Abstract
It is well documented that daily restraint stress (6 hrs per day) for 3 weeks appllied to rats causes atrophy of apical dendrites of hippocampal CA 3 neurons and decreased neurogenesis of granule cells in the dentate gyrus. BDNF plays a crucial role in hippocampal function by promoting cell survival and maintaining dendritic morphology. However, it is still controversial whether BDNF synthesis is affected by chronic stress. We investigated BDNF mRNA levels in the hippocampus, together with plasma glucocortiocid (GC) levels, GC receptors in the hippocampus/hypothalamus and 5-HT synthesis in the raphe nuclei, in animals chronically stressed for 1-3 weeks, using in situ hybridization, immunohistochmistry and denstiometric analyses of these data. Plasma GC and serotonergic projections from the raphe nuclei are considered to play major roles in reducing BDNF synthesis in the hippocampus. In these animals, BDNF mRNA levels were significantly decreased in the CA 3 and dentate gyrus at the end of 6 hrs of restraint, but the ability of restraint to reduce BDNF synthesis seemed less robust compared to that seen in acute stress models. HPA axis response to stress in these animals assessed by plasma GC levels was delayed and sustained, which may affect the regulation of BDNF synthesis in the hippocampus. The finding that GC receptor immunoreactive neurons in the paraventricular hypothalamic nucleus were increased at the end of 1 week may partly explain the altered HPA axis response in these animals. Immunoreactivity for 5-HT synthesizing enzyme, tryptophan hydroxylase, was increased in the median raphe nucleus, neurons of which mainly project to the hippocampus, but not in the dorsal raphe nucleus, in animals stressed for 2-3 weeks. Thus, repetitive stress may influence a variety of neural and endocrine systems. Stress-induced reduction of BDNF synthesis in the hippocampus was less prominent, but still significant in repetitively stressed animals, which may contribute, at least partly, to the neuronal atrophy, neuronal death and resultant reduction of hippocampal volume observed both in animals and humans suffering chronic stress and/or depression.
