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, inflammatory 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, enzymes, 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 in the brain the immune response to acute administration of lipopolysaccharide (LPS), a bacterial endotoxin, 2) mapped the cerebrospinal fluid flow pathways that may be involved in conveying immune signals throughout the brain, 3) shown how an immune stimulus (LPS) behaves once inside the blood-brain barrier, 4) 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, 5) mapped activin and brain-derived neurotrophic factor (BDNF) mRNA induction in the kindling model of epilepsy, and 6) characterized the spatial and temporal cascade of events leading to brain-wide glial activation following intracerebroventricular administration of interleukin-1 (IL-1). Gene transcripts shown to be induced include IL-1, 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), inducible cyclooxygenase (COX-2), and inducible nitric oxide synthase (iNOS). The mRNAs are shown to be induced in specific cell types (endothelia, microglia, astrocytes, and meninges) and in specific patterns (high levels of expression in the blood vessels, choroid plexus and circumventricular organs). Current work examines the role of toll-like receptors (TLRs) in detecting pathogen-associated molecules and alerting the brain about peripheral immune challenges. We are also beginning work aimed at defining the role that the NF-kappaB transcription factor plays in normal brain function and in response to stressors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Intramural Research (Z01)
Project #
1Z01MH001090-26
Application #
6823672
Study Section
(LCMR)
Project Start
Project End
Budget Start
Budget End
Support Year
26
Fiscal Year
2003
Total Cost
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Lehmann, Michael L; Mustafa, Tomris; Eiden, Adrian M et al. (2013) PACAP-deficient mice show attenuated corticosterone secretion and fail to develop depressive behavior during chronic social defeat stress. Psychoneuroendocrinology 38:702-15
Patchev, Alexandre V; Fischer, Dieter; Wolf, Siegmund S et al. (2007) Insidious adrenocortical insufficiency underlies neuroendocrine dysregulation in TIF-2 deficient mice. FASEB J 21:231-8
Steiner, Alexandre A; Chakravarty, Sumana; Rudaya, Alla Y et al. (2006) Bacterial lipopolysaccharide fever is initiated via Toll-like receptor 4 on hematopoietic cells. Blood 107:4000-2
Herkenham, Miles (2005) Folliculo-stellate (FS) cells of the anterior pituitary mediate interactions between the endocrine and immune systems. Endocrinology 146:33-4
Bryceson, Y T; Foster, J A; Kuppusamy, S P et al. (2005) Expression of a killer cell receptor-like gene in plastic regions of the central nervous system. J Neuroimmunol 161:177-82
Chakravarty, Sumana; Herkenham, Miles (2005) Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines. J Neurosci 25:1788-96
Steiner, Alexandre A; Chakravarty, Sumana; Robbins, Jared R et al. (2005) Thermoregulatory responses of rats to conventional preparations of lipopolysaccharide are caused by lipopolysaccharide per se-- not by lipoprotein contaminants. Am J Physiol Regul Integr Comp Physiol 289:R348-R352
Kassed, Cheryl A; Herkenham, Miles (2004) NF-kappaB p50-deficient mice show reduced anxiety-like behaviors in tests of exploratory drive and anxiety. Behav Brain Res 154:577-84
Foster, Jane A; Puchowicz, Michael J; McIntyre, Dan C et al. (2004) Activin mRNA induced during amygdala kindling shows a spatiotemporal progression that tracks the spread of seizures. J Comp Neurol 476:91-102
Butterweck, Veronika; Winterhoff, Hilke; Herkenham, Miles (2003) Hyperforin-containing extracts of St John's wort fail to alter gene transcription in brain areas involved in HPA axis control in a long-term treatment regimen in rats. Neuropsychopharmacology 28:2160-8

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