Welcome to the Section on Functional Neuroanatomy
Laboratory of Cellular and Molecular Regulation, IRP
National Institute of Mental Health
National Institutes of Health, DHHS
Miles Herkenham, Ph.D., Chief
Molecular, Anatomical, Neuroendocrinological, and Neuroimmune Studies of Psychosocial Stress and Environmental Enrichment
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Our previous work showed that immune system activators (LPS, cytokines) transduce a signal at the blood-brain barrier and induce the mRNA expression of cytokines, cyclooxygenase-2 (Cox-2), nitric oxide synthase (iNOS), and other inflammatory molecules in the brain. We also showed that a centrally derived cytokine (IL-1) signal can induce massive leukocyte infiltration into the brain (photograph). We also generated a T cell-driven antineuronal autoimmune reaction directed against the cannabinoid CB1 receptor, a CNS target present in regions involved in movement control. We have shown induced region-specific neuronal expression of type 1 major histocompatibility complex (type I MHC) mRNA, and we have cataloged and mapped immune molecules induced by kindling in rats. Bone marrow chimera work addressed whether LPS signal transduction in hematopoietic versus CNS cells is important for the initiation and maintenance of the brain response |
| following peripheral LPS administration. The contribution of TLR4 expressed in CNS-resident versus hematopoietic cells to the development of CNS inflammation was examined by making reciprocal bone marrow transplants between wild-type and TLR4 mutant (LPS nonresponsive) mice. The data showed that TLR4 on CNS-resident cells is critically required for sustained inflammation in the brain after systemic LPS administration In another set of projects, we seek to understand how immune-related molecules influence mood and anxiety behaviors in rodents. Our focus is on the role of the NF-kB transcription factor in emotional states such as fear and anxiety. We are characterizing anxiety-like behaviors in NFkB1-/- (p50 knockout) mice that show altered emotional states. These mice are normal in most simple tests of appearance and sensorimotor function, but they show altered fear and anxiety-like behaviors. Current work takes advantage of new technologies, including DNA array, real-time PCR, and transgenic animals and primary cell culture. We are using these tools to examine a number of questions, including roles of neuronal NF-kB transcription factor activity expression of emotional behavior. In cell culture, we have found that NF-kB is only minimally active in neurons, in contrast to its strong activity in other primary cells such as astrocytes and hepatocytes, and in certain cell lines. We are using the maternal immune activation (MIA) model to examine how immune perturbation (LPS challenge) during pregnancy in rats and mice affects the behavior and brain structure of the affected offspring. | |
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References: Quan N, Whiteside M, Kim L, Herkenham M. Induction of IkappaB in the central nervous system after peripheral lipopolysaccharide administration: an in situ hybridization study in the rat. Proc Nat'l Acad Sci USA, 1997, 94: 10985-90. Herkenham M, Lee HY, Baker RA. Temporal and spatial patterns of c-fos mRNA induced by intravenous interleukin-1: a cascade of non-neuronal cellular activation at the blood-brain barrier. J Comp Neurol, 1998, 400: 175-196. Quan N, Stern E, Whiteside MB, Herkenham M. Induction of pro-inflammatory cytokine mRNAs in the brain after peripheral injection of subseptic doses of lipopolysaccharide in the rat. J Neuroimmunol, 1999, 93: 72080. Quan N, Mhlanga JDM, Whiteside MB, McCoy AN, Kristensson K, Herkenham, M. Chronic over-expression of pro-inflammatory cytokines and histopathology in the brains of rats infected with Trypanosoma brucei. J Comp Neurol, 1999, 414: 114-130. Quan, N, Mhlanga, JDM, Whiteside, M, Kristensson, K, and Herkenham, M. Chronic sodium salicylate treatment exacerbates brain neurodegeneration in rats infected with Trypanosoma brucei. Neuroscience, 2000, 96: 181-194. Quan, N., He, L., Lai, W., Shen, T., and Herkenham, M. Induction of IkappaBalpha mRNA expression in the brain by glucocorticoids: a negative feedback mechanism for immune-to-brain signaling. J. Neuroscience, 20: 6473-6477, 2000. Quan, N. and Herkenham, M. Connecting cytokines and brain: A review of current issues. Histol. Histopathol., 17: 273-288, 2002. Proescholdt, M. G., Chakravarty, S., Foster, J. A., Foti, S. B., Briley, E. M., and Herkenham, M. Intracerebroventricular but not intravenous interleukin-1beta induces widespread vascular-mediated leukocyte infiltration and immune signal mRNA expression followed by brain-wide glial activation. Neuroscience, 112: 731-749, 2002. Proescholdt, M. G., Quigley, L., Martin, R., and Herkenham, M. Immunization with a cannabinoid receptor type 1 peptide results in experimental allergic meningo-cerebellitis in the Lewis rat: A model for cell-mediated autoimmune neuropathology. J. Neuroscience Res. 70: 150-160, 2002. Foster, J. A., Quan, N., Stern, E. L., Kristensson, K., and Herkenham, M. Induced neuronal expression of class I major histocompatibility complex (MHC) mRNA in acute and chronic inflammation models. J. Neuroimmunology, 131: 83-91, 2002. Foster, J. A., Puchowicz, M. J., McIntyre, D. C., and Herkenham, M. Activin mRNA induced during amygdala kindling shows a spatiotemporal progression that tracks the spread of seizures. J. Comp. Neurol., 476: 91-102, 2004. Chakravarty, S. and Herkenham, M. Toll-like receptor 4 on non-hematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines., J. Neuroscience, 25: 1788-1796, 2005. Bryceson, Y., Foster, J. A., Kuppusamy, S. P., Herkenham, M., and Long, E. O. Expression of a killer cell receptor-like gene in plastic regions of the central nervous system. J. Neuroimmunology, 161: 177-182, 2005. Steiner, A. A., Chakravarty, S. Robbins, J. R., Dragic, A. S., Pan, J., Herkenham, M. and Romanovsky, A. A. 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, 2005. Chen, Q., Zhang, H., Li, Q., An, Y., Herkenham, M., Lai, W., Popovich, P., Agarwal, S., and Quan, N. Three promoters regulate tissue- and cell type-specific expression of murine interleukin-1 receptor type I. J. Biol. Chem., 284: 8703-8713, 2009. Lehmann, M.L., Brachman, R.A., Listwak, S.J., and Herkenham, M., NF-kappaB activity affects learning in aversive tasks: possible actions via modulation of the stress axis. Brain Behav. Immun. 24: 1008-1017, 2010. Oskvig, D.B., Elkahloun, A.G., Johnson, K.R., Phillips, T.M. and Herkenham, M. Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response. Brain, Behavior, Immun., in press, 2012 | |
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