Chronic stress has been implicated in the etiology and progression of various psychiatric disorders including depression and post-traumatic stress disorder (PTSD). In mice, we study the effects of chronic psychosocial stress in a paradigm involving repeated daily exposure to social defeat by a dominant mouse living in a dyadic relationship with the subordinate experimental mouse that develops anxious and depressive-like behaviors associated with enduring neurochemical alterations in identified circuits. The social defeat model in rodents has validity for producing depressive-like effects similarly to depression associated with psychosocial stressors in humans and is thus an ethologically relevant model. Our recent research has shown that social defeat stress triggers a CNS immune response within emotional processing areas. Microglia are the resident immune cells in the brain and are the primary source of brain-derived cytokines that are elevated during acute and chronic stress. Microglia can be activated to the status of an M1-like state to secrete pro-inflammatory cytokines, or they might adopt an alternative M2-like state to secrete anti-inflammatory and pro-repair cytokines and growth factors. Such differential activation states can differentially affect neuronal function in the vicinity of the activation and may differentially direct behavioral outcomes associated with either susceptibility or resilience to the effects of the stress. We have preliminary data showing effects of acute and chronic stress on microglial proliferation and activation states in the prefrontal cortex and hippocampus. We have developed a method to harvest live microglia from the brain using cell separation techniques and Percoll gradients, and we study the cells ex vivo in cell culture. Microglia activation states can be probed in culture by examination of the contents of the cell media, by gene expression profiling, by response to M-1 versus M-2 stimulation, and by phagocytosis of labeled cellular debris. We previously showed a relationship between stress and rates of adult hippocampal neurogenesis, and we now can begin to look at the contributions of the immune system to this phenomenon by studying the interactions in cultures containing hippocampal neurospheres.
The aim of the work is to demonstrate a causal relationship between stress-induced immune alterations and susceptibility or resilience to the stress. We conducted experiments aimed at addressing the role of the adaptive immune system in controlling mood states in the social defeat model. Surprisingly, adaptive immune cells, i.e., lymphocytes, exert effects on affective behavior and hippocampal neurogenesis as demonstrated in lymphocyte depletion studies and studies in which lymphocyte phenotype has been altered experimentally. We developed a novel approach to the question by employing a mouse that lacks an adaptive immune systemthe Rag2-/- mouse that lacks mature lymphocytes. We adoptively transferred lymphocytes from donor mice that had either been chronically stresses or unstressed, and after two weeks of cell reconstitution in the host mouse, behavioral and hippocampal cell proliferation assays were performed. The Rag2-/- mice that received cells from defeated mice showed anti-depressive and anxiolytic behaviors relative to both Rag2-/- mice that received no cell transfer or those that received cells from home-cage control mice. The surprising findings suggest that the adaptive immune system retains a memory for the adverse events and attempts to return the animal to a condition of homeostasis when given the opportunity by transfer of its adaptive immune cells into a lymphopenic host. Future work will examine the molecular and cellular determinants of the interaction and the anatomical and humoral pathways by which the immune system affects brain function and structure. Such studies may lead to insights into new targets for therapeutic interventions in psychiatric disorders.
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