Dottorato in NEUROSCIENZE DEL COMPORTAMENTO

Titolo della tesi: Shared mechanisms underlying the impact of maternal psychophysical stress and obesity on offspring neurodevelopment

Vulnerability to mental illness might find its roots very early during development, already during fetal life. In fact, prenatal adversities can affect brain development by shaping neuronal circuits involved in stress responses, resulting in embedded biological traces that persist throughout life. In this perspective, maternal environment plays a pivotal role in driving fetal neurodevelopment, even more important than purely heritable genetic background. Chapter 1 of this thesis introduces the concept that maternal obesity - a growing public health issue - can be considered as a stressor that, by contributing to establish a sub-optimal intrauterine environment, may derange fetal neurodevelopment. We reviewed in detail clinical and preclinical evidence showing an association between the prenatal exposure to an “obesogenic environment” and a higher risk for the occurrence of neurodevelopmental and psychiatric disorders. An ever increasing body of evidence shows that similar mental health outcomes in the offspring have been observed as a result of either maternal obesity or maternal distress during pregnancy. Thus, in Chapter 2 we propose a “funnel effect” model hypothesizing that prenatal stressors of different nature might trigger shared stress-responsive pathways affecting neuroendocrine system, immune-inflammatory processes and energy metabolism regulation, ultimately resulting in increased vulnerability to psychopathology. Chapter 3 and Chapter 4 (original studies) investigate the shared biological mechanisms underlying the above-mentioned stressors and their effects during specific time windows across neurodevelopment in two C57Bl6/N mouse models of maternal psychophysical stress (PNS) and maternal obesity (mHFD). We focused on oxidative stress as a central player driving fetal brain programming by adverse prenatal conditions. Also for this reason in our mouse models, we administered as preventive strategy the antioxidant N-acetyl-cysteine (NAC) to protect fetal neurodevelopment from stress-derived derangements. In particular, when we focused on the short-term effects, we found a widespread pro-inflammatory profile in fetal brains exposed either to PNS or mHFD - with females being more susceptible - to be associated to placental dysfunctions (Chapter 3). Moreover, investigation of the long-term effects of PNS and mHFD specifically during adolescence showed similar effects in the offspring, characterized by reduced brain anti-oxidant defenses and impairments in hippocampal Bdnf levels, overall leading to alterations in the emotional behavior and hypothalamic-pituitary-adrenal axis functionality, in a sex-dependent fashion. Maternal NAC administration, by restoring the redox balance, showed long-term protective effects on brain development (Chapter 4). Together, our findings contribute to support our original “funnel effect” model to explain the converging effects of different stressors on offspring brain development. Above all, a pivotal role of redox signalling was highlighted as the orchestrator of a synchronized response to early adversities by the neuroendocrine and the immune system, among others. In addition, we unveil clear sex-specific differences that drive the programming effects of prenatal stressors on neurodevelopment.