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Biol Psychiatry. 2016 May 15;79(10):803-813. doi: 10.1016/j.biopsych.2015.07.010. Epub 2015 Jul 26.

Sympathetic Release of Splenic Monocytes Promotes Recurring Anxiety Following Repeated Social Defeat.

Author information

1
Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio; Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio.
2
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.
3
Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio.
4
Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio; Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, Ohio.
5
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.

Abstract

BACKGROUND:

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.

METHODS:

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

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

Anxiety; Macrophages; Microglia; Neuroinflammation; PTSD; Stress

PMID:
26281717
PMCID:
PMC4728074
DOI:
10.1016/j.biopsych.2015.07.010
[Indexed for MEDLINE]
Free PMC Article
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