Ceccatelli Laboratory

We study the impact of neurotoxic insults on the developing brain with special focus on long-term neurodevelopmental and behavioral outcomes.

Research focus

Accumulating evidence indicates that insults occurring during the development of the nervous system alter neurogenesis leading to long-term detrimental outcomes that may well culminate in neuropsychiatric pathologies. 

We have been studying the developmental alterations caused by excess glucocorticoids (GC) or chemical contaminants, such as heavy metals or endocrine disruptors, at levels relevant to human exposure. We use in vitro models (rodent and human neural progenitor cells) as well as in vivo models (rodents and zebrafish) to identify and dissect the molecular mechanisms behind long-lasting alterations in spontaneous explorative and affective behavior.

Illustration of the central clock
The central clock, located in the hypothalamic suprachiasmatic nucleus (SCN) entrains the peripheral molecular clocks to maintain the synchronization with the light-dark cycle. The circuitry involves arginine vasopressin (AVP) output from the SCN and glucocorticoid receptor (GR) signaling in the hippocampus. (A) In utero exposure to DEX down-regulates AVP in the SCN and GR in the hippocampus. (B) Weaker coupling between central and peripheral oscillators is illustrated by desynchronized oscillations in the expression of the clock gene Bmal1 in the hippocampus vs. SCN. Treatment with the noradrenaline reuptake inhibitor desipramine (DMI) could restore the alterations. Blue DEX; orange DEX+ DMI. (C-D) Hypothalamic neurons, derived from human iPSCs, cultured in 2D and 3D. (C) Expression of oxytocin (red) in differentiating hypothalamic neuronal precursors (Tuj1; in 2D culture Red= oxytocin (Oxt); Green= Tuj1; Blue= nuclei. (D) Red=VIP; Green= MAP2; Blue= nuclei.

By taking the in vitro approach, we have shown that high levels of GC affect the methylation state of genes regulating proliferation, differentiation, and migration as well as cellular senescence, mitochondrial function and redox state. This points to epigenetic modifications being part of the neurotoxic mechanism. In vivo we observed alterations in hippocampal neurogenesis in male mice exposed to GC in utero, which develop depression-like behavior in adulthood. The onset of depression is preceded by long-lasting alterations in circadian patterns of activity and weaker coupling between the central clock (located in the hypothalamic suprachiasmatic nucleus) and peripheral oscillators. Preliminary clinical investigations show abnormal circadian activity patterns in depressed patients as well.
 
The hypothalamus is among the brain regions shown to be involved in neuropsychiatric disorders, including depression. Based on this background, we are presently working on the hypothesis that alterations in hypothalamic development triggered by prenatal insults may contribute to the onset of neuropsychiatric conditions.

Group members

Selected publications

Desipramine restores the alterations in circadian entrainment induced by prenatal exposure to glucocorticoids.
Spulber S, Conti M, Elberling F, Raciti M, Borroto-Escuela DO, Fuxe K, Ceccatelli S
Transl Psychiatry 2019 10;9(1):263

NRXN1 Deletion and Exposure to Methylmercury Increase Astrocyte Differentiation by Different Notch-Dependent Transcriptional Mechanisms.
Raciti M, Salma J, Spulber S, Gaudenzi G, Khalajzeyqami Z, Conti M, Anderlid BM, Falk A, Hermanson O, Ceccatelli S
Front Genet 2019 ;10():593

Methylmercury interferes with glucocorticoid receptor: Potential role in the mediation of developmental neurotoxicity.
Spulber S, Raciti M, Dulko-Smith B, Lupu D, Rüegg J, Nam K, Ceccatelli S
Toxicol Appl Pharmacol 2018 09;354():94-100

Glucocorticoids alter neuronal differentiation of human neuroepithelial-like cells by inducing long-lasting changes in the reactive oxygen species balance.
Raciti M, Ong J, Weis L, Edoff K, Battagli C, Falk A, et al
Neuropharmacology 2016 08;107():422-431

Alterations in circadian entrainment precede the onset of depression-like behavior that does not respond to fluoxetine.
Spulber S, Conti M, DuPont C, Raciti M, Bose R, Onishchenko N, et al
Transl Psychiatry 2015 Jul;5():e603

Tet3 mediates stable glucocorticoid-induced alterations in DNA methylation and Dnmt3a/Dkk1 expression in neural progenitors.
Bose R, Spulber S, Kilian P, Heldring N, Lönnerberg P, Johnsson A, et al
Cell Death Dis 2015 Jun;6():e1793

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