Neonatal Maternal Separation Impairs Prefrontal Cortical Myelination and Cognitive Functions in Rats Through Activation of Wnt Signaling

Abstract

Adverse early-life experience such as depriving the relationship between parents and children induces permanent phenotypic changes, and impairs the cognitive functions associated with the prefrontal cortex (PFC). However, the underlying mechanism remains unclear. In this work, we used rat neonatal maternal separation (NMS) model to illuminate whether and how NMS in early life affects cognitive functions, and what the underlying cellular and molecular mechanism is. We showed that rat pups separated from their dam 3 h daily during the first 3 postnatal weeks alters medial prefrontal cortex (mPFC) myelination and impairs mPFC-dependent behaviors. Myelination appears necessary for mPFC-dependent behaviors, as blockade of oligodendrocytes (OLs) differentiation or lysolecithin-induced demyelination, impairs mPFC functions. We further demonstrate that histone deacetylases 1/2 (HDAC1/2) are drastically reduced in NMS rats. Inhibition of HDAC1/2 promotes Wnt activation, which negatively regulates OLs development. Conversely, selective inhibition of Wnt signaling by XAV939 partly rescue myelination arrestment and behavior deficiency caused by NMS. These findings indicate that NMS impairs mPFC cognitive functions, at least in part, through modulation of oligodendrogenesis and myelination. Understanding the mechanism of NMS on mPFC-dependent behaviors is critical for developing pharmacological and psychological interventions for child neglect and abuse.

Early life stress impairs postnatal oligodendrogenesis and adult emotional behaviour through activity-dependent mechanisms

“…Early life stress in humans has been linked with hypo-myelination in the adult prefrontal cortex (5)(6)(7)(8) , a phenotype also reported in rodent models of ELS (9)(10)(11)(12)20). Present findings provide a possible developmental mechanism for this, by showing that a precocious differentiation of the oligodendrocytic lineage during development could be at the origin of the permanent reduction in the adult OPC pool.…”

“…To determine possible causes of the increase in myelin-related transcripts, we investigated oligodendrogenesis in the MS animals. The postnatal period corresponds to an intense proliferation of oligodendrocyte progenitor cells (OPCs) and P15 marks the initiation of differentiation into myelinating oligodendrocytes in the mPFC (20,29). We performed triple immunostaining of Olig2, PDGFRα, and CC1 to distinguish OPCs (Olig2 + PDGFRα + , Figure 2A) from differentiated oligodendrocytes (OLs, Olig2 + CC1 + ) (30).…”

“…Strikingly, these behavioural and structural defects closely reproduce the phenotypes of humans exposed to childhood trauma (10,16). Several of these alterations are already apparent at juvenile or adolescent stages (14,(17)(18)(19)(20) but the causal mechanisms remain poorly understood.…”

Epigenetic regulation of myelination in health and disease

“…It has been known that neonatal maternal separation (NMS) will impair cognitive functions related to medial prefrontal cortex, in which OL development was inhibited. Yang revealled that in NMS rat, the expression of HDAC1/2 was drastically reduced, followed by activation of Wnt signals, which might be one of the reasons for OLs development inhibition (Yang et al., ). In consistent, Zheng found enriched environment, such as learning a new language or complex motor tasks, can promote the expression of HDAC1/2 and inhibit Wnt signals, which initiates “rewiring” of the neural network and accelerate remyelination in demyelination related disease, such as schizophrenia, amyotrophic lateral sclerosis, and bipolar disorder (Zheng, Ding, Li, & Yang, ).…”

“…HDAC1 and HDAC2 can also promote oligodendrocyte differentiation by inhibiting Wnt activation. They disrupt the interaction between ABC (active beta-catenin, a downstream effector of the Wnt pathway) with TCF4 (transcription factor 7-like 2) and switch the role of TCF4 from an activator to a repressor for Id gene expression in OPCs (Billin, Thirlwell, & Ayer, 2000;Yang et al, 2017;Ye et al, 2009). When HDAC1/2 are absent, ID2 (inhibitor of DNA binding 2) and ID4 (inhibitor of DNA binding 4) are upregulated (Conway, O'Bara, Vedia, Pol, & Sim, 2012;Swiss et al, 2011), while markers of mature oligodendrocyte, MBP and CNPase (2′, 3′-cyclic-nucleotide 3′-phosphodiesterase) are reduced.…”