Down-regulation of cholinergic signaling in the habenula induces anhedonia-like behavior
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 leve...
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2017-04-01
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Online Access: | https://doi.org/10.1038/s41598-017-01088-6 |
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doaj-9e4e5fd4bdd14140afe8b403873d4cdf2020-12-08T00:11:44ZengNature Publishing GroupScientific Reports2045-23222017-04-017111310.1038/s41598-017-01088-6Down-regulation of cholinergic signaling in the habenula induces anhedonia-like behaviorSeungrie Han0Soo Hyun Yang1Jin Yong Kim2Seojung Mo3Esther Yang4Ki Myung Song5Byung-Joo Ham6Naguib Mechawar7Gustavo Turecki8Hyun Woo Lee9Hyun Kim10Department of Anatomy, College of Medicine, Korea UniversityDepartment of Anatomy, College of Medicine, Korea UniversityDepartment of Anatomy, College of Medicine, Korea UniversityDepartment of Anatomy, College of Medicine, Korea UniversityDepartment of Anatomy, College of Medicine, Korea UniversityDepartment of Anatomy, College of Medicine, Korea UniversityDepartment of Psychiatry, College of Medicine, Korea UniversityDepartment of Psychiatry, McGill University, Douglas Mental Health University InstituteDepartment of Psychiatry, McGill University, Douglas Mental Health University InstituteDepartment of Anatomy, College of Medicine, Korea UniversityDepartment of Anatomy, College of Medicine, Korea UniversityAbstract 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).https://doi.org/10.1038/s41598-017-01088-6 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Seungrie Han Soo Hyun Yang Jin Yong Kim Seojung Mo Esther Yang Ki Myung Song Byung-Joo Ham Naguib Mechawar Gustavo Turecki Hyun Woo Lee Hyun Kim |
spellingShingle |
Seungrie Han Soo Hyun Yang Jin Yong Kim Seojung Mo Esther Yang Ki Myung Song Byung-Joo Ham Naguib Mechawar Gustavo Turecki Hyun Woo Lee Hyun Kim Down-regulation of cholinergic signaling in the habenula induces anhedonia-like behavior Scientific Reports |
author_facet |
Seungrie Han Soo Hyun Yang Jin Yong Kim Seojung Mo Esther Yang Ki Myung Song Byung-Joo Ham Naguib Mechawar Gustavo Turecki Hyun Woo Lee Hyun Kim |
author_sort |
Seungrie Han |
title |
Down-regulation of cholinergic signaling in the habenula induces anhedonia-like behavior |
title_short |
Down-regulation of cholinergic signaling in the habenula induces anhedonia-like behavior |
title_full |
Down-regulation of cholinergic signaling in the habenula induces anhedonia-like behavior |
title_fullStr |
Down-regulation of cholinergic signaling in the habenula induces anhedonia-like behavior |
title_full_unstemmed |
Down-regulation of cholinergic signaling in the habenula induces anhedonia-like behavior |
title_sort |
down-regulation of cholinergic signaling in the habenula induces anhedonia-like behavior |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-04-01 |
description |
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). |
url |
https://doi.org/10.1038/s41598-017-01088-6 |
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