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

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.

Antidepressant mechanism of classical herbal formula lily bulb and Rehmannia decoction: insights from gene expression profile of medial prefrontal cortex of mice with stress‐induced depression‐like behavior

“…Converging reports on stress‐induced GABA and glutamate dysfunction have shown that the impaired balance of neural excitation and inhibition is a characteristic feature of depression pathophysiology . In addition, novel rapid‐acting agents and allosteric modulators of glutamate or GABA receptor complexes can reset both excitatory and inhibitory neurotransmitter systems . The neurotrophin signaling, MAPK and PI3K‐Akt signaling pathways were closely related to the BDNF/TrkB‐dependent PI3K/Akt/mTOR1 pathway, according to the pathway diagram provided by the KEGG database.…”

Role of oxytocin in the control of stress and food intake

“…102 Administration of oxytocin into the central amygdala has also been shown to reduce anxiety-related behaviour in female rats. 102 Administration of oxytocin into the central amygdala has also been shown to reduce anxiety-related behaviour in female rats.…”

“…Activation of the oxytocin receptor in the central amygdala has been reported to reverse isolation stress-induced anxiety-related behaviour in mice. 102 Administration of oxytocin into the central amygdala has also been shown to reduce anxiety-related behaviour in female rats. 103 Oxytocin has also been suggested to reduce conditioned fear- On the other hand, contradictory findings have also been reported.…”

Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats

“…Oxytocin-synthesizing neurons in the PVN project long-range axonal terminals to the CeL, where the local release of oxytocin directly regulates anxiety levels (35,36), fear memories and fear extinction (37,38). Moreover, a recent study highlighted the pivotal role of oxytocin signaling in the CeA in mouse models of depression (39). While neuroin ammation in the PVN of HF rats has been previously described (25,26), it is at present unknown whether HF-induced neuroin ammation in other brain areas, such as the CeA also occurs, and if so, how it temporally relates to the onset of neuroin ammation in the PVN.…”