STUDIES OF CENTRAL NERVOUS SYSTEM FUNCTIONAL ANATOMY

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

The Section on Functional Neuroanatomy combines molecular and neuroanatomical methods to identify dynamic aspects of nervous system function that relate to issues of mental health, infectious disease, and drug abuse. The current objective of our laboratory is to explore the interaction between the central nervous system (CNS) and the immune system in animals that are subjected to stress, immune stimuli, or infections. Our approach is to identify cellular and molecular components in the brain induced by immunological challenges and to further characterize the responses at molecular, anatomical, and functional levels. Key anatomical pathways and relevant neurotransmitter/receptor systems are mapped using histochemical techniques. In situ hybridization histochemistry (ISHH) is used to localize and quantify mRNA expression of neurotransmitters, cytokines, receptors, transcription factors, and immediate-early genes in studies of adaptive changes to immunological, pharmacological, physiological, or surgical interventions. Immunohistochemistry and double-label techniques are used to characterize the phenotypes of the cells that show induced mRNA expression of immune signaling molecules. We have 1) mapped the brain?s immune response to acute peripheral immune challenge (systemic administration of the bacterial immune stimulant lipopolysaccharide, 2) mapped the cerebrospinal and interstitial fluid flow pathways that may be involved in conveying immune signals throughout the brain, 3) shown how an immune stimulus (lipopolysaccharide) behaves once inside the blood-brain barrier, 4) developed a model of chronic immune system activation (trypanosome parasite infection), and 5) shown activation of class I major histocompatibility complex (MHC) mRNA in both neuronal and non-neuronal cells under conditions of immune and non-immune physiological challenges. Messages shown to be induced in acute and chronic challenges include interleukin-1 beta (IL-1beta), IL-6, IL-12, tumor necrosis factor-alpha (TNF-alpha), IL-1 receptor antagonist (IL-1ra), IL-1 converting enzyme (ICE), transforming growth factor beta (TGF-beta), and other immune signaling molecules such as inhibitory factor kappa B (IkappaB). In one project, DNA array technology has been used to determine the full spectrum of immune molecules that respond to a physiological challenge. The mRNAs are shown to be induced in specific cell types (endothelia, microglia, astrocytes, and meninges) and in specific patterns (high levels in the blood vessels, choroid plexus and circumventricular organs). We propose that an important functional component of the innate immune response involves centrally produced cytokines. New projects underway explore interactions between the brain and the immune system during adaptive immune responses. Experimental models include the development of an antineuronal autoimmune response and a study of the CNS cytokines produced during a delayed-type hypersensitivity response to an antigen present in the brain.