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;
- Identify biomarkers to predict the response to antidepressant treatments;
- Analyze the occurrence of heritable changes in NSC induced by GC and identify specific epigenetically regulated pathways;
- Explore the therapeutic potential of antioxidants.
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 precede the onset of depression-like behaviour which does not respond to fluoxetine, an antidepressant in the selective serotonin reuptake inhibitor (SSRI) class.
Response to circadian re-entrainment in 6 month-old mice. The heatmaps depict representative recordings of spontaneous activity from a control (CTRL) and a mouse exposed to dexamethasone (a synthetic gluococorticoid receptor agonist; DEX) – doubleplotted actograms in 15 min epochs. The onset of the dark phase was advanced by 6 h to force the re-entrainment of spontaneous activity to a shifted light-dark cycle. The dark and light phases in the beginning and at the end of the experiment are indicated by the black and white rectangles at the top and bottom of the figure, respectively. Note that the control mouse took a couple of days to adapt to the phase-advanced light-dark cycle, while the DEX-mouse adapted without delay. This suggests that the central clock, located in the suprachiasmatic nucleus (SCN), has lower resistance to change and is therefore more susceptible to perturbations in mice exposed to DEX in utero.
Depressive-like phenotype induced by prenatal dexamethasone in mice is reversed by desipramine.
Neuropharmacology 2017 Nov;126():242-249
Redox unbalance modifies neurogenic potential.
Oncotarget 2017 Jan;8(3):3762-3763
Glucocorticoids alter neuronal differentiation of human neuroepithelial-like cells by inducing long-lasting changes in the reactive oxygen species balance.
Neuropharmacology 2016 Aug;107():422-431
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
Mirko Conti - PhD student
Luã Tainã – PhD student
Kimio Watanabe – MD PhD guest researcher
Jeffrey Sall – MD PhD guest researcher