EDOARDO PISA

PhD Graduate

PhD program:: XXXIV



Thesis title: Reduced availability of sialylated sugars of the human milk during lactation impairs cognitive function in adult mice

Human milk is the ideal food for the newborn. Its composition results from an evolutionary biological process and represents an essential source of nutrients for the baby. Breastfeeding is associated with multiple benefits for both the infant and the mother herself. These findings result from studies comparing phenotypes of breastfed (BF) and formula-fed (FF) infants. Additionally, maternal milk’s components have been shown to persistently adjust the development of cognitive functions. In particular, experimental evidence indicates that breastfed infants show significantly higher intelligence scores compared to FF children. Among the various components of human milk, sialic acid (Sia) has been proposed to exert a pivotal role in mediating the beneficial effects of breastfeeding on the offspring. Sia is a structural molecule of gangliosides and polySia-NCAM, both highly represented in the central nervous system. and involved in mechanisms such as neurogenesis, synaptogenesis as well as the formation of neural circuits. The role exerted by Sia on brain structure in early postnatal stages has been proposed to contribute to the neurological and intellectual advantages conferred by BF over FF. Specifically, human milk represents an essential source of Sia (in the form of sialylated oligosaccharides) whereby the enzyme responsible for the endogenous synthesis of Sia has very low activity in the newborn. Human milk oligosaccharides (HMOs) represent 8% of the sugar’s milk and have a wide range of beneficial effects on the physiology of the infant. Importantly, while HMOs are abundant in human milk, they are scarce in infant formula; finally, preclinical studies indicate that their supplementation may beget substantial cognitive benefits. During my Ph.D., I have investigated the role exerted by sialyl(alpha2,3)lactose (3’SL) and sialyl(alpha2,6)lactose (6’SL) on the development of cognitive capabilities. The selection of 3’SL and 6’SL rests upon the functional role of these sialylated oligosaccharides during development (brain structure patterning, gut microbiota, immunity) and the evidence that, while 3’SL and 6’SL are abundant in maternal milk, they are not provided in infant formula. Based on these considerations, I have tested the hypothesis that a selective absence of 6’SL alone (Chapter 1), 3’SL alone (Chapter 2), and the combination of 6’SL and 3’SL together (Chapter 3) may persistently impair cognitive capabilities (i.e. memory and attention). Then, I evaluated if an exogenous administration of these sugars may ameliorate the affected phenotype (Chapter 3). To do that, I modulate their concentrations leveraging a mouse model characterized by the absence of genes that synthesize 3’SL and 6’SL (B6.129-St3gal4tm1.1Jxm and St6gal1tm2Jxm-J, knock-out mice, hereafter KO), producing milk lacking 3’SL and/or 6’SL. Then, to expose wild-type (WT) pups to 3’SL and/or 6’SL-poor milk, I adopted a cross-fostering protocol in which WT mice were reared to KO dams. In chapter 1, WT offspring deprived of 6’SL during lactation exhibited consistent alterations in all cognitive functions addressed, hippocampal electrophysiology, and in pathways regulating the serotonergic system (identified through gut microbiota and plasma metabolomics). The impairments observed seem to be associated with a time- (i.e. eye-opening) and region-specific (i.e. pre-frontal cortex) alteration in the expression of genes involved in neurogenesis. In Chapter 2, neonatal access to 3’SL-poor milk resulted in decreased attention, spatial and working memory, and altered LTP compared to the control group Finally, in Chapter 3, I observed similar impairments in cognitive functions compared to the previous studies in mice exposed to reduce neonatal availability of both 3’SL and 6’SL. Regarding the effect of an exogenous administration of 3’SL and 6’SL, the supplementation procedure had reduced the odds to observe the cognitive read-out of the experimental subjects. These results support the hypothesis that early-life dietary sialylated HMOs exert a long-lasting role in the development of cognitive functions.

Research products

11573/1671216 - 2023 - Long-term consequences of reduced availability and compensatory supplementation of sialylated HMOs on cognitive capabilities
Pisa, Edoardo; Traversa, Alice; Caputo, Viviana; Ottomana, Angela Maria; Hauser, Jonas; Macrì, Simone - 01a Articolo in rivista
paper: FRONTIERS IN CELLULAR NEUROSCIENCE (Lausanne (PO Box 110, 1015) : Frontiers Research Foundation, 2007-) pp. - - issn: 1662-5102 - wos: WOS:000931132100001 (2) - scopus: 2-s2.0-85147921445 (2)

11573/1510900 - 2021 - Sialylated human milk oligosaccharides program cognitive development through a non-genomic transmission mode
Hauser, Jonas; Pisa, Edoardo; Arias Vásquez, Alejandro; Tomasi, Flavio; Traversa, Alice; Chiodi, Valentina; Martin, Francois-Pierre; Sprenger, Norbert; Lukjancenko, Oksana; Zollinger, Alix; Metairon, Sylviane; Schneider, Nora; Steiner, Pascal; Martire, Alberto; Caputo, Viviana; Macrì, Simone - 01a Articolo in rivista
paper: MOLECULAR PSYCHIATRY (Nature Publishing Group:Brunel Road Houndmills, Basingstoke RG21 6XS United Kingdom:011 44 20 78334000, EMAIL: institutions@natureny.com, INTERNET: http://www.nature.com, Fax: 011 44 20 78434640) pp. - - issn: 1359-4184 - wos: WOS:000625343900001 (49) - scopus: 2-s2.0-85106348707 (59)

11573/1622186 - 2021 - Exposure to 3′sialyllactose‐poor milk during lactation impairs cognitive capabilities in adulthood
Pisa, E.; Martire, A.; Chiodi, V.; Traversa, A.; Caputo, V.; Hauser, J.; Macri, S. - 01a Articolo in rivista
paper: NUTRIENTS (Basel, Switzerland: Molecular Diversity Preservation International (MDPI)) pp. - - issn: 2072-6643 - wos: WOS:000737083300001 (18) - scopus: 2-s2.0-85119596077 (18)

11573/1413018 - 2020 - Genomic and physiological resilience in extreme environments are associated with a secure attachment style
Caputo, Viviana; Pacilli, Maria Giuseppina; Arisi, Ivan; Mazza, Tommaso; Brandi, Rossella; Traversa, Alice; Casasanta, Giampietro; Pisa, Edoardo; Sonnessa, Michele; Healey, Beth; Moggio, Lorenzo; D’Onofrio, Mara; Alleva, Enrico; Macrì, Simone - 01a Articolo in rivista
paper: TRANSLATIONAL PSYCHIATRY (New York, NY : Nature Pub. Group-Springer Nature) pp. 11- - issn: 2158-3188 - wos: WOS:000542690400004 (6) - scopus: 2-s2.0-85086175054 (9)

11573/1410285 - 2020 - Absence of 6’Sialyllactose during lactation impairs cognitive capabilities and modulates gene expression
Pisa, Edoardo; Traversa, Alice; Caputo, Viviana; Martire, Alberto; Chiodi, Valentina; Hauser, Jonas; Macrì, Simone - 04f Poster
conference: Federation of European Neuroscience Societies 2020 virtual forum (Virtual Forum)
book: FENS 2020 virtual forum abstract book - ()

11573/1348673 - 2019 - Availability of 6’SL in pre-weaning milk influences caecal microbiota and plasma molecular phenotype in pre-weaning offspring
Hauser, Jonas; Pisa, Edoardo; Tomasi, Flavio; Macrì, Simone - 01h Abstract in rivista
paper: JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION (Lippincott, Williams & Wilkins:530 Walnut Street:Philadelphia, PA 19106:(800)638-3030, (301)223-2300, EMAIL: orders@lww.com, INTERNET: http://www.lww.com, Fax: (301)223-2320, (301)223-2320) pp. - - issn: 0277-2116 - wos: (0) - scopus: (0)

11573/1410244 - 2019 - Book review of: la mente in fiamme, un nuovo approccio alla depressione di Edward Bullmore
Napolitani Cheyne, Federica; Pisa, Edoardo; Macrì, Simone - 01d Recensione
paper: ANNALI DELL'ISTITUTO SUPERIORE DI SANITÀ (Latest publisher: Roma: Istituto Superiore di Sanità Roma: Istituto poligrafico dello stato) pp. - - issn: 0021-2571 - wos: (0) - scopus: (0)

11573/1348597 - 2019 - Modulation of 3’SL level in pre-weaning milk impact attention, learning and memory in the adult offspring
Pisa, Edoardo; Tomasi, Flavio; Macrì, Simone; Hauser, Jonas - 01h Abstract in rivista
paper: JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION (Lippincott, Williams & Wilkins:530 Walnut Street:Philadelphia, PA 19106:(800)638-3030, (301)223-2300, EMAIL: orders@lww.com, INTERNET: http://www.lww.com, Fax: (301)223-2320, (301)223-2320) pp. - - issn: 0277-2116 - wos: (0) - scopus: (0)

11573/1349168 - 2019 - Reduced availability of a selective human milk oligosaccharide during lactation impairs post-weaning executive functions
Pisa, Edoardo; Tomasi, Flavio; Traversa, Alice; Caputo, Viviana; Hauser, Jonas; Macrì, Simone - 04f Poster
conference: SINS national meeting of PhD students in neuroscience 2019 (“Federico II” University of Naples, Italy)
book: SINS abstract book - ()

11573/1349181 - 2019 - Increased availability of the human milk oligosaccharide sialyl(alpha2,3)lactose during lactation promotes the development of executive functions
Pisa, Edoardo; Tomasi, Flavio; Traversa, Alice; Caputo, Viviana; Macrì, Simone; Hauser, Jonas - 04d Abstract in atti di convegno
conference: 48th meeting of the european brain and behaviour society (Prague; Czech Republic)
book: 48th meeting of EBBS abstract book - ()

11573/1348682 - 2019 - Presence of 6’SL in pre-weaning milk or mutation of ST6gal1 gene modulated microbiota composition and improved cognitive functions in adult offspring
Tomasi, Flavio; Battistoni, Mariangela; Pisa, Edoardo; Hauser, Jonas; Macrì, Simone - 01h Abstract in rivista
paper: JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION (Lippincott, Williams & Wilkins:530 Walnut Street:Philadelphia, PA 19106:(800)638-3030, (301)223-2300, EMAIL: orders@lww.com, INTERNET: http://www.lww.com, Fax: (301)223-2320, (301)223-2320) pp. - - issn: 0277-2116 - wos: (0) - scopus: (0)

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