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 an ethologically valid form of chronic stress, we are exploring the effects of social conflict stress, which induces depressive-like behaviors and enduring neurochemical alterations in identified neuronal pathways in mice. Social defeat incurred in the conflict paradigm has adverse consequences that can be experimentally validated by administering behavioral tests of depressive-like behaviors, such as helplessness tests, anxiety measures, and social interaction tests. 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 are generally healthier, have better cognitive function, and are less susceptible to neurodegenerative diseases than animals in impoverished housing. 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 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. Conditional transgenic mice with a 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. Ongoing studies are examining the role of the infralimbic area of frontal cortex and of the stress hormone corticosterone in conferring the ability of environmental enrichment to confer resilience to the deleterious effects of social defeat. 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. The second area of research focuses on immune factors that can impact brain function and behavior, both in adult animals and notably in embryos and offspring as a consequence of a maternal immune challenge. Maternal immune activation (MIA) during pregnancy in rats and mice is a model to study the deleterious effects of maternal infections on early brain development and subsequent adolescent and adult behavior, cognition, and mood in the offspring. Low-to-high doses of pathogenic stimuli such as the endotoxin lipopolysaccharide (LPS) have been used to mimic bacterial or viral infections. The biochemical changes are transient, but the MIA appears to have profound, permanent effects on the offspring (effects that mimic depressive, autistic, and psychotic behavior). In a set of experiments performed in rats, we developed an MIA model in which pregnant dams were subjected to an immune challenge (LPS administration) at day 15 of gestation, and the offspring were studied for both behavioral alterations (deficits in exploration and social behaviors) and underlying biochemical causes. At various times after LPS, 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 levels. The data showed that LPS induced a pro-inflammatory cytokine and chemokine storm that passed directly or indirectly into the fetus to induce transient spikes that were accompanied by decreases in anti-inflammatory and growth factor gene expression levels. 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. Links between activation of the immune system and CNS-mediated responses that may be relevant to the malaise of depression and other psychiatric disorders can be examined by basic studies of biochemical pathways that may translate immune signals into a language that neurons might use. We are looking at the involvement of the transcription factor NF-kB (nuclear factor-kappa B) in glial and neuronal function. NF-kB is an intracellular dimer that conveys information, usually about immune activation or cellular stress, from the cell surface and cytoplasm to the nucleus where it binds to DNA and controls the production of immune molecules and regulates 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. NF-kB is found in all cells, and 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 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) the p50 subunit of NF-kB is involved in spatial learning in mice, 2) many of the antibodies used in the literature to characterize NF-kB activity are not specific for their targets, and 3) NF-kB dimers (p50 and p65) are constitutively present, but there are very few stimuli that can induce movement in and out of the nucleus and produce DNA binding activity, suggesting that NF-kB normally plays a small role in neuronal function.
Showing the most recent 10 out of 16 publications
