Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain

Biol Psychiatry. 2014 Jun 15;75(12):970-81. doi: 10.1016/j.biopsych.2013.11.029. Epub 2013 Dec 10.


Background: Persistent anxiety-like symptoms may have an inflammatory-related pathophysiology. Our previous work using repeated social defeat (RSD) in mice showed that recruitment of peripheral myeloid cells to the brain is required for the development of anxiety. Here, we aimed to determine if 1) RSD promotes prolonged anxiety through redistribution of myeloid cells and 2) prior exposure to RSD sensitizes the neuroimmune axis to secondary subthreshold stress.

Methods: Mice were subjected to RSD and several immune and behavioral parameters were determined .5, 8, or 24 days later. In follow-up studies, control and RSD mice were subjected to subthreshold stress at 24 days.

Results: Repeated social defeat-induced macrophage recruitment to the brain corresponded with development and maintenance of anxiety-like behavior 8 days after RSD, but neither remained at 24 days. Nonetheless, social avoidance and an elevated neuroinflammatory profile were maintained at 24 days. Subthreshold social defeat in RSD-sensitized mice increased peripheral macrophage trafficking to the brain that promoted re-establishment of anxiety. Moreover, subthreshold social defeat increased social avoidance in RSD-sensitized mice compared with naïve mice. Stress-induced monocyte trafficking was linked to redistribution of myeloid progenitor cells in the spleen. Splenectomy before subthreshold stress attenuated macrophage recruitment to the brain and prevented anxiety-like behavior in RSD-sensitized mice.

Conclusions: These data indicate that monocyte trafficking from the spleen to the brain contributes re-establishment of anxiety in stress-sensitized mice. These findings show that neuroinflammatory mechanisms promote mood disturbances following stress-sensitization and outline novel neuroimmune interactions that underlie recurring anxiety disorders such as posttraumatic stress disorder.

Keywords: Anxiety; PTSD; microglia; monocytes; neuroinflammation; stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anxiety / complications
  • Anxiety / immunology*
  • Anxiety / pathology
  • Anxiety / surgery
  • Brain / cytology
  • Brain / immunology*
  • Cell Movement*
  • Central Nervous System Sensitization
  • Macrophages / cytology
  • Macrophages / immunology
  • Male
  • Mice
  • Monocytes / cytology*
  • Monocytes / immunology
  • Social Behavior
  • Spleen / cytology
  • Spleen / immunology*
  • Splenectomy
  • Stress, Psychological / complications
  • Stress, Psychological / immunology*
  • Stress, Psychological / pathology