title: 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.
authors.affiliation: Center for Neuropsychiatric Disorders, Institute of Life Science, Nanchang University, Nanchang 330031, P.R. China.
authors.forename: Youjun
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Center for Neuropsychiatric Disorders, Institute of Life Science, Nanchang University, Nanchang 330031, P.R. China.
authors.forename: Zongyue
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Center for Neuropsychiatric Disorders, Institute of Life Science, Nanchang University, Nanchang 330031, P.R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Tang
authors.affiliation: Center for Neuropsychiatric Disorders, Institute of Life Science, Nanchang University, Nanchang 330031, P.R. China.
authors.forename: Huifeng
authors.initials: H
authors.lastname: Jiao
authors.affiliation: Center for Neuropsychiatric Disorders, Institute of Life Science, Nanchang University, Nanchang 330031, P.R. China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Sun
authors.affiliation: Center for Neuropsychiatric Disorders, Institute of Life Science, Nanchang University, Nanchang 330031, P.R. China.
authors.forename: Qiuzhu
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Center for Neuropsychiatric Disorders, Institute of Life Science, Nanchang University, Nanchang 330031, P.R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Luo
authors.affiliation: Center for Neuropsychiatric Disorders, Institute of Life Science, Nanchang University, Nanchang 330031, P.R. China.
authors.forename: Haili
authors.initials: H
authors.lastname: Pan
authors.affiliation: Center for Neuropsychiatric Disorders, Institute of Life Science, Nanchang University, Nanchang 330031, P.R. China.
authors.forename: Chaolin
authors.initials: C
authors.lastname: Ma
authors.affiliation: Center for Neuropsychiatric Disorders, Institute of Life Science, Nanchang University, Nanchang 330031, P.R. China.
authors.forename: Baoming
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000209:etiology; D003072:Cognition Disorders / Q000209:etiology* / Q000473:pathology; D003711:Demyelinating Diseases / Q000209:etiology / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008426:Maternal Deprivation; D018782:Maze Learning / Q000187:drug effects; D004676:Myelin Basic Protein / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000494:pharmacology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D008070:Lipopolysaccharides; D004676:Myelin Basic Protein; D051153:Wnt Proteins; C544261:XAV939; D014635:Valproic Acid; D006655:Histone Deacetylases
keywords: early-life stress; histone deacetylases 1/2; learning; memory; oligodendrocyte