Studies Of Central Nervous System Functional Anatomy

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

Our approaches to understanding the relationship between the immune system and the CNS are manifold. On a molecular level, we are working to identify the cellular and molecular pathways in the brain that are engaged in immune challenges, seizures, and behavior manipulations. We are working to further characterize these responses at molecular, anatomical, and functional levels. On a systems and behavioral level, we are working with animal models of chronic stress and prenatal immune challenge to understand the mechanism by which the brain effects the immune system and by which the immune system effects the brain.[unreadable] Our molecular studies focus on the immune molecule NF-kB and the role it plays in neuronal function. 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 other roles, possibly related to cell survival or neuronal plasticity. We are designing 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 use the technique of in situ hybridization histochemistry (the binding of RNA probes to transcribed RNA targets) to localize and quantify mRNA expression of neurotransmitters, cytokines, enzymes, receptors, transcription factors, and immediate-early genes in studies of adaptive changes to immunological, pharmacological, physiological, behavioral, or surgical manipulations. We are also using the technique of immunohistochemistry (the binding of antibodies to target moieties) to try and localize and characterize NF-kB activation in neurons. Additionally, we are working with several strains of transgenic mice that either report NF-kB activity or have selectively altered NF-kB function. These mice allow us to analyze the NF-kB response at a neuron-specific cellular level. Some of our findings with these tools include: 1) that the p50 subunit of the NF-kB transcription factor is involved in resilience to stressors in mice, 2) that one function of p50 in controlling gene expression is to modify the epigenetic (chromatin) state of cytokine and chemokine gene promoters, 3) that neuronal NF-kB may be involved in neuroprotection in seizures and in the ability to recall a fearful experience, and 4) that phosphorylation of the p65 subunit of NF-kB occurs in the nuclei of neurons in cell culture and that phosphorylation levels are increased by glutamate stimulation.[unreadable] Also in mice, we are studying the effects of chronic psychosocial stress and environmental enrichment on depressive behavior and immune function. Chronic stress has been implicated in the cause and progression of various psychiatric disorders, including depression and post-traumatic stress disorder (PTSD). Furthermore, chronic stress has been shown to activate the stress axis (hypothalamic-pituitary-adrenal (HPA) axis) and to dysregulate the inflammatory response to infectious elements. Working with a naturalistic model of unavoidable chronic social stress, using a dominant-subordinate animal pairing design, we have shown that exposure to chronic stress dysregulates the immune system. We are continuing to work to identify the mechanisms by which stress has this deleterious effect. Additionally, our lab has shown that environmental enrichment can actually prevent and attenuate this immune dysfunction as well as depressive-like behaviors in subordinate mice exposed to social stress. Moreover, 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 and should be considered as an alternative therapy in depressive diseases.[unreadable] Sickness behavior, like that which follows bacterial or viral infection, has CNS-mediated components that mimic depression in that loss of appetite, sleepiness, anhedonia, and lethargy accompany both. There have been arguments that infections and immune system disorders contribute to depression and other mental disorders. Low-to-high doses of pathogenic stimuli such as the bacterial endotoxin lipopolysaccharide (LPS) have been used to mimic infections in animal models of inflammation-induced neurochemical and behavioral alterations. The changes are usually transient in adult animals. However, there are some data showing that high-dose LPS administration can cause long-lasting and even permanent CNS inflammatory and neurodegenerative changes. Moreover, 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 dysfunctions 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.