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ABSTRACT:Brain-derived neurotrophic factor (BDNF) is strongly expressed in the hippocampus, where it has been associated with memory processes. In the central nervous system, some learning processes, as well as brain insults, including stress, induce modifications in BDNF mRNA expression. Because stress and memory appear to share some neuronal pathways, we studied BDNF mRNA and BDNF peptide variations in response to short times of immobilization stress. Using an RNase protection assay, we demonstrated that short-time stress application induced a significant increase (at 60 min) in BDNF mRNA levels in the whole rat hippocampus. Changes in BDNF mRNA content appear to reflect increased expression of BDNF transcripts containing exons I, II, and III, that were also significantly modified at this time. The time course of stress-induced changes in BDNF transcript levels revealed that mRNA containing exon III was the first increased, significantly elevated by 15 min, attaining maximal levels at 60 min, as BDNF transcripts containing exons I and II. However, at longer times of stress (180 min), BDNF mRNA levels were decreased as well as mRNA containing exon IV. In situ hybridization analysis of discrete hippocampal layers demonstrated that BDNF mRNA expression increased as early as 15 min in most hippocampal regions, with no modification in the number of labeled cells. The same signal pattern, although less pronounced, was determined at 60 min, but at this time a significant increase in BDNF-positive cells was visualized in the CA3 layer. The peptide, measured by immunoassay, was significantly augmented after 180 min of stress exposure whereas at 300 min, levels were similar to those measured in control animals. These data suggest that rapid changes in BDNF expression may be part of a compensatory response to preserve hippocampal homeostasis or a form of neuronal plasticity to cope with new stimuli. Hippocampus 2003;13:646 -655.