Phd in PHARMACOLOGY AND TOXICOLOGY

Thesis title: INDIVIDUAL DIFFERENCES IN STRESS SUSCEPTIBILITY: NEUROBIOLOGICAL MECHANISMS AND THERAPEUTIC TARGETS

Post-Traumatic Stress Disorder (PTSD) is a psychiatric condition that develops after traumatic experiences, affecting both cognitive and emotional regulation. While its neurobiological mechanisms have been widely studied, important aspects such as sex differences, vulnerability during critical developmental periods, and long-term effects of stress remain less explored. This thesis examines these factors using preclinical models to better understand PTSD susceptibility and potential therapeutic approaches. The first study tested whether a PTSD model previously validated in male rats could also replicate PTSD-like alterations in female rats, considering their higher susceptibility. We found that trauma exposure led to persistent fear retention, reduced exploratory behavior, and impaired social interactions, similar to findings in males. Additionally, individual differences in exploratory behavior immediately after trauma predicted long-term vulnerability or resilience, supporting the idea that variability in stress responses plays a key role in PTSD development. The second study focused on critical developmental periods, investigating how stress exposure during these phases influences cognitive and emotional outcomes. Using the single prolonged stress (SPS) paradigm, we found that stress exposure led to sex-dependent changes in emotional responses, while cognitive functions remained largely unaffected. Analysis of oxidative stress markers in the prefrontal cortex and hippocampus further suggested that redox imbalances may contribute to vulnerability to stress-related disorders. The final study examined social buffering as a potential therapeutic strategy, evaluating the impact of social support on fear extinction and social behavior. Results showed that social interaction during extinction sessions helped reduce fear responses and social avoidance, highlighting its role in mitigating PTSD-related symptoms. Overall, these findings emphasize the importance of sex differences, stress exposure during critical periods, and social factors in PTSD. By integrating biological and behavioral perspectives, this thesis contributes to understanding the mechanisms behind stress vulnerability and resilience, offering insights for future therapeutic strategies.