Chronic psychosocial stress has been implicated in the etiology and progression of psychiatric disorders such as major depression and post-traumatic stress disorder (PTSD). In mice, we study the effects of psychosocial stress in a conflict paradigm that leads to behavioral alterations such as deficits in social interaction or increases in anhedonia, anxiety, and depressive-like states. In our social defeat paradigm, two mice are placed in a continuous dyadic living relationship in which the subordinate experimental mouse is chronically exposed to and periodically defeated by a dominant mouse. Over the course of weeks in this living situation, the experimental mouse develops anxious and depressive-like behaviors that are associated with distinct neurochemical alterations in identified brain circuits. A decreased rate of hippocampal neurogenesis is one well-documented readout of stress effects. Thus the paradigm is an ethologically relevant and validated model that can provide insights into the bases for mental illness in humans. Our research focuses on the roles played by immune factors in the etiology of psychosocial stress-induced depressive states. We hypothesize that whereas there is a bidirectional dialog between the brain and the immune system that serves to maintain homeostasis within the two systems in healthy conditions, disturbances in these pathways lead to homeostatic corrections or dysfunction that contribute to the onset and course of psychiatric disease. Two projects are underway; one focuses on the role of the adaptive immune system in maintaining homeostatic balance, and the second investigates immune cells and molecules within the brain itself. 1) We conducted experiments aimed at addressing the role of the adaptive immune system in controlling mood states in the social defeat model. The adaptive immune system, separate from the innate immune system, comprises cells lymphocytes that adapt, i.e., acquire and retain a memory of prior challenges. Surprisingly, lymphocytes appear to exert effects on the brain and behavior as suggested by results of lymphocyte depletion experiments. We developed a novel approach to the question by studying the Rag2-/- mouse, which lacks a gene needed to produce mature lymphocytes. We adoptively transferred lymphocytes into this lymphopenic mouse from normal donor mice that had either been chronically stressed or unstressed, and after two weeks of lymphocyte reconstitution in the host mouse, behavioral tests and hippocampal cell proliferation assays were performed. The Rag2-/- mice that received cells from defeated mice showed anti-depressive and anxiolytic behaviors relative to Rag2-/- mice that received no cell transfer or transfer of cells from home-cage control mice. These surprising findings suggested that the adaptive immune system retains a memory for adverse events and attempts to return the lymphopenic host animal to a condition of homeostasis. News stories about the study likened the outcome to a vaccination against stress. We subsequently determined that Rag2-/- mice that had been rendered depressed following a chronic restraint procedure showed recovery from that state after being transplanted with cells from defeated donor mice, indicating that the transferred cells actually are anti-depressant. 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. 2) The immune system comprises cells of peripheral immune organs and also specialized immune cells within the brain microglia that share many properties with peripheral immune cells, particularly the ability to respond to immune challenges and produce immune molecules like cytokines. Our recent research has shown that social defeat stress triggers a CNS immune response within emotion-processing brain areas. We have data showing effects of acute and chronic defeat stress on microglial proliferation and activation states in the prefrontal cortex and hippocampus. 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, pro-repair cytokines, and growth factors. These activation states can affect neuronal function in the vicinity and may differentially direct behavioral outcomes associated with either susceptibility or resilience to the effects of the stress. We developed a method to harvest microglia from the brain using cell separation techniques and Percoll gradients, and we study the cells ex vivo in cell culture. Microglia activation states are probed in cell culture by examination of the contents of the culture media, by gene expression profiling, by response to M-1 versus M-2 stimulation, and by phagocytosis of labeled cellular debris. We can also analyze isolated microglia by flow cytometry to characterize cell-surface markers of activation and by microarray analysis to assess gene expression patterns. Ongoing experiments showed that microglia isolated from defeated mice that had been susceptible to the depressive effects of social defeat were functionally distinct from microglia taken from defeated mice that showed behavioral resilience to the stress procedure. The microglial characteristics of the resilient group were more like those from unstressed control mice, suggesting that microglia participate in the protective effects of psychosocial stress in the resilient group. Drugs that prevent the conversion of microglia into a reactive pro-inflammatory state like that seen in the susceptible group may protect the animals from the depressive effects of the defeat stress. Preliminary experiments with microglial blocking treatment supported this hypothesis.
The aims of the work are to demonstrate a causal relationship between stress-induced immune alterations and susceptibility or resilience to the stress, and to suggest new therapeutic targets for the treatment of stress-related mood disorders.

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Lehmann, Michael L; Weigel, Thaddeus K; Cooper, Hannah A et al. (2018) Decoding microglia responses to psychosocial stress reveals blood-brain barrier breakdown that may drive stress susceptibility. Sci Rep 8:11240
Lehmann, Michael L; Weigel, Thaddeus K; Elkahloun, Abdel G et al. (2017) Chronic social defeat reduces myelination in the mouse medial prefrontal cortex. Sci Rep 7:46548
Herkenham, Miles; Kigar, Stacey L (2017) Contributions of the adaptive immune system to mood regulation: Mechanisms and pathways of neuroimmune interactions. Prog Neuropsychopharmacol Biol Psychiatry 79:49-57
Lehmann, Michael L; Cooper, Hannah A; Maric, Dragan et al. (2016) Social defeat induces depressive-like states and microglial activation without involvement of peripheral macrophages. J Neuroinflammation 13:224
Scheinert, Rachel B; Haeri, Mitra H; Lehmann, Michael L et al. (2016) Therapeutic effects of stress-programmed lymphocytes transferred to chronically stressed mice. Prog Neuropsychopharmacol Biol Psychiatry 70:1-7
Brachman, Rebecca A; Lehmann, Michael L; Maric, Dragan et al. (2015) Lymphocytes from chronically stressed mice confer antidepressant-like effects to naive mice. J Neurosci 35:1530-8
Listwak, Samuel J; Rathore, Priyanka; Herkenham, Miles (2013) Minimal NF-?B activity in neurons. Neuroscience 250:282-299
Lehmann, Michael L; Geddes, Claire E; Lee, Jennifer L et al. (2013) Urine scent marking (USM): a novel test for depressive-like behavior and a predictor of stress resiliency in mice. PLoS One 8:e69822
Lehmann, Michael L; Brachman, Rebecca A; Martinowich, Keri et al. (2013) Glucocorticoids orchestrate divergent effects on mood through adult neurogenesis. J Neurosci 33:2961-72
Oskvig, Devon B; Elkahloun, Abdel G; Johnson, Kory R et al. (2012) Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response. Brain Behav Immun 26:623-34

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