Gene expression profile of the hippocampus of a behavioural model of depression

Although the neurobiological basis of depression has not been fully elucidated, numerous studies have emphasized that in the etiology of depression stress may be the most significant cause, together with genetic vulnerability. Stress induces a coordinated and complex response that is adaptive and integral to survival. The brain's ability to adapt and change over time is refered to neuroplasticity and long-term plasticity in the brain requires changes in gene expression. However, exposure to intense or chronic stressors leads to an increased risk for the development of stress-related disorders including major depression. Numerous studies demonstrate that neuronal atrophy and loss of plasticity occur in hippocampus in response to stress and depression. Therefore, the hippocampal region may play a central role in depressive illness. Likewise changes in gene expression underlying the plasticity of hippocampal structures appear to be relevant in undenstanding the molecular and cellular mechanisms involved in the etiology as well as the treatment of depression, and the mechanisms leading vulnerability or resilience to stress. In fact, humans display a remarkable heterogeneity in their responses to stress and adversity. Although we are beginning to understand how maladaptive neurobiological changes may contribute to depression, relatively little is known about the molecular mechanisms that may underlie stress resilience. Here we set out to investigate the changes in the gene expression profile underlying the effects of stress on the hippocampus using a behavioural paradigm of depression, the chronic escape deficit model [1], which is based on the modified reactivity of rats to external stimuli, the escape deficit, induced by exposure to intense and unavoidable stress. The chronic escape deficit model starts as an acute escape deficit which can be indefinitely sustained by repeated administration of mild stressors. This approach has proved to be a valid and useful model of depression because it consider depressive symptoms like behavioural despair. We performed gene expression profiling in the rat hippocampus, using GeneChip Rat Exon Array (Affymetrix). Using this new platform we carried out analyses of gene expression on three different levels: gene, transcript and exon level analyses. The behavioural results showed that exposure to intense and unavoidable stressful procedure induced escape deficit only in 60% of them. Whereas the animals remaining display a behaviour apparently identical to control animals which did not undergo the stressful procedure. Comparing gene expression profiles and performing functional analysis on differently expressed genes we have indicated multiple pathways that may be involved in the underlying mechanisms of stress condition associated with escape deficit. Moreover we identified possible cellular functions and biological processes that could represent targets that may contribute to mediate the effects of stress on the hippocampal plasticity. Such as, gene expression profiling of stress-vulnerable and stress-resilient animals revealed distinct transcriptional profiles, suggesting that resilient behaviour represents an active neurobiological process and not simply the absence of vulnerability.