Koda, M. | Search bioRxiv

bioRxiv2024

Transcriptional landscape of the dorsal raphe serotonin neurons rendering stress resiliency

Major depressive disorder (MDD) is a serious and large social problem, yet the pathophysiology of MDD and the action mechanism of antidepressants are still poorly understood. A number of studies have reported that activation and inactivation of serotonin neurons in the dorsal raphe nucleus (DRN) cause antidepressant-like effects and depressive-like behaviors, respectively. Also, their physiological neural activities are increased when mice were chronically administered an SSRI and decreased in mice exposed to chronic social defeat stress (CSDS), a mouse model of depression. However, the molecular mechanism underlying these neural activity changes in DRN serotonin neurons remains unclear. In this study, we performed a DRN serotonin neuron-specific comprehensive gene expression analysis by using Translating Ribosome Affinity Purification (TRAP) technology in both chronic SSRI-treated mice as a model of antidepressant treatment and CSDS mice as a model of depression. It revealed that many gene expression changes were the opposite between SSRI-treated mice and CSDS-susceptible mice. Among these, we identified S100a10 as a prodepressive gene in DRN serotonin neurons, and we found that Interleukin-4 (IL-4) - Signal Transducer and Activator of Transcription 6 (STAT6) pathway and 5-HT1B receptor were the upstream and downstream molecules of S100a10, respectively. Our findings provide insights into molecular mechanisms underlying the action of antidepressants and stress resiliency.

pharmacology and toxicology↗

bioRxiv2019

Serum miR-379 expression is related to the development and progression of hypercholesterolemia in non-alcoholic fatty liver disease

IntroductionNon-alcoholic fatty liver disease (NAFLD) has a wide spectrum, eventually leading to cirrhosis and hepatic carcinogenesis. We previously reported that a series of microRNAs (miRNAs) mapped in the 14q32.2 maternally imprinted gene region (Dlk1-Dio3 mat) are related to NAFLD development and progression in a mouse model. We examined the suitability of miR-379, a circulating Dlk1-Dio3 mat miRNA, as a human NAFLD biomarker.\n\nMethodsEighty NAFLD patients were recruited for this study. miR-379 was selected from the putative Dlk1-Dio3 mat miRNA cluster because it exhibited the greatest expression difference between NAFLD and non-alcoholic steatohepatitis in our preliminary study. Real-time PCR was used to examine the expression levels of miR-379 and miR-16 as an internal control.\n\nResultsCompared to normal controls, serum miR-379 expression was significantly up-regulated in NAFLD patients. Receiver operating characteristic curve analysis suggested that miR-379 is a suitable marker for discriminating NAFLD patients from controls, with an area under the curve value of 0.72. Serum miR-379 exhibited positive correlations with alkaline phosphatase, total cholesterol, and low-density-lipoprotein cholesterol levels in patients with early stage NAFLD (Brunt fibrosis stage 0 to 1). The correlation between serum miR-379 and cholesterol levels was lost in early stage NAFLD patients treated with statins. Software-based predictions indicated that various energy metabolism-related genes, including insulin-like growth factor-1 (IGF-1) and IGF-1 receptor, are potential targets of miR-379.\n\nConclusionsSerum miR-379 exhibits high potential as a biomarker for NAFLD. miR-379 appears to increase cholesterol lipotoxicity, leading to the development and progression of NAFLD, via interference with the expression of target genes, including those related to the IGF-1 signaling pathway. Our results could facilitate future research into the pathogenesis, diagnosis, and treatment of NAFLD.

molecular biology↗