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Journal of Neuroscience, Vol 14, 4951-4964, Copyright © 1994 by Society for Neuroscience
Systemic interleukin-1 induces early and late patterns of c-fos mRNA expression in brain
LS Brady, AB Lynn, M Herkenham and Z Gottesfeld
Section on Functional Neuroanatomy, National Institute of Mental Health, Bethesda, Maryland 20892.
This study was designed to examine the mechanisms by which systemic
interleukin-1 affects neuroendocrine systems in the brain. Intraperitoneal
injections of interleukin-1 beta (1.25 micrograms/rat) were administered to
rats. One or three hours after injection, the expression levels of the
immediate-early gene c-fos and of genes for several neuropeptides,
receptors, and enzymes were examined by in situ hybridization
histochemistry. In the brainstem at 1 hr, c-fos mRNA was elevated in the
area postrema and nucleus of the solitary tract, but not in the locus
coeruleus. At 3 hr, the c-fos mRNA levels had increased further in the
nucleus of the solitary tract. Rostrally, elevations in c-fos mRNA levels
were found in the hypothalamic and thalamic paraventricular nuclei, central
nucleus of amygdala, bed nucleus of the stria terminalis, and medial
preoptic area, peaking at 1 hr and diminishing at 3 hr. In addition, at 3
hr a new pattern of c-fos activity emerged--the arcuate nucleus and cells
at the external margins throughout the brain now expressed c-fos mRNA.
Corticotropin-releasing hormone mRNA levels were doubled in the
paraventricular nucleus at 1 and 3 hr, concomitant with elevations in
plasma adrenocorticotrophic hormone (ACTH) and corticosterone. Tyrosine
hydroxylase mRNA levels in the brainstem did not change. The c-fos mRNA
induction patterns reveal a temporally dynamic response to interleukin-1
administration. We propose that the early set of structures responding to
interleukin-1 initiates the neuroendocrine response to cytokines.
Coactivation of the area postrema and nucleus of the solitary tract may
reflect entry into the brain and neural transduction of the peripheral
signal. The late set--including the nucleus of the solitary tract, arcuate
nucleus, and the brain's edge--may reflect cellular activation along the
diffusion routes traveled by interleukin-1 or a bioactive transduction
product, because the pattern of edge labeling is similar to the
autoradiographic pattern of flow lf radiolabeled tracer substances in the
cerebrospinal fluid. The late c-fos mRNA response to interleukin-1,
therefore, may represent a demonstration of information transfer in the
parasynaptic mode, also known as volume transmission.
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