672. Adolescence at the crossroads of prenatal stress: unraveling neurobiological vulnerabilities and the early protective role of a ketogenic diet

Abstract

Abstract Background Stress is a major etiological factor in the development of mental disorders, particularly when exposure occurs during sensitive developmental windows. Prenatal stress (PNS) has been shown to induce long-lasting behavioral and neurobiological alterations that emerge during adolescence and persist into adulthood. Increasing evidence suggests that these effects are mediated by early disruptions of placental function, immune–inflammatory pathways, and redox balance, ultimately shaping trajectories of vulnerability or resilience to psychopathology. Aims & Objectives My talk aims to elucidate the mechanisms through which prenatal stress programs long-term emotional and cognitive outcomes, with a specific focus on vulnerability and resilience phenotypes. In addition, it will explore whether dietary interventions, such as the ketogenic diet, can mitigate the adverse neurodevelopmental consequences of gestational stress by modulating immune–inflammatory and oxidative pathways in a sex-dependent manner. Method Using a validated rodent model of prenatal stress, pregnant dams were exposed to repeated stress during late gestation. Behavioral outcomes were assessed in adolescent offspring across domains relevant to psychiatric disorders, including sociability and anxiety-like behavior. Molecular analyses were conducted along the prefrontal cortex–hippocampal axis to identify neurobiological signatures associated with stress vulnerability and resilience. In parallel, the impact of a ketogenic diet administered during critical developmental periods was evaluated in terms of behavioral outcomes and inflammatory and redox-related molecular pathways, while also considering sex differences. Results Prenatal stress induced persistent emotional dysregulation in a subset of adolescent offspring, characterized by reduced sociability and increased anxiety-like behavior, while other individuals displayed resilience. These divergent phenotypes were associated with distinct molecular signatures along the prefrontal cortex–hippocampal axis, involving immune–inflammatory and oxidative stress pathways. Gestational stress was also found to disrupt placental function, promoting inflammation and oxidative stress that interfere with normal neurodevelopmental trajectories. Importantly, exposure to a ketogenic diet during adolescence attenuated the behavioral and molecular consequences of prenatal stress, reducing vulnerability and enhancing resilience through sex-dependent modulation of immune–inflammatory and antioxidant mechanisms. Discussion & Conclusions Together, these findings support the concept that prenatal stress programs long-term vulnerability to mental disorders through early immune and redox dysregulation, while also highlighting the existence of resilience trajectories. The data further indicate that dietary interventions such as the ketogenic diet may represent a promising preventive strategy to counteract the neurodevelopmental impact of gestational stress. Importantly, the sexually dimorphic effects observed underscore the need to consider sex as a critical biological variable in the development of personalized preventive and therapeutic approaches for stress-related psychopathology.