13 were expressed in blood vessel endothelial cells after ischemia-induction, whereas Mmp-12 was expressed in activated microglia. The expression of Mmp-13 in resting microglia and in neurons of uninjured cerebral cortex was lost in the infarct region. Therefore, the MMPs responding to CCR5 are differentially regulated during ischemic stroke.