Sympathetic Release of Splenic Monocytes Promotes Recurring Anxiety Following Repeated Social Defeat.
Neuroinflammatory signaling may contribute to the pathophysiology of chronic anxiety disorders. Previous work showed that repeated social defeat (RSD) in mice promoted stress-sensitization that was characterized by the recurrence of anxiety following subthreshold stress 24 days after RSD. Furthermore, splenectomy following RSD prevented the recurrence of anxiety in stress-sensitized mice. We hypothesize that the spleen of RSD-exposed mice became a reservoir of primed monocytes that were released following neuroendocrine activation by subthreshold stress.



Mice were subjected to subthreshold stress (i.e., single cycle of social defeat) 24 days after RSD, and immune and behavioral measures were taken.



Subthreshold stress 24 days after RSD re-established anxiety-like behavior that was associated with egress of Ly6C(hi) monocytes from the spleen. Moreover, splenectomy before RSD blocked monocyte trafficking to the brain and prevented anxiety-like behavior following subthreshold stress. Splenectomy, however, had no effect on monocyte accumulation or anxiety when determined 14 hours after RSD. In addition, splenocytes cultured 24 days after RSD exhibited a primed inflammatory phenotype. Peripheral sympathetic inhibition before subthreshold stress blocked monocyte trafficking from the spleen to the brain and prevented the re-establishment of anxiety in RSD-sensitized mice. Last, β-adrenergic antagonism also prevented splenic monocyte egress after acute stress.



The spleen served as a unique reservoir of primed monocytes that were readily released following sympathetic activation by subthreshold stress that promoted the re-establishment of anxiety. Collectively, the long-term storage of primed monocytes in the spleen may have a profound influence on recurring anxiety disorders.
Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio; Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio.
Daniel B
DB
McKim
Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio; Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio.
Jenna M
JM
Patterson
Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio; Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio; Department of Psychiatry, School of Medicine, Yale University, New Haven, Connecticut.
Eric S
ES
Wohleb
Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio; Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio.
Brant L
BL
Jarrett
Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio.
Brenda F
BF
Reader
Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio; Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, Ohio.
Jonathan P
JP
Godbout
Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio; Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio; Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, Ohio. Electronic address: sheridan.1@osu.edu.
John F
JF
Sheridan
D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000503:physiopathology*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D015331:Cohort Studies; D004195:Disease Models, Animal; D004291:Dominance-Subordination; D006145:Guanethidine / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D013154:Spleen / Q000187:drug effects / Q000503:physiopathology*; D013156:Splenectomy; D013315:Stress, Psychological / Q000150:complications / Q000503:physiopathology*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D013565:Sympatholytics / Q000494:pharmacology
D013565:Sympatholytics; D006145:Guanethidine
Anxiety; Macrophages; Microglia; Neuroinflammation; PTSD; Stress