THE RIPID AND LONG-TERM IMPACT OF ACUTE STRESS ON NEUROPLASTICITY. A NOVEL PARADIGM FOR DISSECTION OF STRESS RESPONSE

The response to stressful events is physiologically required to adapt to external challenges. However, the stress response can either have a ‘pro-adaptive’ outcome, when the response is efficiently activated and then inactivated, or exert ‘maladaptive’ effects, when the subject is vulnerable and the response is dysregulated. Unfortunately, it is still unknown what mechanisms address the individual responses towards pro-adaptive or maladaptive outcome of stress. In previous studies we found that acute inescapable footshock (FS)-stress rapidly enhances depolarization-evoked glutamate release from prefrontal and frontal cortex (PFC/FC) purified synaptic terminals (synaptosomes), with a mechanism involving rapid, nongenomic enlargement of the readily releasable pool (RRP) of glutamate presynaptic vesicles. Moreover, we showed that the same protocol of acute stress induces long-term atrophy/remodeling of apical dendrites in the same area up to 14 days later, thus suggesting that the consequences of acute stress are far from being simply acute. Traditional models of chronic stress reproduce only the endpoint of several changes occurring in brain and body during the stress response. On the opposite, analyzing short- and long-term alterations induced by acute stress could be a useful tool to dissect adaptive and maladaptive components underlying stress response. Here, we aimed at dissecting the early and delayed alterations induced by a single session of acute FS-stress, focusing on the putative effectors that trigger towards adaptive/maladaptive trajectories of the stress response. We demonstrated that FS-stress increases both glutamate release evoked by depolarization and RRP size up to 24h after the stress protocol. In parallel, we found that acute FS-stress exerts different time-dependent molecular alterations in synaptic membranes from PFC/FC. We then set up a behavioral paradigm that discriminates resilience/vulnerability towards acute stress, based on stress-induced behavioral alterations. We demonstrated that the different behavioral phenotypes are associated with specific functional and molecular alterations in PFC glutamatergic synapses. Our approach, dissecting rapid and delayed effects of acute stress response, and their adaptive/maladaptive components, could lead to better understand mechanisms that turn stress response from a physiological adaptation into maladaptive alterations. The final aim is to look for the putative effectors of this switch, searching for markers of vulnerability and novel targets for the therapies of neuropsychiatric disorders.