Deficient Autophagy in Microglia Aggravates Repeated Social Defeat Stress-Induced Social Avoidance
Major depressive disorder (MDD) is associated with repeated exposure to environmental stress. Autophagy is activated under various stress conditions that are associated with several diseases in the brain. This study was aimed at elucidating the autophagy signaling changes in the prefrontal cortex (P...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-01-01
|
| Series: | Neural Plasticity |
| Online Access: | http://dx.doi.org/10.1155/2022/7503553 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832549422969389056 |
|---|---|
| author | Mai Sakai Zhiqian Yu Ryo Hirayama Masa Nakasato Yoshie Kikuchi Chiaki Ono Hiroshi Komatsu Miharu Nakanishi Hatsumi Yoshii David Stellwagen Tomoyuki Furuyashiki Masaaki Komatsu Hiroaki Tomita |
| author_facet | Mai Sakai Zhiqian Yu Ryo Hirayama Masa Nakasato Yoshie Kikuchi Chiaki Ono Hiroshi Komatsu Miharu Nakanishi Hatsumi Yoshii David Stellwagen Tomoyuki Furuyashiki Masaaki Komatsu Hiroaki Tomita |
| author_sort | Mai Sakai |
| collection | DOAJ |
| description | Major depressive disorder (MDD) is associated with repeated exposure to environmental stress. Autophagy is activated under various stress conditions that are associated with several diseases in the brain. This study was aimed at elucidating the autophagy signaling changes in the prefrontal cortex (PFC) under repeated social defeat (RSD) to investigate the involvement of microglial autophagy in RSD-induced behavioral changes. We found that RSD stress, an animal model of MDD, significantly induced initial autophagic signals followed by increased transcription of autophagy-related genes (Atg6, Atg7, and Atg12) in the PFC. Similarly, significantly increased transcripts of ATGs (Atg6, Atg7, Atg12, and Atg5) were confirmed in the postmortem PFC of patients with MDD. The protein levels of the prefrontal cortical LC3B were significantly increased, whereas p62 was significantly decreased in the resilient but not in susceptible mice and patients with MDD. This indicates that enhanced autophagic flux may alleviate stress-induced depression. Furthermore, we identified that FKBP5, an early-stage autophagy regulator, was significantly increased in the PFC of resilient mice at the transcript and protein levels. In addition, the resilient mice exhibited enhanced autophagic flux in the prefrontal cortical microglia, and the autophagic deficiency in microglia aggravated RSD-induced social avoidance, indicating that microglial autophagy involves stress-induced behavioral changes. |
| format | Article |
| id | doaj-art-185fa5bf209a4df9a6f5b2bee9476b45 |
| institution | Kabale University |
| issn | 1687-5443 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Neural Plasticity |
| spelling | doaj-art-185fa5bf209a4df9a6f5b2bee9476b452025-02-03T06:11:17ZengWileyNeural Plasticity1687-54432022-01-01202210.1155/2022/7503553Deficient Autophagy in Microglia Aggravates Repeated Social Defeat Stress-Induced Social AvoidanceMai Sakai0Zhiqian Yu1Ryo Hirayama2Masa Nakasato3Yoshie Kikuchi4Chiaki Ono5Hiroshi Komatsu6Miharu Nakanishi7Hatsumi Yoshii8David Stellwagen9Tomoyuki Furuyashiki10Masaaki Komatsu11Hiroaki Tomita12Department of PsychiatryDepartment of PsychiatryDepartment of PsychiatryDepartment of PsychiatryDepartment of PsychiatryDepartment of PsychiatryDepartment of PsychiatryDepartment of Psychiatric NursingDepartment of Psychiatric NursingDepartment of Neurology and NeurosurgeryDivision of PharmacologyDepartment of PhysiologyDepartment of PsychiatryMajor depressive disorder (MDD) is associated with repeated exposure to environmental stress. Autophagy is activated under various stress conditions that are associated with several diseases in the brain. This study was aimed at elucidating the autophagy signaling changes in the prefrontal cortex (PFC) under repeated social defeat (RSD) to investigate the involvement of microglial autophagy in RSD-induced behavioral changes. We found that RSD stress, an animal model of MDD, significantly induced initial autophagic signals followed by increased transcription of autophagy-related genes (Atg6, Atg7, and Atg12) in the PFC. Similarly, significantly increased transcripts of ATGs (Atg6, Atg7, Atg12, and Atg5) were confirmed in the postmortem PFC of patients with MDD. The protein levels of the prefrontal cortical LC3B were significantly increased, whereas p62 was significantly decreased in the resilient but not in susceptible mice and patients with MDD. This indicates that enhanced autophagic flux may alleviate stress-induced depression. Furthermore, we identified that FKBP5, an early-stage autophagy regulator, was significantly increased in the PFC of resilient mice at the transcript and protein levels. In addition, the resilient mice exhibited enhanced autophagic flux in the prefrontal cortical microglia, and the autophagic deficiency in microglia aggravated RSD-induced social avoidance, indicating that microglial autophagy involves stress-induced behavioral changes.http://dx.doi.org/10.1155/2022/7503553 |
| spellingShingle | Mai Sakai Zhiqian Yu Ryo Hirayama Masa Nakasato Yoshie Kikuchi Chiaki Ono Hiroshi Komatsu Miharu Nakanishi Hatsumi Yoshii David Stellwagen Tomoyuki Furuyashiki Masaaki Komatsu Hiroaki Tomita Deficient Autophagy in Microglia Aggravates Repeated Social Defeat Stress-Induced Social Avoidance Neural Plasticity |
| title | Deficient Autophagy in Microglia Aggravates Repeated Social Defeat Stress-Induced Social Avoidance |
| title_full | Deficient Autophagy in Microglia Aggravates Repeated Social Defeat Stress-Induced Social Avoidance |
| title_fullStr | Deficient Autophagy in Microglia Aggravates Repeated Social Defeat Stress-Induced Social Avoidance |
| title_full_unstemmed | Deficient Autophagy in Microglia Aggravates Repeated Social Defeat Stress-Induced Social Avoidance |
| title_short | Deficient Autophagy in Microglia Aggravates Repeated Social Defeat Stress-Induced Social Avoidance |
| title_sort | deficient autophagy in microglia aggravates repeated social defeat stress induced social avoidance |
| url | http://dx.doi.org/10.1155/2022/7503553 |
| work_keys_str_mv | AT maisakai deficientautophagyinmicrogliaaggravatesrepeatedsocialdefeatstressinducedsocialavoidance AT zhiqianyu deficientautophagyinmicrogliaaggravatesrepeatedsocialdefeatstressinducedsocialavoidance AT ryohirayama deficientautophagyinmicrogliaaggravatesrepeatedsocialdefeatstressinducedsocialavoidance AT masanakasato deficientautophagyinmicrogliaaggravatesrepeatedsocialdefeatstressinducedsocialavoidance AT yoshiekikuchi deficientautophagyinmicrogliaaggravatesrepeatedsocialdefeatstressinducedsocialavoidance AT chiakiono deficientautophagyinmicrogliaaggravatesrepeatedsocialdefeatstressinducedsocialavoidance AT hiroshikomatsu deficientautophagyinmicrogliaaggravatesrepeatedsocialdefeatstressinducedsocialavoidance AT miharunakanishi deficientautophagyinmicrogliaaggravatesrepeatedsocialdefeatstressinducedsocialavoidance AT hatsumiyoshii deficientautophagyinmicrogliaaggravatesrepeatedsocialdefeatstressinducedsocialavoidance AT davidstellwagen deficientautophagyinmicrogliaaggravatesrepeatedsocialdefeatstressinducedsocialavoidance AT tomoyukifuruyashiki deficientautophagyinmicrogliaaggravatesrepeatedsocialdefeatstressinducedsocialavoidance AT masaakikomatsu deficientautophagyinmicrogliaaggravatesrepeatedsocialdefeatstressinducedsocialavoidance AT hiroakitomita deficientautophagyinmicrogliaaggravatesrepeatedsocialdefeatstressinducedsocialavoidance |