Down-regulation of cholinergic signaling in the habenula induces anhedonia-like behavior

Seungrie Han,Hyun Kim,Esther Yang,Gustavo Turecki,Naguib Mechawar,Byung-Joo Ham,Ki Myung Song,Jin Yong Kim,Seojung Mo,Soo Hyun Yang,Hyun Woo Lee

doi:10.1038/s41598-017-01088-6

Abstract

Dysfunction of cholinergic signaling in the brain has long been believed to be associated with depressive disorders. However, the functional impact of habenular cholinergic signaling on the specified depressive behaviors is not well understood. Here, we demonstrated that the expression levels of cholinergic signaling genes (CHAT, VACHT, CHT, CHRNA3, CHRNB3 and CHRNB4) were down-regulated in a chronic restraint stress (CRS) rat model of depression, in which rats display depression-like behaviors such as anhedonia and mood despair. Moreover, knockdown of CHAT in the rat habenula was sufficient to evoke anhedonia-like behavior. The anhedonia-like behavior induced by CHAT knockdown was not reversed by chronic administration of the selective serotonin reuptake inhibitor fluoxetine. To determine whether habenular cholinergic signaling is associated with regulation of dopamine neurons in the ventral tegmental area (VTA) and serotonin neurons in the dorsal raphe nucleus (DRN), we used CHAT::cre transgenic mice expressing the Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Pharmacogenetic activation of habenular cholinergic neurons induces the excitation of dopamine neurons in the VTA and reduces the immunoreactivity of 5-hydroxytryptamine (5-HT) in the DRN. Habenular cholinergic gene down-regulation was recapitulated in the postmortem habenula of suicide victims diagnosed with major depressive disorder (MDD).

Highlights

Major depressive disorder (MDD) is a serious psychiatric disorder that is frequently associated with suicide attempts and a major contributor to the global burden of disease[1]
We tested whether rats subjected to chronic restraint stress (CRS) showed depression-like behaviors in the sucrose preference test (SPT) and forced swim test (FST)
We found that the gene expression levels for choline acetyltransferase (CHAT), vesicular acetylcholine transporter (VACHT), choline transporter (CHT), CHRNA3, CHRNB3, and CHRNB4 were all significantly reduced in the habenula of CRS rats compared with those of NS rats (NS vs. CRS expressed as fold change: CHAT, 1.000 ± 0.087 vs. 0.579 ± 0.024, P = 0.0004; VACHT, 1.000 ± 0.085 vs. 0.686 ± 0.027, P = 0.0033; CHT, 1.000 ± 0.069 vs. 0.624 ± 0.025, P = 0.0002; CHRNA3, 1.000 ± 0.070 vs. 0.649 ± 0.031, P = 0.0004; CHRNB3, 1.000 ± 0.025 vs. 0.638 ± 0.049, P = 0.0001; CHRNB4, 1.000 ± 0.085 vs. 0.611 ± 0.033, P = 0.0008; Fig. 1b–g), which is consistent with our gene expression findings in another animal model of depression, learned helpless rats (Supplementary Figure S2)

Summary

Introduction

Major depressive disorder (MDD) is a serious psychiatric disorder that is frequently associated with suicide attempts and a major contributor to the global burden of disease[1]. Inhibition of nicotinic acetylcholine receptors (nAChRs) or muscarinic acetylcholine receptors (mAChRs) ameliorates depression symptoms[7,8]. These lines of evidence clearly suggest that ACh signaling contributes to depression, it is not yet clear which specific cholinergic neuronal populations are responsible for specific depression symptoms. Several lines of evidence from studies in animal models and humans suggest that the MHb plays a major role in nicotine addiction[11,12,13], whereas dysregulation of the LHb is likely to be involved in several psychiatric disorders, including depression. Reduced MHb cholinergic signaling-induced anhedonia-like symptom is not reversed by chronic administration of fluoxetine. Our analyses indicate that abnormal MHb cholinergic signaling is associated with the pathogenesis of depression

Methods

Results

Conclusion