Long-Term Isolation Elicits Depression and Anxiety-Related Behaviors by Reducing Oxytocin-Induced GABAergic Transmission in Central Amygdala

Rafael T. Han, Young Beom Kim, Eui Ho Park, Jin Yong Kim, Changhyeon Ryu, Hye Y. Kim, Jae Hee Lee, Kisoo Pahk, Cui Shanyu, Hyun Kim, Seung K. Back, Hee J. Kim, Yang In Kim, Heung S. Na

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53 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number246
JournalFrontiers in Molecular Neuroscience
Volume11
DOIs
Publication statusPublished - 2018 Aug 14

Bibliographical note

Funding Information:
We would like to thank Dr. Morris Manning for generous donation of the neuropeptide receptor antagonists and Dr. Hyun Jung Kim for helpful comments on immunohistochemistry. Funding. This research was supported by Korea University Future Research grant (K1721361), National Research Foundation of Korea (NRF) grants funded by the Korean government (Ministry of Science, Information and Communications Technology and Future Planning) (2016R1D1A1B03932771 to Y-BK and 2017R1A2B2002277 to YK), and the ChungYang, Cha Young Sun, M.D., and Jang Hi Joo Yeu Sa Memorial Fund.

Funding Information:
This research was supported by Korea University Future Research grant (K1721361), National Research Foundation of Korea (NRF) grants funded by the Korean government (Ministry of Science, Information and Communications Technology and Future Planning) (2016R1D1A1B03932771 to Y-BK and 2017R1A2B2002277 to YK), and the ChungYang, Cha Young Sun, M.D., and Jang Hi Joo Yeu Sa Memorial Fund.

Publisher Copyright:
© 2018 Han, Kim, Park, Kim, Ryu, Kim, Lee, Pahk, Shanyu, Kim, Back, Kim, Kim and Na.

Keywords

  • Central amygdala (CeA)
  • Depression and anxiety disorders
  • Gamma-aminobutyric acid
  • Inhibitory synaptic transmission
  • Isolation
  • Oxytocin

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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