TY - JOUR
T1 - TNF-α from hippocampal microglia induces working memory deficits by acute stress in mice
AU - Ohgidani, Masahiro
AU - Kato, Takahiro A.
AU - Sagata, Noriaki
AU - Hayakawa, Kohei
AU - Shimokawa, Norihiro
AU - Sato-Kasai, Mina
AU - Kanba, Shigenobu
N1 - Funding Information:
The authors would like to thank Ms. Mayumi Tanaka and Ms. Miwa Irie for their technical assistance. We appreciate technical support from the Research Support Center, Graduate School of Medical Sciences, Kyushu University. This work was supported by a Grant-in-Aid for Scientific Research on (1) KAKENHI – the Japan Society for the Promotion of Science (to T.A.K., M.O., and S.K.: 26713039 , 26860933 , 25293252 and 24650227 ), (2) Innovative Areas “Glia Assembly” of The Ministry of Education, Culture, Sports, Science, and Technology , Japan (No. 25117011 to S.K.), (3) The Japan Agency for Medical Research and Development ( AMED ) –The Japanese Ministry of Health, Labour and Welfare (H27 – Seishin-Syogai Taisaku-Jigyo to SK), (4) Young Principal Investigators’ Research Grant of Innovation Center for Medical Redox Navigation, Kyushu University (to T.A.K.), (5) Takeda Medical Research Foundation (to T.A.K.), and (5) the SENSHIN Medical Research Foundation (to T.A.K., M.O., and S.K.). The funders had no role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - The role of microglia in stress responses has recently been highlighted, yet the underlying mechanisms of action remain unresolved. The present study examined disruption in working memory due to acute stress using the water-immersion resistant stress (WIRS) test in mice. Mice were subjected to acute WIRS, and biochemical, immunohistochemical, and behavioral assessments were conducted. Spontaneous alternations (working memory) significantly decreased after exposure to acute WIRS for 2 h. We employed a 3D morphological analysis and site- and microglia-specific gene analysis techniques to detect microglial activity. Morphological changes in hippocampal microglia were not observed after acute stress, even when assessing ramification ratios and cell somata volumes. Interestingly, hippocampal tumor necrosis factor (TNF)-α levels were significantly elevated after acute stress, and acute stress-induced TNF-α was produced by hippocampal-ramified microglia. Conversely, plasma concentrations of TNF-α were not elevated after acute stress. Etanercept (TNF-α inhibitor) recovered working memory deficits in accordance with hippocampal TNF-α reductions. Overall, results suggest that TNF-α from hippocampal microglia is a key contributor to early-stage stress-to-mental responses.
AB - The role of microglia in stress responses has recently been highlighted, yet the underlying mechanisms of action remain unresolved. The present study examined disruption in working memory due to acute stress using the water-immersion resistant stress (WIRS) test in mice. Mice were subjected to acute WIRS, and biochemical, immunohistochemical, and behavioral assessments were conducted. Spontaneous alternations (working memory) significantly decreased after exposure to acute WIRS for 2 h. We employed a 3D morphological analysis and site- and microglia-specific gene analysis techniques to detect microglial activity. Morphological changes in hippocampal microglia were not observed after acute stress, even when assessing ramification ratios and cell somata volumes. Interestingly, hippocampal tumor necrosis factor (TNF)-α levels were significantly elevated after acute stress, and acute stress-induced TNF-α was produced by hippocampal-ramified microglia. Conversely, plasma concentrations of TNF-α were not elevated after acute stress. Etanercept (TNF-α inhibitor) recovered working memory deficits in accordance with hippocampal TNF-α reductions. Overall, results suggest that TNF-α from hippocampal microglia is a key contributor to early-stage stress-to-mental responses.
UR - http://www.scopus.com/inward/record.url?scp=84948808924&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84948808924&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2015.08.022
DO - 10.1016/j.bbi.2015.08.022
M3 - Article
C2 - 26551431
AN - SCOPUS:84948808924
VL - 55
SP - 17
EP - 24
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
SN - 0889-1591
ER -