Miyagishi Hiroko, Tsuji Minoru, Miyagawa Kazuya, Kurokawa Kazuhiro, Mochida-Saito Atsumi, Takahashi Kohei, Kosuge Yasuhiro, Ishige Kumiko, Takeda Hiroshi
Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan; Laboratory of Pharmacology, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan.
Brain Res. 2022 May 15;1783:147859. doi: 10.1016/j.brainres.2022.147859. Epub 2022 Mar 2.
The ability to adapt to stress is an essential defensive function of a living body, and disturbance of this ability in the brain may contribute to the development of affective illness. Previously, we reported that mice exposed to unadaptable restraint stress show emotional abnormality. Moreover, this emotional abnormality was alleviated by chronic treatment with flesinoxan, a serotonin (5-HT) receptor agonist. 5-HT receptor expression is regulated by several transcription factors such as nuclear deformed epidermal autoregulatory factor (NUDR/Deaf-1) and five prime repressors under dual repression binding protein 1 (Freud-1). The present study was designed to investigate the expression levels of 5-HT receptor and its transcription factors in the midbrain and hippocampus of stress-adaptive and -unadaptive mice. Mice were exposed to 14 days of repeated adaptable (1 h/day) or repeated unadaptable (4 h/day) restraint stress, or were left in their home cage (non-stressed groups). In a western blot analysis, a significant increase in the expression levels of 5HT receptor protein were observed in the hippocampal membrane fraction in stress-adaptive mice. In contrast, the expression levels of 5-HT receptor protein in stress-unadaptive mice were significantly increased in both cytoplasmic and membrane fraction of the midbrain. Furthermore, real-time PCR analysis revealed that, in the midbrain of stress-unadaptive mice, the expression levels of 5-HT receptor mRNA and Freud-1 or NUDR mRNA were significantly increased and decreased, respectively. These results suggest that increased expression of 5-HT receptor due to decrease in the expression of Freud-1 and NUDR in the midbrain may play a pivotal role in the emotional abnormality of stress-unadaptive mice.
适应压力的能力是生物体一项重要的防御功能，而大脑中这种能力的紊乱可能会导致情感性疾病的发生。此前，我们报道过，暴露于无法适应的束缚应激下的小鼠会出现情绪异常。此外，用血清素（5-羟色胺，5-HT）受体激动剂氟西诺生进行长期治疗可缓解这种情绪异常。5-HT受体的表达受多种转录因子调控，如核变形表皮自调节因子（NUDR/Deaf-1）和双抑制结合蛋白1（Freud-1）作用下的5′端阻遏物。本研究旨在调查应激适应型和非适应型小鼠中脑和海马体中5-HT受体及其转录因子的表达水平。将小鼠暴露于14天的重复适应性（每天1小时）或重复非适应性（每天4小时）束缚应激下，或置于其饲养笼中（非应激组）。在蛋白质免疫印迹分析中，应激适应型小鼠海马体膜组分中5HT受体蛋白的表达水平显著增加。相比之下，应激非适应型小鼠中脑的细胞质和膜组分中5-HT受体蛋白的表达水平均显著增加。此外，实时定量聚合酶链反应分析显示，在应激非适应型小鼠的中脑中，5-HT受体信使核糖核酸（mRNA）以及Freud-1或NUDR mRNA的表达水平分别显著增加和降低。这些结果表明，中脑中Freud-1和NUDR表达的减少导致5-HT受体表达增加，这可能在应激非适应型小鼠的情绪异常中起关键作用。
