Constitutive expression of the interferon-γ receptor protein (IFN-γR), and the distribution of cells in which Fos, a marker of cell activation, is induced by intracerebroventricular administration of IFN-γ, were studied in the rat brain by immunohistochemistry. IFN-γR immunopositivity was found in neuronal elements, which exhibited a selective distribution being concentrated in the piriform and entorhinal cortex, midline thalamus and medial hypothalamic structures, brainstem nociceptive relays (including the periaqueductal gray, the parabrachial nuclei and the caudal part of the spinal trigeminal nuclei), and circumventricular organs such as the median eminence and area postrema. IFN-γ-induced Fos expression mostly corresponded to neuronal sites of receptor distribution. Because of its topographical distribution, it is suggested that activation of the IFN-γR in neurons may play a role to limit spread of infections in the brain and, in concert with other proinflammatory cytokines, to modulate adaptive responses to an antigen challenge mediated by the central nervous system. Copyright (C) 2000 Elsevier Science Inc.