Activation of septal OXTr neurons induces anxiety- but not depressive-like behaviors

Tuanjie Huang,Yunlei Yang,Fangxia Guan,Ma-Li Wong,Julio Licinio

doi:10.1038/s41380-021-01283-y

Abstract

The neuropeptide oxytocin (OXT) is well recognized for eliciting anxiolytic effects and promoting social reward. However, emerging evidence shows that OXT increases aversive events. These seemingly inconsistent results may be attributable to the broad OXT receptor (OXTr) expression in the central nervous system. This study selectively activated septal neurons expressing OXTr using chemogenetics. We found that chemogenetic activation of septal OXTr neurons induced anxiety- but not depressive-like behavior. In addition, septal OXTr neurons projected dense fibers to the horizontal diagonal band of Broca (HDB), and selective stimulation of those HDB projections also elicited anxiety-like behaviors. We also found that septal OXTr neurons express the vesicular GABA transporter (vGAT) protein and optogenetic stimulation of septal OXTr projections to the HDB inactivated HDB neurons. Our data collectively reveal that septal OXTr neurons increase anxiety by projecting inhibitory GABAergic inputs to the HDB.

Highlights

It has been well-demonstrated that anxiety is under the control of multiple neuronal populations and complex neural circuits primarily concentrated in the limbic system
We observed that the intensity of GCaMP6s signals recorded on hippocampal projections to the lateral septum was increased when mice were in the light chamber of the light-dark box (LDB) (Fig. 7f, g) or the open arms of the Elevated-plus maze (EPM) (Fig. 7h). It is well-recognized that OXT elicits anxiolytic effects [34, 35] and promotes social reward [10,11,12,13,14,15,16,17] in rodents; human studies show that OXT administration increases recall of aversive events or stressful stimuli [19, 36, 37]
Overexpression of OXT receptor (OXTr) in the septum exacerbates stress-induced fear [38]. These seemingly inconsistent findings might be attributable to different experimental paradigms and reconciled because OXTr is widely expressed in different brain regions

Summary

Introduction

It has been well-demonstrated that anxiety is under the control of multiple neuronal populations and complex neural circuits primarily concentrated in the limbic system. There is ample evidence showing that OXT elicits anxiolytic effects [13,14,15,16,17] and ameliorates depression [18], while emerging evidence indicates that OXT exerts anxiogenic effects [19]. These seemingly inconsistent findings could be reconciled because the OXTr is widely expressed in the CNS, and different experimental paradigms were used in those studies. Neuronal populations participating in the anxiogenic effects of OXT remain to be identified

Methods

Results

Conclusion