Exposure of animals to an enriched environment triggers widespread modifications in brain circuitry and function. While this paradigm leads to marked plasticity in animals chronically or acutely exposed to the enriched environment, the molecular mechanisms that enable or regulate such modifications require further characterization. To this end, we have investigated the expression profiles of both mRNA and protein products of a candidate-plasticity gene, nerve growth factor induced-A (NGFI-A), in the brains of rats exposed to increased environmental complexity. We found that NGFI-A mRNA is markedly up-regulated throughout the brains of animals exposed to the enriched environment, but not in the brains of either handled-only or undisturbed control groups. The most pronounced effects were observed in the somatosensory and visual cortices, in layers III and V, while more modest increases were observed in all other cortical layers, with the exception of layer I. A striking NGFI-A mRNA up-regulation was also observed in the striatum and hippocampal formation, notably in the CA1 subfield, of animals exposed to the enriched environment paradigm. Immunocytochemistry was also used to investigate the distribution of NGFI-A protein in response to the environmental enrichment protocol. A marked increase in the number of NGFI-A positive nuclei was identified in the enriched environment condition, as compared to undisturbed and handled-only controls, throughout the rat brain. While the greatest number of NGFI-A immunolabeled neurons was found in cortical layers III and V, up-regulation of NGFI-A protein was also detectable in layers II, IV and VI, in both the somatosensory and visual cortices. NGFI-A immunopositive neurons were also more numerous in the CA1 subfield of the hippocampal formation of animals exposed to the enriched environment, but remained at basal levels in both control groups. Our results implicate NGFI-A as one of the possible early genetic signals that ultimately lead to plastic changes in the CNS.