Adult neurogenesis ensure continuous generation of new functional neurons throughout life, contributing on specific brain functions, such as learning and memory. There are mainly two discrete regions where this process occurs: the sub-granular zone (SGZ) within the dentate gyrus of the hippocampus and the subventricolar zone (SVZ) lining the lateral ventricles. The neural stem cells (NSCs) residing in these neurogenic niches are in a quiescence state and responsive to several environmental cues, including nutrient availability and physical stimuli, such as electromagnetic fields. In our studies we investigated the effect induced by
in vivo exposure to extremely low-frequency electromagnetic fields (ELFEFs, 1mT 50Hz) on both hippocampal and SVZ neurogenic niches. Data we reported clearly demonstrated the positive effects of ELFEFs on both adult NSC sources, suggesting ELFEFs as promising tools to enhance NSC self-renewal, neuronal differentiation and survival (Cuccurazzu et al., 2010, Podda et. al., 2014 Leone et al., 2014, 2015). In particular, we showed that mice exposed to ELFEFs enhanced hippocampal neurogenesis and synaptic plasticity leading to improved spatial learning and memory. The ELFEF-promoted enhancement of NSC proliferation and neuronal cell-fate specification was associated with increased histone H3 acetylation at lysine 9 (H3K9) and binding of both activated cAMP response element-binding protein (pCREB) and the transcriptional co-regulator CREB-binding protein (CBP) at the promoter of specific neurogenic genes. These data suggest that the transcription factor CREB plays an important role in regulating gene expression during NSC neuronal differentiation via the control of histone acetylation. The recruitment of CBP on the regulatory sequences of neurogenic genes was enhanced by ELFEF stimulation, whereas binding of several transcription repressors including the histone deacetylase SIRT1 was not significantly modulated by ELFEFs.
In line with these findings, our recent data obtained on adult hippocampal NSCs throughout glucose availability experiment suggest a crucial role for CREB recruitment at promoter of the stemness gene Hes-1. In particular, the molecular network whereby CREB and histone deacetylase SIRT1 regulate in opposite direction the stemness determinant Hes1, is by alternating with each other and its promoter in response to glucose availability (Fusco, Leone et al., 2016).
Both stimuli, ELFEFs exposure and low glucose availability, increased the proliferation of NSCs through a signaling cascade mediated by CREB activation, its binding at promoter of the neurogenic genes and the recruitment of CBP in these loci, finally inducing an increase in histone acetylation and consequent neurogenic gene activation. The balance between histone acetylation and deacetylation would regulate the expression of genes controlling the switch between NSC self-renewal and differentiation.
Collectively, our data add a piece to intricate puzzle of epigenetic mechanism and molecular pathway involved in adult neurogenesis regulation and lay the foundation for future therapeutic approaches aimed to counteract the diminished hippocampal neurogenesis and cognitive impairment occurring during normal aging and in several neurodegenerative diseases.
