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

• Published in: Biological psychiatry (1969) Vol. 79; no. 10; pp. 803 - 813
• Main Authors: McKim, Daniel B, Patterson, Jenna M, Wohleb, Eric S, Jarrett, Brant L, Reader, Brenda F, Godbout, Jonathan P, Sheridan, John F
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.05.2016
• Subjects: Animals; Anxiety; Anxiety - etiology; Anxiety - physiopathology; Brain - drug effects; Brain - physiopathology; Cell Movement - drug effects; Cell Movement - physiology; Cohort Studies; Disease Models, Animal; Dominance-Subordination; Guanethidine - pharmacology; Macrophages; Male; Mice, Inbred C57BL; Microglia; Monocytes - drug effects; Monocytes - physiology; Neuroimmunomodulation - drug effects; Neuroimmunomodulation - physiology; Neuroinflammation; Psychiatry; PTSD; Spleen - drug effects; Spleen - physiopathology; Splenectomy; Stress; Stress, Psychological - complications; Stress, Psychological - physiopathology; Sympathetic Nervous System - drug effects; Sympathetic Nervous System - physiopathology; Sympatholytics - pharmacology; PTSD; Neuroinflammation; Anxiety; Macrophages; Stress; Microglia
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2015.07.010

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 Ly6Chi 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.