Han Rafael T, Kim Young-Beom, Park Eui-Ho, Kim Jin Yong, Ryu Changhyeon, Kim Hye Y, Lee JaeHee, Pahk Kisoo, Shanyu Cui, Kim Hyun, Back Seung K, Kim Hee J, Kim Yang In, Na Heung S
Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine, Seoul, South Korea.
Department of Anatomy, Korea University College of Medicine, Seoul, South Korea.
Front Mol Neurosci. 2018 Aug 14;11:246. doi: 10.3389/fnmol.2018.00246. eCollection 2018.
Isolation stress is a major risk factor for neuropsychiatric disorders such as depressive and anxiety disorders. However, the molecular mechanisms underlying isolation-induced neuropsychiatric disorders remain elusive. In the present study, we investigated the subcellular mechanisms by which long-term isolation elicits depression and anxiety-related behaviors in mice. First, we found that long-term isolation induced depression-related behaviors in the forced swimming test (FST) and the sucrose preference test, as well as anxiety-related behaviors in the elevated zero maze test (EZMT) and the open field test. Next, we showed that intracentral amygdala (CeA) injection of oxytocin (OXT), but not intracerebroventricular injection, attenuated isolation-induced depression and anxiety-related behaviors via oxytocin receptor (OXTR), not vasopressin-1a receptor (V1aR), in the FST and EZMT, respectively. Quantitative real-time polymerase chain reaction analysis revealed that after 5 weeks of isolation, mRNA transcription of OXTR in the CeA, but not that of V1aR, significantly decreased, whereas OXT and vasopressin mRNA transcription in the paraventricular nucleus of hypothalamus did not change significantly. Whole-cell patch clamping of acute brain slices demonstrated that the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in CeA neurons, but not their amplitude, was lower in isolated mice than in group-housed mice. Notably, OXT treatment increased the mIPSC frequency in the CeA neurons, but to a lesser extent in the case of isolated mice than in that of group-housed mice via OXTR. Taken together, our findings suggest that long-term isolation down-regulates OXTR mRNA transcription and diminishes OXT-induced inhibitory synaptic transmission in the CeA and may contribute to the development of depression and anxiety-related behaviors in isolated mice through the enhancement of CeA activity.
隔离应激是抑郁和焦虑症等神经精神疾病的主要危险因素。然而，隔离诱发神经精神疾病的分子机制仍不清楚。在本研究中，我们探究了长期隔离引发小鼠抑郁和焦虑相关行为的亚细胞机制。首先，我们发现在强迫游泳试验（FST）和蔗糖偏好试验中，长期隔离诱发了抑郁相关行为，在高架零迷宫试验（EZMT）和旷场试验中诱发了焦虑相关行为。接下来，我们表明，在FST和EZMT中，向中央杏仁核（CeA）注射催产素（OXT），而非脑室内注射，分别通过催产素受体（OXTR）而非血管升压素1a受体（V1aR）减轻了隔离诱发的抑郁和焦虑相关行为。定量实时聚合酶链反应分析显示，隔离5周后，CeA中OXTR的mRNA转录显著下降，而V1aR的mRNA转录没有显著变化，而下丘脑室旁核中OXT和血管升压素的mRNA转录没有显著改变。急性脑片的全细胞膜片钳记录表明，隔离小鼠CeA神经元中微小抑制性突触后电流（mIPSCs）的频率低于群居小鼠，但幅度没有差异。值得注意的是，OXT处理增加了CeA神经元中的mIPSC频率，但通过OXTR，隔离小鼠增加的程度小于群居小鼠。综上所述，我们的研究结果表明，长期隔离下调了CeA中OXTR的mRNA转录，并减少了OXT诱导的抑制性突触传递，可能通过增强CeA活性导致隔离小鼠出现抑郁和焦虑相关行为。
