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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00246

Long-term isolation elicits depression and anxiety-related behaviors by reducing oxytocin-induced GABAergic transmission in the central amygdala

 Rafael T. Han1, 2,  Young-Beom Kim1, 2,  Eui-Ho Park1, 2,  Jinyong Kim2, 3, Changhyeon Ryu4, Hye Young Kim1, 2, JaeHee Lee1, 2, Kisoo Pahk2, 5, Cui Shanyu1, 2,  Hyun Kim2, 3, Seung Keun Back6, Hee Jin Kim7,  Yang-In Kim1, 2 and Heung Sik Na1, 2*
  • 1Neuroscience Research Institute, Korea University, South Korea
  • 2Department of Physiology, College of Medicine, Korea University, South Korea
  • 3Department of Anatomy, College of Medicine, Korea University, South Korea
  • 4Deparment of Physiology, College of Medicine, Seoul National University, South Korea
  • 5Department of Neuroscience, College of Medicine, Korea University, South Korea
  • 6Department of Pharmaceutics and Biotechnology, College of Medical Engineering, Konyang University, South Korea
  • 7Division of Biological Science and Technology, Science and Technology College, Yonsei University, South Korea

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 intra-central 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 PCR 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 PVN 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 lesser extent in the case of isolated mice in group-housed mice via OXTR.
Taken together, our findings suggest that long-term isolation down-regulated OXTR mRNA transcription and diminished OXT-induced inhibitory synaptic transmission in the CeA, which may contribute to the development of depression and anxiety-related behaviors in isolated mice through the enhancement of CeA activity.

Keywords: Oxytocin, inhibitory synaptic transmission, Central amygdala (CeA), gamma-Aminobutyric Acid, Isolation, depression and anxiety disorders

Received: 20 May 2018; Accepted: 26 Jun 2018.

Edited by:

Rolf Sprengel, Max-Planck-Institut für medizinische Forschung, Germany

Reviewed by:

Valery Grinevich, Deutsches Krebsforschungszentrum, Helmholtz-Gemeinschaft Deutscher Forschungszentren (HZ), Germany
Alexandre Charlet, Centre national de la recherche scientifique (CNRS), France  

Copyright: © 2018 Han, Kim, Park, Kim, Ryu, Kim, Lee, Pahk, Shanyu, Kim, Back, Kim, Kim and Na. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD, PhD. Heung Sik Na, Korea University, Neuroscience Research Institute, Seoul, South Korea,