Our work currently falls into three major but related areas. The first area is focused on the study in mice of central determinants of psychosocial stress-induced depressive-like behaviors and the amelioration or prevention of these behavioral states by environmental enrichment supplemented with physical exercise in a running wheel. We previously developed an ethologically valid form of chronic stress in mice. Chronic stress has been implicated in the cause 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 daily exposure to social defeat by a dominant mouse living in a dyadic relationship with the subordinate experimental mouse that develops over time depressive-like behaviors and enduring neurochemical alterations in identified neuronal pathways. The social defeat incurred in the conflict paradigm has adverse consequences that can be experimentally validated by administering behavioral tests such as helplessness in forced swim, anxiety in the elevated zero maze, and social interaction with another mouse. These depressive-like behaviors following social defeat can be reversed by a period of environmental enrichment that includes exercise on a running wheel. The enrichment can also provide a means to measure resilience to subsequent bouts of social conflict. Animals exposed to environmental enrichment prior to social defeat develop a resilience to he aggressor mouse and do not go on to develop depressive-like behaviors. The social defeat stress produces changes in neuronal activity in regions of the brain known to be involved in emotional processing and memory. Regions of interest include the medial prefrontal cortex, hippocampus, ventral striatum, and amygdala. We showed that a lesion of the medial prefrontal cortex blocks the ability of environmental enrichment to confer resiliency to subsequent social defeat. Ongoing studies are examining the role of the stress hormone corticosterone in conferring the ability of environmental enrichment to confer resilience. We are also asking whether these effects require adult neurogenesis. 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 are now being used to test the role of neurogenesis in supporting the effects of corticosterone on behavior. A second area of study focuses on maternal infections and the manner in which they affect fetal brain development and subsequent adult behavior of the offspring. Infection during pregnancy in humans has been theorized as a potential cause of schizophrenia, autism, and mood disorders in the children of the infected mothers. We use the model of maternal immune activation (MIA) during pregnancy in rats and mice, and we examine early brain development and later adolescent and adult behavior, cognition, and mood. The endotoxin lipopolysaccharide (LPS) is used to mimic bacterial infection. The biochemical changes are transient, but the single LPS injection to the dam appears to have profound, permanent effects on the offspring (behavioral effects that mimic depressive, autistic, and psychotic behavior). LPS was administered at day 15 of gestation, and the offspring were studied for deficits in exploration and social behaviors. In experiments designed to detect the earliest changes occurring in the fetus, maternal serum and amniotic fluid and fetal brains were harvested for analysis of cytokine, chemokine, and growth factor levels. Fetal brain RNA was subjected to microarray analysis of genome-wide changes in mRNA expression level changes. The data showed that LPS induced a pro-inflammatory cytokine and chemokine storm that passed indirectly into the fetus to induce transient changes in gene expression levels within the first 4 h. Microarray data pointed to changes in genes associated with hypoxia and with neuronal migration. These striking findings lead to the hypothesis that immune molecules, perhaps originating in the placenta, alter the course of development of the nervous system in subtle ways that lead to altered cognitive functions in adolescent and adult life. The findings from our studies may lead us to one day understand the increased susceptibility to mental disorder associated with maternal infections and obstetric complications. The third 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 are looking at the involvement of the transcription factor NF-kB (nuclear factor-kappa B) in glial and 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 and cytoplasm to the nucleus where key molecular dimers 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. Because NF-kB is so important in fundamental cellular processes like death and survival, a better understanding of its role may one day lead to interventions to protect neurons during seizure, traumatic brain injury, or severe stress. The presence of NF-kB in neurons suggests a role in cell survival or neuronal plasticity. We have amassed tools to measure NF-kB exclusively in neurons in vivo and to identify the genes it regulates in models of neuronal excitation immune activation. We have obtained transgenic and knockout mice that allow for the selective activation or silencing of NF-kB activity in neurons. We also have transgenic mice that report NF-kB activity in cells on the basis of induced production of proteins that can be stained histochemically and visualized microscopically or with film images. Some of our findings include: 1) many of the antibodies used in the literature to characterize NF-kB activity are not specific for their targets, a fact that has led to the erroneous impression in the field that neuronal NF-kB activity is constitutively present and easily induced by common stimuli such as glutamate, and 2) NF-kB dimers (p50 and p65) are present but relatively inactive in neurons, responding to very few stimuli by moving into the nucleus and produce DNA binding activity. Whereas in pure neuronal cultures, glutamate is not potent, the cytokine TNFalpha can trigger activity. The findings suggest that NF-kB normally plays a small role in neuronal function, but it can be responsive to changes in the local immune environment.

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Project End
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Budget End
Support Year
34
Fiscal Year
2011
Total Cost
$1,512,446
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
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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
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
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
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
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

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