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

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

doi:10.3389/fnmol.2018.00246

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.

Highlights

MATERIALS AND METHODSDepressive and anxiety disorders are among the most prevalent neuropsychiatric disorders (Fava et al, 2000)
We examined the effects of long-term isolation on inhibitory synaptic transmission in the medial part of the CeA (CeM)
The miniature inhibitory postsynaptic currents (mIPSCs) amplitude in the CeM was not significantly changed after longterm isolation (Figures 5A,C). These results suggested that long-term isolation attenuated inhibitory synaptic transmission in the CeM via reduction of GABA release from presynaptic terminals

Summary

Introduction

Depressive and anxiety disorders are among the most prevalent neuropsychiatric disorders (Fava et al, 2000). Despite their distinct difference in symptoms, both disorders frequently coexist in one patient (Ballenger, 1999; Ionescu et al, 2013) and share common pathophysiology and risk factors, including abnormal activity in the amygdala and social stressors, respectively (England and Sim, 2009; Grav et al, 2012; Wang et al, 2014). In addition to the dysregulated activity of the amygdala, social stress is a common risk factor of depressive and anxiety disorders. Social isolation is a major risk factor for depressive and anxiety disorders (Wang et al, 2014)

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