Mecanismes moleculars i àrees del sistema nerviós central implicades en els efectes a llarg termini d'una sola exposició a l'estrès sobre l'eix hipotalàmic-pituitari-adrenal

We have previously observed that a single exposure of rats to a severe stressor such as immobilization (IMO)reduced the response of the hypothalamic-pituitary-adrenal (HPA) axis to the same, but not to a novel stressor, days or weeks later. The main, and unusual, features of the phenomenon were that the longer the time elapsed between the two exposures and the stronger the stressor the greater the long-term effects observed. These data suggest that we are dealing with anovel kind of learning linked to particularly severe stressful situations, what may be relevant to the post-traumatic stress disorder (PTSD) in humans. The objectives of the present project are the characterization of the molecular changes caused by a single exposure to IMO in the CNS, with special emphasis in the regulation of the HPA activity, and its putative value as an animal model of PTSD. To this end, it will be studied, using behavioural test, stereotaxic procedures and biochemical and histological techniques: 1) whether a single exponsure to IMO could be able to trigger a classical fear-conditioned response with characteristics similar to those observed in PTSD patients; b) the relationship between the activation of intracellular pathways of the neurons of the paraventricular nucleus of the hypothalamus (PVN), the key area in the control of the HPA axis, and the transcriptional changes (induction of transcription factors and the expression of CRF and vasopressin genes); c) the changes induced by a previous experiencie with IMO in the intracellular pathways of PVN neurons: d) the possible role of lymbic areas such as prefrontal cortex, hippocampal formation, amygdala and septum in the induction of the phenomenon, using a synaptic plasticity marker such as Arc and the revcersible enactivation of the areas probably involved by means of local administration of tetrodotoxin before the first exposure to IMO