title: Microglial production of TNF-alpha is a key element of sustained fear memory.
abstract: The proinflammatory cytokine productions in the brain are altered in a process of fear memory formation, indicating a possibility that altered microglial function may contribute to fear memory formation. We aimed to investigate whether and how microglial function contributes to fear memory formation. Expression levels of M1- and M2-type microglial marker molecules in microglia isolated from each conditioned mice group were assessed by real-time PCR and immunohistochemistry. Levels of tumor necrosis factor (TNF)-α, but not of other proinflammatory cytokines produced by M1-type microglia, increased in microglia from mice representing retention of fear memory, and returned to basal levels in microglia from mice representing extinction of fear memory. Administration of inhibitors of TNF-α production facilitated extinction of fear memory. On the other hand, expression levels of M2-type microglia-specific cell adhesion molecules, CD206 and CD209, were decreased in microglia from mice representing retention of fear memory, and returned to basal levels in microglia from mice representing extinction of fear memory. Our findings indicate that microglial TNF-α is a key element of sustained fear memory and suggest that TNF-α inhibitors can be candidate molecules for mitigating posttraumatic reactions caused by persistent fear memory.
authors: Department of Disaster Psychiatry, International Research Institute of Disaster Psychiatry, Tohoku University, Sendai, Japan; Department of Disaster Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
authors: Zhiqian
authors: Z
authors: Yu
authors: Departments of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan.
authors: Hotaka
authors: H
authors: Fukushima
authors: Department of Disaster Psychiatry, International Research Institute of Disaster Psychiatry, Tohoku University, Sendai, Japan.
authors: Chiaki
authors: C
authors: Ono
authors: Department of Disaster Psychiatry, International Research Institute of Disaster Psychiatry, Tohoku University, Sendai, Japan; Department of Disaster Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors: Mai
authors: M
authors: Sakai
authors: Department of Disaster Psychiatry, International Research Institute of Disaster Psychiatry, Tohoku University, Sendai, Japan; Department of Disaster Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors: Yoshiyuki
authors: Y
authors: Kasahara
authors: Department of Disaster Psychiatry, International Research Institute of Disaster Psychiatry, Tohoku University, Sendai, Japan.
authors: Yoshie
authors: Y
authors: Kikuchi
authors: Department of Disaster Psychiatry, International Research Institute of Disaster Psychiatry, Tohoku University, Sendai, Japan.
authors: Nicole
authors: N
authors: Gunawansa
authors: Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors: Yuta
authors: Y
authors: Takahashi
authors: Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors: Hiroo
authors: H
authors: Matsuoka
authors: Departments of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan.
authors: Satoshi
authors: S
authors: Kida
authors: Department of Disaster Psychiatry, International Research Institute of Disaster Psychiatry, Tohoku University, Sendai, Japan; Department of Disaster Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan. Electronic address: htomita@med.tohoku.ac.jp.
authors: Hiroaki
authors: H
authors: Tomita
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005108:Extinction, Psychological; D005239:Fear; D006624:Hippocampus / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008911:Minocycline / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000097:blood; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008911:Minocycline; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
keywords: Extinction; Fear memory; Retention; TNF-alpha