CHIARA MUSILLO

PhD Graduate

PhD program:: XXXV



Thesis title: 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.

Research products

  • 11573/1395320 - 2020 - Prenatal N-acetyl-cysteine administration moderates the long-term negative effects of maternal obesity in adolescent male and female mouse offspring (04d Abstract in atti di convegno)
    MUSILLO, CHIARA
  • 11573/1395299 - 2019 - Nutraceuticals counteract memory decline in murine models of aging (04d Abstract in atti di convegno)
    MUSILLO, CHIARA
  • 11573/1389801 - 2018 - Improving our understanding of sex-dependent mechanisms regulating healthspan through novel methodological approaches (04d Abstract in atti di convegno)
    MUSILLO, CHIARA; POGGINI, SILVIA
  • 11573/1387765 - 2020 - Trehalose administration in C57BL/6N old mice affects healthspan improving motor learning and brain anti-oxidant defences in a sex-dependent fashion: a pilot study (01a Articolo in rivista)
    MUSILLO, CHIARA
  • 11573/1387747 - 2020 - Maternal obesity as a risk factor for brain development and mental health in the offspring (01g Articolo di rassegna (Review))
    MUSILLO, CHIARA
  • 11573/1390288 - 2019 - Western diet combined with rosmarinic acid in old mice exerts negative effects on metabolism but improves cognitive and emotional behaviour in a sex-dependent fashion (04d Abstract in atti di convegno)
    MUSILLO, CHIARA; POGGINI, SILVIA
  • 11573/1390273 - 2018 - Antioxidant N-acetyl-cysteine administration in pregnant mice has long-term positive effects on metabolic and behavioural endpoints of male and female offspring prenatally exposed to a high-fat-diet (04d Abstract in atti di convegno)
    MUSILLO, CHIARA; MAGNIFICO, MARIA CHIARA; ARESE, MARZIA
  • 11573/1390281 - 2019 - Nutraceuticals have sex-dependent positive effects on healthy ageing in murine models (04d Abstract in atti di convegno)
    MUSILLO, CHIARA
  • 11573/1395289 - 2019 - The-healthy-Worm Database (04d Abstract in atti di convegno)
    MUSILLO, CHIARA
  • 11573/1395323 - 2020 - Rosmarinic acid administration improves cognitive and emotional behaviour and brain anti-oxidant defences in a sex-dependent manner in C57BL/6N aged mice fed a Western diet (04d Abstract in atti di convegno)
    MUSILLO, CHIARA
  • 11573/1493840 - 2021 - N-acetyl-cysteine administration during foetal life improves social behaviour and restores hippocampal BDNF levels in adolescent mice prenatally exposed to a high-fat diet (04d Abstract in atti di convegno)
    MUSILLO, CHIARA
  • 11573/1493839 - 2020 - Prenatal N-acetyl-cysteine administration alleviates the long-term effects of maternal obesity of adolescent male and female mouse offspring (01h Abstract in rivista)
    MUSILLO, CHIARA
  • 11573/1489029 - 2021 - Natural products improve healthspan in aged mice and rats: a systematic review and meta-analysis (01g Articolo di rassegna (Review))
    MUSILLO, CHIARA
  • 11573/1541319 - 2021 - High-fat diet during adulthood interacts with prenatal stress, affecting both brain inflammatory and neuroendocrine markers in male rats (01a Articolo in rivista)
    MUSILLO, CHIARA
  • 11573/1619930 - 2021 - Prenatal N-acetyl-cysteine administration prevents social anxiety and modulates brain immune- and plasticity-related genes in adolescent offspring born from high-fat diet C57Bl6/N mouse dams (04b Atto di convegno in volume)
    MUSILLO, CHIARA
  • 11573/1627202 - 2022 - Prenatal psychological or metabolic stress increases the risk for psychiatric disorders: the “funnel effect” model (01g Articolo di rassegna (Review))
    MUSILLO, CHIARA
  • 11573/1662071 - 2022 - Inflammatory Signatures of Maternal Obesity as Risk Factors for Neurodevelopmental Disorders: Role of Maternal Microbiota and Nutritional Intervention Strategies (01g Articolo di rassegna (Review))
    MUSILLO, CHIARA
  • 11573/1662070 - 2022 - Ion-Pairing Chromatography and Amine Derivatization Provide Complementary Approaches for the Targeted LC-MS Analysis of the Polar Metabolome. (01a Articolo in rivista)
    MUSILLO, CHIARA
  • 11573/1672904 - 2023 - Shared mechanisms underlying the impact of maternal psychophysical stress and obesity on offspring neurodevelopment (07a Tesi di Dottorato)
    MUSILLO, CHIARA
  • 11573/1619922 - 2021 - Prenatal N-acetyl-cysteine prevents social anxiety and modulates hippocampal inflammatory-and plasticity-related genes in adolescent mice prenatally exposed to a high-fat diet (04h Atto di convegno in rivista scientifica o di classe A)
    MUSILLO, CHIARA

© Università degli Studi di Roma "La Sapienza" - Piazzale Aldo Moro 5, 00185 Roma