Our work currently falls into two major areas. The first area is focused on the study in mice of neurobiological and immune system factors that contribute to altered behaviors induced by psychosocial stress-induced depressive-like states and the amelioration or prevention of these states by environmental enrichment coupled with voluntary wheel running exercise. We previously developed an ethologically valid form of chronic psychosocial stress in mice. 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 are exploring the effects of social conflict 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 depressive-like behaviors and enduring neurochemical alterations in identified neuronal pathways. Specifically, adult hippocampal neurogenesis is a target of these manipulations, and we showed that the survival of newborn hippocampal neurons is reduced by repeated social defeat and increased by environmental enrichment. The defeat-induced depressive-like behaviors and reduced new cell survival can be reversed by a period of environmental enrichment that includes access to a running wheel. Animals exposed to environmental enrichment prior to social defeat develop resilience to the aggressor mouse and do not go on to develop depressive-like behaviors. The concomitant reduction in neurogenesis is reversed as well. Stress hormones are known to affect neurogenesis, so we examined the role of the adrenal hormone corticosterone in affecting behavior and new cell survival. Transgenic mice with the GFAP-HSV-tk construct, when given the antibiotic drug gancyclovir, lack adult neurogenesis, and these animals are not able to regain normal behavior after being subjected to the social defeat followed by environmental enrichment. The mice have been used to test the role of hippocampal neurogenesis in supporting the effects of corticosterone on behavior. In these studies, mice were adrenalectomized and corticosterone-replaced to eliminate the high surges that occur following stressful events. We were thus able to investigate causal roles of glucocorticoids and neurogenesis in induction of depressive-like behavior and its amelioration by environmental enrichment. By blocking neurogenesis and surgically clamping adrenal hormone secretions, we showed that neurogenesisvia the hypothalamic-pituitary-adrenal (HPA) axis interactions is directly involved in precipitating the depressive phenotype following social defeat. Mice adrenalectomized prior to social defeat showed enhanced behavioral resiliency and increased survival of adult-born hippocampal neurons compared to sham-operated defeated mice. However, mice lacking hippocampal neurogenesis did not show protective effects of adrenalectomy. Moreover, glucocorticoids secreted during environmental enrichment promoted neurogenesis and were required for restoration of normal behavior after social defeat. The data demonstrated that glucocorticoid-dependent declines in neurogenesis drive changes in mood following social defeat and that glucocorticoids secreted during enrichment promote neurogenesis and restore normal behavior after defeat. These data provide new evidence for direct involvement of neurogenesis in the etiology of depression, suggesting that treatments promoting neurogenesis can enhance stress resilience. The adverse consequences of social defeat can be experimentally validated by administering behavioral tests that assess helplessness in forced swim, anxiety in the elevated zero maze, and affiliation in the social interaction task. We sought to develop better ways to characterize the depressive-like states generated by psychosocial stressors such as social defeat. Reasoning that naturalistic behaviors support the best assays, we developed a highly sensitive, easy-to-perform, and reliable method to assess depressive state in a test that we named the urine scent marking (USM) test. In this test, male mice with various prior experiences will scent mark a spot of female urine in an open field to varying degrees, and the marks can be quantified for determination of depressive-like status. A major focus of the lab is aimed at exploring the role of microglia in the response to psychosocial stress. We have preliminary data showing differential effects of acute and chronic stress on activation of microglia in the prefrontal cortex. We will document this phenomenon in extensive experiments and show the role played by the brains immune cells in contributing to neuronal function and circuit activity. The second area of research examines biochemical pathways that may translate immune signals into a language that neurons might use. The studies address the more general question of how the immune system exerts its effect on brain function. We studied the involvement of the transcription factor NF-kB (nuclear factor-kappa B) in neuronal function. NF-kB exists in the molecular form of a complex of well characterized proteins that can convey information, usually about immune activation or cellular stress, from the cell surface to the nucleus where key molecular pairs bind to DNA to induce the production of immune molecules that regulate key cellular functions such as cell proliferation, cell survival, cell death, immunity, and inflammation. Interestingly, the NF-kB pathway is active in the brain. The role of NF-kB in neurons has yet to be clearly elucidated. Neuronal NF-kB reportedly responds to immune and toxic stimuli, glutamate, and synaptic activity. However, because the brain contains many cell types, assays specifically measuring neuronal NF-kB activity are difficult to perform and interpret. To address this, we compared NF-kB activity in cultures of primary neocortical neurons, mixed brain cells, and liver cells. Functional assays showed that constitutive NF-kB activity was nearly absent in neurons. Induced activity was many fold lower than in other cell types, as measured by degradation of the inhibitor IkBa, nuclear accumulation of the subunit p65, binding to kB DNA consensus sites, NF-kB reporting, or induction of NF-kB-responsive genes. The most efficacious activating stimuli for neurons were the proinflammatory cytokines tumor necrosis factor alpha (TNFa) and interleukin-1beta (IL-1b). Neuronal NF-kB was not responsive to glutamate, or to other putative stimuli. Importantly, the level of induced neuronal NF-kB activity in response to TNFa or any other stimulus was lower than the level of basal activity in non-neuronal cells, calling into question the functional significance of neuronal NF-kB activity.

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U.S. National Institute of Mental Health
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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
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
Listwak, S J; Rathore, P; Herkenham, M (2013) Minimal NF-*B activity in neurons. Neuroscience 250:282-99
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
Herkenham, Miles; Rathore, Priyanka; Brown, Pierre et al. (2011) Cautionary notes on the use of NF-ýýB p65 and p50 antibodies for CNS studies. J Neuroinflammation 8:141
Lehmann, Michael L; Herkenham, Miles (2011) Environmental enrichment confers stress resiliency to social defeat through an infralimbic cortex-dependent neuroanatomical pathway. J Neurosci 31:6159-73
Schloesser, R J; Lehmann, M; Martinowich, K et al. (2010) Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress. Mol Psychiatry 15:1152-63

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