Molecular analysis of the mouse brain exposed to chronic mild stress: The influence of hepatocyte nuclear factor 4α on physiological homeostasis

Ikubo, Kaoru; Yamanishi, Kyosuke; Doe, Nobutaka; Hashimoto, Takeji; Sumida, Miho; Watanabe, Yuko; El‐Darawish, Yosif; Li, Wen; Okamura, Haruki; Yamanishi, Hiromichi; Matsunaga, Hisato

doi:10.3892/mmr.2017.6577

Cited by 6 publications

(9 citation statements)

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“…RT-qPCR showed that mRNA expression decreased significantly for 16 of 18 molecules in Il18 −/− mice. In our previous study [ 25 ], we proposed that Ahsg and S100 calcium binding protein A9 ( S100a9 ) were key mediators not only of depression but also of physiological dysregulation, for example, diabetes mellitus. Additionally, Ttr was suggested to be an inducer of MDD.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, higher AHSG was reported in male MDD patients compared with controls [ 52 ]. While AHSG expression in the PFC, but not the thalamus and hippocampus, was increased in our depressive model mice, its expression in Il18 −/− mice was unchanged [ 25 ] ( Figure 3(b) ). Thus, these results suggest that AHSG is a key factor connecting depression, energy homeostasis, and the immune system in IL-18 deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…After confirming shallow or absent breathing or a lack of response to pain stimulation, blood from their heart was collected immediately. The serum and brain regions (PFC, hypothalamus, and hippocampus) were removed as previously described, immediately placed in liquid nitrogen, and stored at −80°C until required [ 24 , 25 ].…”

Section: Methodsmentioning

confidence: 99%

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Exploring Molecular Mechanisms Involved in the Development of the Depression-Like Phenotype in Interleukin-18-Deficient Mice

Yamanishi

Miyauchi

Mukai

et al. 2021

BioMed Research International

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Interleukin-18 (IL-18) is an inflammatory cytokine that has been linked to energy homeostasis and psychiatric symptoms such as depression and cognitive impairment. We previously revealed that deficiency in IL-18 led to hippocampal abnormalities and resulted in depression-like symptoms. However, the impact of IL-18 deficiency on other brain regions remains to be clarified. In this study, we first sought to confirm that IL-18 expression in neural cells can be found in human brain tissue. Subsequently, we examined the expression of genes in the prefrontal cortex of Il18−/− mice and compared it with gene expression in mice subjected to a chronic mild stress model of depression. Extracted genes were further analyzed using Ingenuity® Pathway Analysis, in which 18 genes common to both the chronic mild stressed model and Il18−/− mice were identified. Of those, 16 were significantly differentially expressed between Il18+/+ and Il18−/− mice. We additionally measured protein expression of α-2-HS-glycoprotein (AHSG) and transthyretin (TTR) in serum and the brain. In the prefrontal cortex of Il18−/− mice, TTR but not AHSG was significantly decreased. Conversely, in the serum of Il18−/− mice, AHSG was significantly increased but not TTR. Therefore, our results suggest that in IL-18-deficit conditions, TTR in the brain is one of the mediators causally related to depression, and AHSG in peripheral organs is one of the regulators inducing energy imbalance. Moreover, this study suggests a possible “signpost” to clarify the molecular mechanisms commonly underlying the immune system, energy metabolism, neural function, and depressive disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Exploring Molecular Mechanisms Involved in the Development of the Depression-Like Phenotype in Interleukin-18-Deficient Mice

Yamanishi

Miyauchi

Mukai

et al. 2021

BioMed Research International

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“…Furthermore, S100a9 expression has been found in AD patients and genetically modified AD animal models, suggesting that S100a9 expression may be involved in the pathology of AD [ 13 ]. It has been reported that S100a9 is also expressed in animal models of major depressive disorder [ 16 ] and is significantly higher in the dorsolateral prefrontal cortex of schizophrenia patients [ 9 ], suggesting that S100a9 is associated not only with dementia but also with psychiatric disorders such as depression. Although SDT fatty rats are hyperglycemic and obese models and thus may be exposed to chronic inflammation and stress, no increase in TNF-α or HSP70 was observed in this study.…”

Section: Discussionmentioning

confidence: 99%

Pathophysiological features in the brains of female Spontaneously Diabetic Torii (SDT) fatty rats

Maekawa

Sugimoto

Kume

et al. 2022

The Journal of Veterinary Medical Science

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Diabetes mellitus (DM) and obesity are associated with neurodegenerative diseases such as Alzheimer's disease and psychiatric disorders such as major depression. In this study, we investigated pathophysiological changes in the brains of female spontaneously diabetic torii (SDT) fatty rats with diabetes and obesity. Brains of SD, SDT and SDT fatty rats were collected at 58 weeks of age. The parietal cortical thickness was measured and the number of pyramidal cells in the hippocampal cornu ammonis 1 and 3 (CA1 and CA3) and the number of granule cells in the dentate gyrus (DG) regions were counted. The area of glial fibrillary acidic protein (GFAP) positivity in CA1, CA3 and DG regions were measured. The parietal cortical thickness and the number of cells in CA3 and DG regions of SDT and SDT fatty rats did not show obvious changes. On the other hand, in the CA1 region, the number of cells in SDT rats and SDT fatty rats was significantly lower than that in SD rats, and that in SDT fatty rats was significantly lower than that in SDT rats. The GFAP-positive area in SDT fatty rats was significantly reduced compared to that in SD rats only in the DG region. Preliminarily result showed that the expression of S100a9, an inflammation-related gene, was increased in the brains of SDT fatty rats. These results suggest that female SDT fatty rat may exhibit central nervous system diseases due to obesity and DM.

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“…Details regarding RNA purification, microarray analysis, RT-qPCR, and IPA (Ingenuity ® Systems; ingenuity.com) have been described in our previous studies (15)(16)(17).…”

Section: Methodsmentioning

confidence: 99%

Analysis of genes linked to depressive‑like behaviors in interleukin‑18‑deficient mice: Gene expression profiles in the brain

et al. 2019

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Interleukin (IL)-18 is an interferon γ-inducing inflammatory cytokine associated with function of the immune system and other physiological functions. IL-18-deficient (Il18-/-) mice exhibit obesity, dyslipidemia, non-alcoholic steatohepatitis and depressive-like behavioral changes. Therefore, IL-18 has a number of important roles associated with immunity, energy homeostasis and psychiatric conditions. In the present study, gene expression in the brains of Il18-/mice was analyzed to identify genes associated with the depressive-like behaviors and other impairments displayed by Il18-/mice. Using whole genome microarray analysis, gene expression patterns in the brains of Il18 +/+ and Il18-/mice at 6 and 12 weeks of age were examined and compared. Subsequently, genes were categorized using Ingenuity ® Pathway Analysis (IPA). At 12 weeks of age, 2,805 genes were identified using microarray analysis. Genes related to 'Major depression' and 'Depressive disorders' were identified by IPA core analysis, and 13 genes associated with depression were isolated. Among these genes, fibroblast growth factor receptor 1 (Fgfr1); protein tyrosine phosphatase, non-receptor type 1 (Ptpn1); and urocortin 3 (Ucn3) were classed as depression-inducing and the other genes were considered depression-suppressing genes. Subsequently, the interactions between the microarray results at 6 weeks of age and the above three depression-inducing genes were analyzed to search for effector genes of depression at 12 weeks of age. This analysis identified cyclin D1 (Ccnd1) and NADPH oxidase 4 (Nox4). The microarray analysis results were correlated with the results of reverse transcription-quantitative PCR (RT-qPCR). Overall, the results suggest that Fgfr1, Ptpn1 and Ucn3 may be involved in depression-like changes and Ccnd1 and Nox4 regulate these three genes in IL-18-deficient mice.

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Molecular analysis of the mouse brain exposed to chronic mild stress: The influence of hepatocyte nuclear factor 4α on physiological homeostasis

Cited by 6 publications

References 50 publications

Exploring Molecular Mechanisms Involved in the Development of the Depression-Like Phenotype in Interleukin-18-Deficient Mice

Exploring Molecular Mechanisms Involved in the Development of the Depression-Like Phenotype in Interleukin-18-Deficient Mice

Pathophysiological features in the brains of female Spontaneously Diabetic Torii (SDT) fatty rats

Analysis of genes linked to depressive‑like behaviors in interleukin‑18‑deficient mice: Gene expression profiles in the brain

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