High Fat Diet Multigenerationally Affects Hippocampal Neural Stem Cell Proliferation via Epigenetic Mechanisms

Early-life metabolic stress has been demonstrated to affect brain development, persistently\r\ninfluence brain plasticity and to exert multigenerational effects on cognitive functions. However,\r\nthe impact of an ancestor’s diet on the adult neurogenesis of their descendants has not yet been\r\ninvestigated. Here, we studied the effects of maternal high fat diet (HFD) on hippocampal adult\r\nneurogenesis and the proliferation of neural stem and progenitor cells (NSPCs) derived from the\r\nhippocampus of both the second and the third generations of progeny (F2HFD and F3HFD). Maternal\r\nHFD caused a multigenerational depletion of neurogenic niche in F2HFD and F3HFD mice. Moreover,\r\nNSPCs derived from HFD descendants showed altered expression of genes regulating stem cell\r\nproliferation and neurodifferentiation (i.e., Hes1, NeuroD1, Bdnf). Finally, ancestor HFD-related\r\nhyper-activation of both STAT3 and STAT5 induced enhancement of their binding on the regulatory\r\nsequences of Gfap gene and an epigenetic switch from permissive to repressive chromatin on the\r\npromoter of the NeuroD1 gene. Collectively, our data indicate that maternal HFD multigenerationally\r\naffects hippocampal adult neurogenesis via an epigenetic derangement of pro-neurogenic gene\r\nexpression in NSPCs