Immune signaling molecules like cytokines and chemokines mediate the interactions between the immune system and the CNS and between neurons and glia within the brain. The transcription factor NF-kB (nuclear factor-kappa B) is a protein that controls the production of immune molecules and has been shown to regulate key cellular functions such as cell proliferation, cell survival, and 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. NF-kB is found in all cells, but it is normally associated with regulating inflammatory cascades in immune cells. However, its presence 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 and excitotoxicity (both of which occur in seizure). We have obtained transgenic 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. We use the technique of in situ hybridization histochemistry (the binding of complementary ribonucleotide probes to transcribed mRNA targets) to localize and quantify transcript expression of neurotransmitters, cytokines, enzymes, receptors, transcription factors, and immediate-early genes in studies of response to immunological challenges, seizures, and stressors. We use the technique of immunohistochemistry (the binding of antibodies to target moieties) to localize and characterize NF-kB activation in neurons. Some of our findings with these tools include: 1) the p50 subunit of NF-kB is involved in spatial learning in mice, 2) one function of p50 in controlling gene expression is to modify the epigenetic (chromatin) state of cytokine and chemokine gene promoters, and 3) NF-kB activity in neurons is always present but there are very few stimuli that can change levels of activity, suggesting that it normally plays a small role in neuronal function. Maternal infection in animals is a model to study the deleterious effects of immune challenge during pregnancy on early brain development and subsequent adolescent and adult behavior, cognition, and mood. Studies have shown that early exposure to an immune challenge can result in developmental disturbances with long-term consequences. 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. Exposure to certain forms of stress during pregnancy has been shown to have similar effects. We are studying the mechanisms by which activation of the immune system during development may cause CNS dysfunction that persists across the lifetime. Low-to-high doses of pathogenic stimuli such as the bacterial endotoxin lipopolysaccharide (LPS) have been used to mimic infections in animals. The changes are usually transient in adult animals given LPS. However, exposure to immune challenge during development appears to have profound, permanent effects on the offspring of the infected mother (effects that mimic depressive, autistic, and psychotic behavior). In clinical studies, correlations have been reported between maternal infections and higher prevalence of mental illness in their children. We are using the maternal immune activation (MIA) model to study disorders with early neurodevelopmental etiology, such as schizophrenia, autism, and anxiety disorder. In a set of experiments performed in rats, we have developed a MIA model in which pregnant dams are subjected to an immune challenge (LPS administration) at day 15 of gestation, and the offspring are studied for behavioral alterations (like social deficits that mirror autism and cognitive deficits that mirror schizophrenia) and their underlying biochemical causes. By studying the biological changes underlying these behavioral changes, we hope to better understand the etiology and pathogenesis of these and other diseases. Fetal brains were harvested and subjected to genome-wide analysis of altered levels of gene expression using DNA microarrays. As early as 4 hours after the immune challenge, the fetal brains expressed altered expression levels of gene associated with neuronal development and axon guidance. These striking findings lead to the hypothesis that immune molecules, perhaps secreted by microglia in the fetal brain, 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 causes of debilitating mental conditions in some people with early life immune challenges such as maternal infections. Chronic stress has been implicated in the cause and progression of various psychiatric disorders, including depression and post-traumatic stress disorder (PTSD). In a project focused on the effects of psychosocial stress, we are exploring the effect of chronic psychosocial stress in animals in which it induces depressive-like behaviors and causes enduring neurochemical alterations in identified neuronal pathways. Working with this naturalistic model of unavoidable chronic social stress, using a dominant-subordinate animal pairing design, we have shown that exposure to chronic stress produces subordinate behavior and depressive-like behavioral signs. We have also found that following psychosocial stress, defeated and subordinate animals can be rescued by subsequent exposure to an enriched environment that includes access to objects and running wheels. Molecular and anatomical studies are showing the importance of certain brain regions, including the hippocampus and frontal cortex, in the recovery that occurs after exposure to the enriched environment. We are continuing to work to identify the mechanisms and neuronal pathways by which stress has this deleterious effect. We have shown a role for adult neurogenesis in mediating the recovery of normal behavior in the defeated animals following a period of exposure to an enriched environment. Animals exposed to environmental enrichment are generally healthier, have better cognitive function, and are less susceptible to neurodegenerative diseases than animals not exposed to environmental enrichment. This work offers insight into the ways in which the CNS and the immune system interact, and it suggests that environmental enrichment can counter the damaging effects of chronic stress. These findings may someday be translated to therapeutic applications that include not only enrichment conditions but also manipulations that can be shown to affect neuronal activity in key brain circuits that we have defined experimentally.
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