Our previous work showed that immune system activators (LPS, cytokines) transduce a signal at the blood-brain barrier and induce the expression of cytokines, cyclooxygenase-2 (Cox-2), nitric oxide synthase (iNOS), and other inflammatory molecules in the brain. Other work 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 electroconvulsive shock (ECS) and kindling in rats.

One set of current projects is aimed at understanding how peripheral immunological challenges elicit CNS responses.

Bone marrow chimera work addresses 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 using chimeric mice. Reciprocal bone marrow chimeras between wild-type and TLR4 mutant mice showed that TLR4 on CNS-resident cells is critically required for sustained inflammation in the brain after systemic LPS administration.

We are characterizing toll-like receptor (TLR) expression patterns and their regulation in the brain, and assessing if divergent pathways activated downstream of TLR4 contribute equally to the CNS response in vivo.

We are identifying similarities and differences in the CNS response to LPS versus other TLR agonists like CpG DNA (TLR9) and dsRNA (TLR3).

In another set of current projects, we seek to understand how immune-related molecules influence mood and anxiety behaviors in rodents: our focus in the role of the NF-kB transcription factor, especially subunit p50, in emotional states such as fear and anxiety.

We are characterizing anxiety-like behaviors in p50 knockout mice that show altered emotional states. These mice are normal in most simple tests of appearance and sensorimotor function, but they show greatly reduced fear and anxiety-like behaviors.

Biochemical and anatomical studies will characterize the roles of p50 and the NF-kB transcription factor in emotional behaviors.

Current work takes advantage of new technologies, including DNA array, real-time PCR, and transgenic animals and cell lines. We are using these tools to examine a number of questions, including roles of TLRs in immune signaling to the brain, neuronal involvement in CNS immune signaling, immune signal molecule involvement in seizures, and the role of neuronal NF-kB transcription factor activity expression of emotional behavior. We are expanding our studies of the NFKB1 -/- mouse that lacks the p50 subunit of the NF-kB transcription factor. This mouse shows reduced anxiety and has other remarkable alterations in expression of emotional behavior. A number of studies are being done to further characterize the phenotype and disclose the underlying biochemical alterations.

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.

Quan N, Whiteside M, Herkenham M. Time course and localization patterns of interleukin-1beta messenger RNA expression in brain and pituitary after peripheral administration of lipopolysaccharide. Neuroscience, 1998, 83: 281-293.

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, Whiteside M, Herkenham M. Cyclooxygenase 2 mRNA expression in rat brain after peripheral injection of lipopolysaccharide. Brain Res, 1998, 802: 189-197.

Whiteside M, Quan N, Herkenham M. Induction of pituitary cytokine transcripts by peripheral lipopolysaccharide. J Neuroendocrinol, 1999, 11: 115-120.

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.

Kassed, C. A. and Herkenham, M. NF-kappaB p50-deficient mice show reduced anxiety-like behaviors in tests of exploratory drive and anxiety. Behav. Brain Res., 154: 577-584, 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. Rudaya, A. Y., Herkenham, M., and Romanovsky, A. A, Bacterial lipopolysaccharide fever is initiated via Toll-like receptor 4 on hematopoietic cells, Blood, 107; 4000-4002, 2006.

Patchev, A., Fischer, D., Wolf, S., Herkenham, M., Gotz, F., Gehin, M., Chambon, P., Patchev, V., and Almeida, O., Insidious adrenocortical insufficiency underlies neuroendocrine dysregulation in TIF-2 deficient mice. FASEB J., 21: 231-238, 2007.

O'Connor, J.C., Lawson, M.A., Andre, C., Briley, E.M., Szegedi, S.S., Lestage, J., Castanon, N, Herkenham, M., Dantzer, R. and Kelley, K.W. Induction of indoleamine 2,3-dioxygenase by Bacille Calmette-Guerin is responsible for development of murine depressive-like behavior. J. Immunology, 182: 3202-3212, 2009.

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.