Dorsal raphe projection inhibits the excitatory inputs on lateral habenula and alleviates depressive behaviors in rats

• Published in: Brain Structure and Function Vol. 223; no. 5; pp. 2243 - 2258
• Main Authors: Zhang, Hai, Li, Kuan, Chen, Hong-Sheng, Gao, Shuang-Qi, Xia, Zhi-Xuan, Zhang, Jie-Ting, Wang, Fang, Chen, Jian-Guo
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2018; Springer Nature B.V
• Subjects: Animal models; Animals; Aversion; Biomedical and Life Sciences; Biomedicine; c-Fos protein; Cell Biology; Channelrhodopsins - genetics; Channelrhodopsins - metabolism; Cholera toxin; Cholera Toxin - metabolism; Depression - etiology; Depression - therapy; Disease Models, Animal; Dorsal raphe nucleus; Dorsal Raphe Nucleus - diagnostic imaging; Dorsal Raphe Nucleus - physiology; Electric Stimulation; Excitability; Exploratory Behavior; Fluorodeoxyglucose F18 - metabolism; Food Preferences - drug effects; Glutamate Decarboxylase - metabolism; Grooming - physiology; Habenula; Habenula - cytology; Habenula - diagnostic imaging; Habenula - physiology; In Vitro Techniques; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Luteinizing hormone; Male; Maze Learning; Mental depression; Nerve Tissue Proteins - metabolism; Neural Inhibition - physiology; Neural networks; Neural Pathways - diagnostic imaging; Neural Pathways - physiology; Neurology; Neurons; Neurons - drug effects; Neurons - physiology; Neurosciences; Optogenetics; Original Article; Positron-Emission Tomography; Proto-Oncogene Proteins c-fos - metabolism; Raphe nuclei; Rats; Rats, Sprague-Dawley; Red Fluorescent Protein; Rodents; Serotonin; Serotonin - metabolism; Serotonin Agents - pharmacology; Stress, Psychological - complications; Stress, Psychological - psychology; Sucrose - administration & dosage; Swimming - psychology; Synaptic Potentials - drug effects; Synaptic Potentials - physiology; Transduction, Genetic; Tryptophan Hydroxylase - metabolism; Depression; Lateral habenula; Optogenetics; Chronic unpredictable mild stress; Serotonin; Dorsal raphe nucleus
• ISSN: 1863-2653; 1863-2661; 1863-2661; 0340-2061
• DOI: 10.1007/s00429-018-1623-3

Hypofunction of the serotonergic (5-HT) system has close relationship with the symptoms in major depressive disorders (MDD), however, the underlying neural circuitry mechanisms are not fully understood. Lateral habenula (LHb) plays a crucial role in aversive behaviors and is activated in conditions of depression. It has been reported that 5-HT inhibits the excitability of LHb neurons, leading to the hypothesis that decreased transmission of 5-HT would elevate the activity of LHb and therefore mediates depressive symptoms. Using retrograde tract tracing with cholera toxin subunit B, we find that dorsal raphe nucleus (DRN) sends primary 5-HT projection to the LHb. In vitro slice patch-clamp recording reveals that opto-stimulation of DRN inputs to the LHb suppresses the frequency of miniature excitatory postsynaptic current, while increases paired pulse ratio in LHb neurons, indicating 5-HT projection presynaptically suppresses the excitability of LHb neurons. In chronic unpredictable mild stress (CUMS) rat model of depression, optogenetic stimulation of DRN–LHb projection alleviates the depressive symptoms in CUMS models. Meanwhile, opto-inhibition of this circuit results in elevated c-fos expression in LHb and induces depression-like behaviors. This study demonstrates that the 5-HT projection from DRN to LHb suppresses the excitability of LHb neurons, and hypofunction of 5-HT transmission induces depressive behavior via the activation of LHb. Our results reveal the functional connectivity of DRN–LHb circuit and its antidepressant action, which may provide a novel target for the treatment of depression.