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

11573/1662071 - 2022 - Inflammatory Signatures of Maternal Obesity as Risk Factors for Neurodevelopmental Disorders: Role of Maternal Microbiota and Nutritional Intervention Strategies
Cirulli, Francesca; De Simone, Roberta; Musillo, Chiara; Ajmone-Cat, Maria Antonietta; Berry, Alessandra - 01g Articolo di rassegna (Review)
paper: NUTRIENTS (Basel, Switzerland: Molecular Diversity Preservation International (MDPI)) pp. 3150- - issn: 2072-6643 - wos: WOS:000839786200001 (2) - scopus: 2-s2.0-85136343038 (4)

11573/1627202 - 2022 - Prenatal psychological or metabolic stress increases the risk for psychiatric disorders: the “funnel effect” model
Musillo, C.; Berry, A.; Cirulli, F. - 01g Articolo di rassegna (Review)
paper: NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS (Elsevier Science Limited:Oxford Fulfillment Center, PO Box 800, Kidlington Oxford OX5 1DX United Kingdom:011 44 1865 843000, 011 44 1865 843699, EMAIL: asianfo@elsevier.com, tcb@elsevier.co.UK, INTERNET: http://www.elsevier.com, http://www.elsevier.com/locate/shpsa/, Fax: 011 44 1865 843010) pp. 104624- - issn: 0149-7634 - wos: WOS:000790381200001 (12) - scopus: 2-s2.0-85126872817 (12)

11573/1662070 - 2022 - Ion-Pairing Chromatography and Amine Derivatization Provide Complementary Approaches for the Targeted LC-MS Analysis of the Polar Metabolome.
Sagi-Kiss, V.; Li, Y.; Carey, M. R.; Grover, S. J.; Siems, K.; Cirulli, F.; Berry, A.; Musillo, C.; Wilson, I. D.; Want, E. J.; Bundy, J. G. - 01a Articolo in rivista
paper: JOURNAL OF PROTEOME RESEARCH (Washington, D.C. : American Chemical Society, c2002-) pp. 1428-1437 - issn: 1535-3907 - wos: WOS:000810591500006 (9) - scopus: 2-s2.0-85130932831 (10)

11573/1541319 - 2021 - High-fat diet during adulthood interacts with prenatal stress, affecting both brain inflammatory and neuroendocrine markers in male rats
Berry, A.; Mazzelli, M.; Musillo, C.; Riva, M. A.; Cattaneo, A.; Cirulli, F. - 01a Articolo in rivista
paper: EUROPEAN JOURNAL OF NEUROSCIENCE (Blackwell Science Limited:PO Box 88, Oxford OX2 0NE United Kingdom:011 44 1865 776868, 011 44 1865 206038, EMAIL: journals.cs@blacksci.co.uk, INTERNET: http://www.blackwell-science.com, Fax: 011 44 1865 721205) pp. - - issn: 0953-816X - wos: WOS:000632977300001 (8) - scopus: 2-s2.0-85103179322 (9)

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
Musillo, C.; Berry, A.; Collacchi, B.; Pieroni, E.; Lepre, M.; Creutzberg, K. C.; Begni, V.; Riva, M.; Cirulli, F. - 04d Abstract in atti di convegno
conference: 29th European Congress of Psychiatry (Virtuale)
book: Abstract book of the 29th European Congress of Psychiatry - ()

11573/1489029 - 2021 - Natural products improve healthspan in aged mice and rats: a systematic review and meta-analysis
Musillo, C.; Borgi, M.; Saul, N.; Moller, S.; Luyten, W.; Berry, A.; Cirulli, F. - 01g Articolo di rassegna (Review)
paper: NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS (Elsevier Science Limited:Oxford Fulfillment Center, PO Box 800, Kidlington Oxford OX5 1DX United Kingdom:011 44 1865 843000, 011 44 1865 843699, EMAIL: asianfo@elsevier.com, tcb@elsevier.co.UK, INTERNET: http://www.elsevier.com, http://www.elsevier.com/locate/shpsa/, Fax: 011 44 1865 843010) pp. 89-105 - issn: 0149-7634 - wos: WOS:000611799000001 (12) - scopus: 2-s2.0-85098211204 (13)

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
Musillo, C; Berry, A; Ajmone-Cat, Ma; De Simone, R; Creutzberg, Kc; Collacchi, B; Begni, V; Riva, Ma; Cirulli, F - 04h Atto di convegno in rivista scientifica o di classe A
paper: EUROPEAN NEUROPSYCHOPHARMACOLOGY (Elsevier BV:PO Box 211, 1000 AE Amsterdam Netherlands:011 31 20 4853757, 011 31 20 4853642, 011 31 20 4853641, EMAIL: nlinfo-f@elsevier.nl, INTERNET: http://www.elsevier.nl, Fax: 011 31 20 4853598) pp. S49-S50 - issn: 0924-977X - wos: WOS:000753359500065 (0) - scopus: (0)
conference: 34th ECNP Congress (Lisbona, Portogallo)

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
Musillo, Chiara; Berry, Alessandra; Antonietta Ajmone-Cat, Maria; De Simone, Roberta; Camile Creutzberg, Kerstin; Collacchi, Barbara; Begni, Veronica; Andrea Riva, Marco; Cirulli, Francesca - 04b Atto di convegno in volume
conference: 49th Meeting of the European Brain and Behaviour Society (Losanna, Svizzera)
book: Abstract book of the 49th Meeting of the European Brain and Behaviour Society - ()

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
Berry, A.; Marconi, M.; Musillo, C.; Chiarotti, F.; Bellisario, V.; Matarrese, P.; Gambardella, L.; Vona, R.; Lombardi, M.; Foglieni, C.; Cirulli, F. - 01a Articolo in rivista
paper: EXPERIMENTAL GERONTOLOGY (PERGAMON-ELSEVIER SCIENCE LTD, THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD, ENGLAND, OX5 1GB) pp. - - issn: 0531-5565 - wos: WOS:000501989000013 (16) - scopus: 2-s2.0-85074687629 (18)

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
Berry, Alessandra; Musillo, Chiara; Zarse, Kim; Bundy, Jacob G.; Sagi-Kiss, Virag; Siems, Karsten; Luyten, Walter; Ristow, Michael; Cirulli, Francesca - 04d Abstract in atti di convegno
conference: 12th Annual General Meeting Federation of European Neuroscience Societies - FENS 2020 (Glasgow, UK)
book: FENS abstract book 2020 - ()

11573/1387747 - 2020 - Maternal obesity as a risk factor for brain development and mental health in the offspring
Cirulli, F.; Musillo, C.; Berry, A. - 01g Articolo di rassegna (Review)
paper: NEUROSCIENCE (Oxford: Elsevier Ltd. Oxford; New York: Pergamon Press) pp. - - issn: 0306-4522 - wos: WOS:000579946800011 (46) - scopus: 2-s2.0-85079226106 (50)

11573/1493839 - 2020 - Prenatal N-acetyl-cysteine administration alleviates the long-term effects of maternal obesity of adolescent male and female mouse offspring
Musillo, C.; Berry, A.; Collacchi, B.; Lepre, M.; Creutzberg, K. C.; Begni, V.; Riva, M.; Cirulli., F. - 01h Abstract in rivista
paper: EUROPEAN NEUROPSYCHOPHARMACOLOGY (Elsevier BV:PO Box 211, 1000 AE Amsterdam Netherlands:011 31 20 4853757, 011 31 20 4853642, 011 31 20 4853641, EMAIL: nlinfo-f@elsevier.nl, INTERNET: http://www.elsevier.nl, Fax: 011 31 20 4853598) pp. - - issn: 0924-977X - wos: WOS:000593520800451 (0) - scopus: (0)

11573/1395320 - 2020 - Prenatal N-acetyl-cysteine administration moderates the long-term negative effects of maternal obesity in adolescent male and female mouse offspring
Musillo, C.; Berry, A.; Collacchi, B.; Lepre, M.; Creutzberg, K.; Begni, V.; Riva, M.; Cirulli, F. - 04d Abstract in atti di convegno
conference: 12th Annual General Meeting Federation of European Neuroscience Societies - FENS 2020 (Glasgow, UK)
book: FENS abstract book 2020 - ()

11573/1395299 - 2019 - Nutraceuticals counteract memory decline in murine models of aging
Berry, Alessandra; Musillo, Chiara; Saul, Nadine; Borgi, Marta; Möller, Steffen; Fuellen, Georg; Luyten, Walter; Cirulli, Francesca - 04d Abstract in atti di convegno
conference: 48th Meeting of European Brain and Behaviour Society – EBBS meeting (Prague, Czech Republic)
book: EBBS abstract book 2019 - ()

11573/1390281 - 2019 - Nutraceuticals have sex-dependent positive effects on healthy ageing in murine models
Musillo, Chiara; De Cristofaro, Gaia; Berry, Alessandra; Cirulli, Francesca - 04d Abstract in atti di convegno
conference: New perspectives in neuroscience: research results of young italian neuroscientists, National meeting of PhD students in neuroscience, SINS 2019 (Naples, Italy)
book: SINS National meeting of PhD students in neuroscience abstract book - ()

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
Musillo, Chiara; Poggini, Silvia; De Cristofaro, Gaia; Zarse, Kim; Ristow, Michael; Bundy, Jacob G.; Sagi-Kiss, Virag; Siems, Karsten; Luyten, Walter; Berry, Alessandra; Cirulli, Francesca - 04d Abstract in atti di convegno
conference: 48th Annual General Meeting of European Brain and Behaviour Society - EBBS 2019 (Prague, Czech Republic)
book: EBBS abstract book 2019 - ()

11573/1395289 - 2019 - The-healthy-Worm Database
Saul, Nadine; Möller, Steffen; Berry, Alessandra; Cirulli, Francesca; Musillo, Chiara; Schmitz-Linneweber, Christian; Luyten, Walter; Fuellen, Georg - 04d Abstract in atti di convegno
conference: The Undoing Aging Conference (Berlin, Germany)
book: The Undoing Aging Conference Abstract book 2019 - ()

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
Berry, Alessandra; Panetta, Pamela; Raggi, Carla; Musillo, Chiara; De Cristofaro, Gaia; Magnifico, Maria Chiara; Arese, Marzia; Cirulli, Francesca - 04d Abstract in atti di convegno
conference: 11th Annual General Meeting Federation of European Neuroscience Societies - FENS 2018 (Berlin, Germany)
book: FENS abstract book 2018 - ()

11573/1389801 - 2018 - Improving our understanding of sex-dependent mechanisms regulating healthspan through novel methodological approaches
Berry, Alessandra; Raggi, Carla; Musillo, Chiara; De Cristofaro, Gaia; Branchi, Igor; Poggini, Silvia; Viglione, Aurelia; Cirulli, Francesca - 04d Abstract in atti di convegno
conference: 11th Annual General Meeting Federation of European Neuroscience Societies - FENS 2018 (Berlin, Germany)
book: FENS abstract book - ()

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