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The Journal of Neuroscience, May 26, 2004, 24(21):4928-4934; doi:10.1523/JNEUROSCI.1077-04.2004

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Behavioral/Systems/Cognitive
Long-Term Alterations in Neuroimmune Responses after Neonatal Exposure to Lipopolysaccharide

Lysa Boissé, Abdeslam Mouihate, Shaun Ellis, and Quentin J. Pittman

Calgary Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta T2N 4N1, Canada

Fever is an integral part of the host's defense to infection that is orchestrated by the brain. A reduced febrile response is associated with reduced survival. Consequently, we have asked if early life immune exposure will alter febrile and neurochemical responses to immune stress in adulthood. Fourteen-day-old neonatal male rats were given Escherichia coli lipopolysaccharide (LPS) that caused either fever or hypothermia depending on ambient temperature. Control rats were given pyrogen-free saline. Regardless of the presence of neonatal fever, adult animals that had been neonatally exposed to LPS displayed attenuated fevers in response to intraperitoneal LPS but unaltered responses to intraperitoneal interleukin 1 or intracerebroventricular prostaglandin E₂. The characteristic reduction in activity that accompanies fever was unaltered, however, as a function of neonatal LPS exposure. Treatment of neonates with an antigenically dissimilar LPS (Salmonella enteritidis) was equally effective in reducing adult responses to E. coli LPS, indicating an alteration in the innate immune response. In adults treated as neonates with LPS, basal levels of hypothalamic cyclooxygenase 2 (COX-2), determined by semiquantitative Western blot analysis, were significantly elevated compared with controls. In addition, whereas adult controls responded to LPS with the expected induction of COX-2, adults pretreated neonatally with LPS responded to LPS with a reduction in COX-2. Thus, neonatal LPS can alter CNS-mediated inflammatory responses in adult rats.

Key words: stress; interleukin; COX-2; cytokine; prostaglandin; fever

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Received Feb 11, 2004; revised April 7, 2004; accepted April 8, 2004.

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