70. Sympathetic innervation initiates myeloid cell trafficking from the spleen to the brain that causes the re-establishment of anxiety in stress-sensitized mice

Abstract

Repeated social defeat (RSD) in mice recapitulates key immunological, physiological, and behavioral deficits associated with psychosocial stress in humans. We have reported that exposure to sub-threshold stress 24 days after RSD caused re-establishment of anxiety that was dependent on myeloid cell trafficking from the spleen to the brain. Therefore, we hypothesized that the spleen of RSD-exposed mice becomes a critical reservoir of reactive myeloid cells that are rapidly released following sympathetic activation by sub-threshold stressors. In the first experiments, the spleen was removed before 6 cycles of RSD yet this did not alter initial stress-induced myeloid redistribution or anxiety. Splenectomy prior to RSD, however, prevented the re-distribution of myeloid cells and re-establishment of anxiety following sub-threshold stress 24 days after RSD. Thus, the spleen did not contribute to myeloid cell trafficking and anxiety immediately following RSD, but rather served as a reservoir of myeloid cells that are readily released following sub-threshold stress. To address how these cells are released from the spleen, control and RSD-sensitized mice were treated with guanethidine, a peripheral sympathetic inhibitor, 24 days after RSD prior to sub-threshold stress. Intervention with guanethidine, prior to sub-threshold stress blocked myeloid cell redistribution and anxiety in RSD-sensitized mice. Thus, sympathetic initiation of spleen-to-brain myeloid cell trafficking represents a novel mechanism in the context of recurring anxiety disorders.