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The Journal of Neuroscience, June 1, 2005, 25(22):5314-5322; doi:10.1523/JNEUROSCI.0687-05.2005

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Behavioral/Systems/Cognitive
Neuronal, Endocrine, and Anorexic Responses to the T-Cell Superantigen Staphylococcal Enterotoxin A: Dependence on Tumor Necrosis Factor-{alpha}

Alba Rossi-George,1 Daniella Urbach,2 Danielle Colas,1 Yael Goldfarb,1 and Alexander W. Kusnecov1,2

1Behavioral Neuroscience Program, Department of Psychology, Rutgers University, and 2Joint Graduate Program in Toxicology, University of Medicine and Dentistry of New Jersey and Rutgers University, Piscataway, New Jersey 08854

Staphylococcal enterotoxin A (SEA) is a microbial superantigen that activates T-lymphocytes and induces production of various cytokines, including tumor necrosis factor-{alpha} (TNF{alpha}). Previously, it was shown that SEA activates the hypothalamic-pituitary-adrenal axis and augments gustatory neophobic behaviors. In the present study, it was hypothesized that these effects involve neuronal activation in forebrain regions mediating fear and/or anxiety and are dependent on the production of TNF{alpha}. Male C57BL/6J mice were given intraperitoneal injections of 10 µg of SEA and 5 µg of lipopolysaccharide (LPS) or saline and perfused 2 h later for histochemical determination of brain c-Fos immunoreactivity (IR). The results showed increased c-Fos IR in the paraventricular nucleus, arcuate nucleus, central nucleus of the amygdala, bed nucleus of the stria terminalis, and lateral septum. Challenge of TNF-/- mice with SEA did not produce a significant increase in brain c-Fos IR, although c-Fos was increased after exposure to a psychogenic stressor (i.e., open field). In additional experiments, the elevated corticosterone response to SEA was abrogated in TNF-/- mice and was shown to be corticotropin-releasing hormone dependent. Finally, the augmented reduction in novel food intake after SEA challenge was attenuated in TNF-/- mice as well as in wild-type mice administered antibody to TNF{alpha}. In conclusion, challenge with SEA recruits brain regions mediating stress and anxiety responses, an effect that requires endogenous TNF{alpha}. Whether this is indicative of all T-cell superantigens remains to be determined, although it stands in contrast to other models of neuroimmunomodulation (e.g., LPS) that involve multiple cytokine influences.

Key words: anorexia; corticosterone; immunity; limbic; neuromodulation; tumor necrosis factor; staphylococcal enterotoxin A


Received Dec 31, 2004; revised April 20, 2005; accepted April 20, 2005.






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