Phd in PHARMACOLOGY AND TOXICOLOGY

Thesis title: NEW INSIGHTS IN TRASLATIONAL SCIENCE: CHRONICITY, SEX DIFFERENCES AND INTERINDIVIDUAL VARIABILITY IN ANIMAL MODELS OF STRESS-RELEATED DISORDERS

Stress increases the risk of mental health diseases such as anxiety, depression, and post-traumatic stress disorder. Everyone is affected by stress, but it may not always be detrimental. Coping with stress can be challenging to some, but not to all. Stressful events must interact with a wide variety of background factors to manifest as an illness. Moreover, our response to stressful events changes throughout our life and it is strongly gender dependent. Particularly, adolescence is a crucial developmental stage and stress experienced during this period has more detrimental effects compared with those experienced in adulthood. Therefore, the first goal of my thesis was to investigate in rats, whether exposure to 2 stressors at different stages in life has long-term effects on emotional and cognitive capabilities, and whether the interaction between the 2 stressors influences stress resilience. We found that rats subjected to social defeat stress (SDS, first hit) in adolescence and to a single episode of prolonged stress (SPS, second hit) in adulthood, reported differences in behavioral outcomes, hippocampal expression of brain-derived neurotrophic factor, and plasma corticosterone levels when tested in adulthood compared to control or single-stressed rats. Regarding the interaction between adolescence, sex and stress, we developed a new rat model of brief and repeated social isolation stress (SIS). Adolescents who daily spend hours playing videogames or forced to keep physical distancing for containing the spread of the COVID-19 are, indeed, on high risk to develop many psychological disturbances. We demonstrated that rats exposed to SIS in adolescence and SPS in adulthood reported altered behavioral phenotype in a sex-dependent manner, when compared to control or single-stressed rats. In addition, considering that women have a two-fold greater risk to develop PTSD, and that most preclinical studies have been carried out in males, we wanted to further test the long-term sex differences in response to SPS. We provide the first evidence that SPS reproduces long-term emotional alterations in male, but not in female, rats which persist 30 days following trauma exposure, thus resembling some of the hallmark symptoms of PTSD. Furthermore, our results show for the first time a long-term SPS-induced alteration of cued fear extinction in females. Clinical data shown that not only the susceptibility to stress is gender dependent, but more deeply, it has a strong variability between individuals of the same gender. Even if subjects experiencing a traumatic event during lifetime all show an acute response to the trauma, only a subset of them (susceptible) ultimately develops PTSD, meanwhile the others (resilient) fully recover after the first acute response. Therefore, we implemented our experimental PTSD model previously developed, making it suitable to differentiate between susceptible (high responders, HR) and resilient (low responders, LR) rats in terms of over-consolidation, impaired extinction, and social impairment long after trauma. Our findings showed that exploratory activity after trauma in a novel environment is a very robust variable to predict susceptibility towards a PTSD-like phenotype. This experimental model is thus able to screen and differentiate, before extinction learning and potential therapeutic intervention, susceptible and resilient PTSD-like rats, paving the way to the development of potential personalized therapies. The interindividual variability, indeed, not only affects the susceptibility to stress disorders, but it also determines the success or the failure of a therapeutic treatment. Recommended interventions such as trauma-focused psychotherapies or pharmacological treatments are effective only in a portion of PTSD patients, most of whom report relapses and recrudescence of the pathology. The swift progress of neuroscience and animal studies, aimed at modulating learning and memory processes with drugs, has encouraged many research efforts to pave the way for clinical trials in humans. Therefore, we ultimately summarized some of the latest compounds whose efficacy in boosting psychological therapy has been evaluated in preclinical and clinical trials. All together our results provide new insights on molecular and behavioral effects of stress, considering the chronicity, sex and interindividual variability which were also observed in human PTSD patients. Particularly, investigating how the effects of traumatic events could change the long-term responsiveness in a sex-dependent and individual-oriented manner, could lead to important advances in daily clinical practices, particularly in treating stress related disorders such as PTSD.