Epidemiological and experimental studies have shown that alterations in the intrauterine programming during critical periods of nervous system development can have adverse consequences that increase the propensity for pathological conditions in adults. Our research aims at identifying mechanisms of prenatal damage that trigger the appearance of irreversible alterations and behavioral impairment later in life. We use in vivo (rodents and zebrafish) as well as in vitro (rodent and human neural stem cells - NSC) models, and methods ranging from behavioral to single-cell analysis. Currently our studies focus on the developmental alterations caused by excess glucocorticoids (GC) or oxidative stress-inducers. We aim to:
- Clarify the mechanisms behind the long-term alterations in affective behavior, i.e. depression, induced by developmental exposure to high levels of GC;
- Investigate specific circadian rhythms alterations that precede the onset of depression;
- Analyze the occurrence of heritable changes in NSC induced by GC and identify specific epigenetically regulated pathways;
- Explore the therapeutic potential of antioxidants;
- Identify biomarkers to predict the response to antidepressant treatments.
We believe that understanding the mechanisms behind long-lasting detrimental consequences of adverse prenatal milieu on the nervous system is critical for the development of novel diagnostic and therapeutic strategies. By following this way of thinking, we have recently shown that progressive alterations in circadian entrainment of spontaneous activity (i.e. the synchronization of self-sustained oscillations in spontaneous activity in relation to an external pacemaker) and blunted circadian oscillations in clock gene expression in skin fibroblasts precede the onset of depression-like behaviour which does not respond to the selective serotonin reuptake inhibitor (SSRI).
Mitochondrial alterations in hippocampal cells.
A–B After exposure to methylmercury (MeHg) cytochrome c (green fluorescence) is released from the mitochondria into the cytosol (arrow in B).
C–D Loss of mitochondrial potential induced by MeHg, as measured by TMRE assay
Glucocorticoids alter neuronal differentiation of human neuroepithelial-like cells by inducing long-lasting changes in the reactive oxygen species balance.
Neuropharmacology 2016 Aug;107():422-31
Alterations in circadian entrainment precede the onset of depression-like behavior that does not respond to fluoxetine.
Transl Psychiatry 2015 Jul;5():e603
Tet3 mediates stable glucocorticoid-induced alterations in DNA methylation and Dnmt3a/Dkk1 expression in neural progenitors.
Cell Death Dis 2015 Jun;6():e1793
Glucocorticoids induce long-lasting effects in neural stem cells resulting in senescence-related alterations.
Cell Death Dis 2010 Nov;1():e92
Long-lasting depression-like behavior and epigenetic changes of BDNF gene expression induced by perinatal exposure to methylmercury.
J. Neurochem. 2008 Aug;106(3):1378-87
Sandra Ceccatelli - Professor, group leader
Stefan Spulber - MD PhD, Senior Lab Manager
Marilena Raciti - PhD, postdoctoral fellow
Dirleise Colles - PhD student
Mirko Conti - PhD student
Maria Cristina Battagli -PhD student
Elena Paci - PhD student
Emilia Koskinen - master student