Resistance of Postnatal Hippocampal Neurogenesis to Alcohol Toxicity in a Third Trimester‐Equivalent Mouse Model of Gestational Alcohol Exposure

Gustus, Kymberly; Lozano, Evelyn; Newville, Jessie; Li, Lü; Valenzuela, C. Fernando; Cunningham, Lee Anna

doi:10.1111/acer.14207

Cited by 3 publications

(1 citation statement)

References 85 publications

(114 reference statements)

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“…For these studies, we utilized nestin‐CreER T2 :tdTomato reporter mice, maintained on a C57Bl/J6 background, to be consistent with our prior study (Newville et al, 2017). In this strain, reporter gene expression can be selectively induced in nestin+ progenitors by tamoxifen administration, as previously described and characterized in detail (Chow et al, 2015; Gustus et al, 2019, 2020; Lagace et al, 2007; Madisen et al, 2010; Newville et al, 2017; Patzlaff et al, 2017). However, since fate mapping of progenitors was not required for this study, tamoxifen was not administered at any time.…”

Section: Methodsmentioning

confidence: 99%

Persistent myelin abnormalities in a third trimester‐equivalent mouse model of fetal alcohol spectrum disorder

Newville

Howard

Chavez

et al. 2021

Alcoholism Clin & Exp Res

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Background Abnormal diffusion within white matter (WM) tracts has been linked to cognitive impairment in children with fetal alcohol spectrum disorder. Whether changes to myelin organization and structure underlie the observed abnormal diffusion patterns remains unknown. Using a third trimester‐equivalent mouse model of alcohol exposure, we previously demonstrated acute loss of oligodendrocyte lineage cells with persistent loss of myelin basic protein and lower fractional anisotropy (FA) in the corpus callosum (CC). Here, we tested whether these WM deficits are accompanied by changes in: (i) axial diffusion (AD) and radial diffusion (RD), (ii) myelin ultrastructure, or (iii) structural components of the node of Ranvier. Methods Mouse pups were exposed to alcohol or air vapor for 4 h daily from postnatal day (P)3 to P15 (BEC: 160.4 ± 12.0 mg/dl; range = 128.2 to 185.6 mg/dl). Diffusion tensor imaging (DTI) and histological analyses were performed on brain tissue isolated at P50. Diffusion parameters were measured with Paravision™ 5.1 software (Bruker) following ex vivo scanning in a 7.0 T MRI. Nodes of Ranvier were identified using high‐resolution confocal imaging of immunofluorescence for Nav1.6 (nodes) and Caspr (paranodes) and measured using Imaris™ imaging software (Bitplane). Myelin ultrastructure was evaluated by calculating the G‐ratio (axonal diameter/myelinated fiber diameter) on images acquired using transmission electron microscopy. Results Consistent with our previous study, high resolution DTI at P50 showed lower FA in the CC of alcohol‐exposed mice (p = 0.0014). Here, we show that while AD (diffusion parallel to CC axons) was similar between treatment groups (p = 0.30), RD (diffusion perpendicular to CC axons) in alcohol‐exposed subjects was significantly higher than in controls (p = 0.0087). In the posterior CC, where we identified the highest degree of abnormal diffusion, node of Ranvier length did not differ between treatment groups (p = 0.41); however, the G‐ratio of myelinated axons was significantly higher in alcohol‐exposed animals than controls (p = 0.023). Conclusions High resolution DTI revealed higher RD at P50 in the CC of alcohol‐exposed animals, suggesting less myelination of axons, particularly in the posterior regions. In agreement with these findings, ultrastructural analysis of myelinated axons in the posterior CC showed reduced myelin thickness in alcohol‐exposed animals, evidenced by a higher G‐ratio.

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Section: Methodsmentioning

confidence: 99%

Persistent myelin abnormalities in a third trimester‐equivalent mouse model of fetal alcohol spectrum disorder

Newville

Howard

Chavez

et al. 2021

Alcoholism Clin & Exp Res

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Early Ethanol Exposure Inhibits the Differentiation of Hippocampal Dentate Gyrus Granule Cells in a Mouse Model of Fetal Alcohol Spectrum Disorders

et al. 2020

Alcoholism Clin & Exp Res

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BackgroundAlcohol consumption during pregnancy may damage the developing central nervous system of the fetus and lead to brain structural and functional deficits in the children, known as fetal alcohol spectrum disorders. The underlying mechanisms have not been fully elucidated. Previously, using a third trimester–equivalent mouse model, ethanol (EtOH)‐induced behavioral deficits (including spatial learning and memory dysfunction) in the mice were detected on postnatal day (PD) 35. The hippocampal formation is critically involved in spatial learning/memory and contains 2 major neuron populations: the pyramidal cells in the hippocampus proper and the dentate gyrus granule cells (DGGCs) in the dentate gyrus (DG). In rodents, while the pyramidal cells are almost exclusively generated prenatally, the DG granule neurons are majorly generated during the first 2 weeks postnatally, which coincides with the period of EtOH exposure in our mouse model. Therefore, in the current study the effects of EtOH exposure on the development of the DGGCs were examined.MethodsC57BL/6 mice were treated with 4 g/kg of EtOH by intubation on PD 4 to 10 to mimic alcohol exposure to the fetus during the third trimester in humans, and the development of DGGCs was examined by immunohistochemistry and quantified on PD 35.ResultsEtOH exposure does not affect the number of total or newly generated DGGCs, but reduces the number of mature DGGCs on PD 35 in both male and female mice. The ratio of immature DGGCs over total DGGCs was increased, and the ratio of mature DGGCs over total DGGCs was decreased by EtOH exposure. In addition, no sex‐dependent effects of EtOH treatment were detected.ConclusionOur data indicate that EtOH exposure in mice during PD 4 to 10 does not affect the generation/proliferation but inhibits the differentiation of the DGGCs on PD 35.

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Functional and Structural Correlates of Impaired Enrichment-Mediated Adult Hippocampal Neurogenesis in a Mouse Model of Prenatal Alcohol Exposure

Gustus

Newville

et al. 2020

BPL

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Fetal alcohol spectrum disorders (FASDs) are associated with a wide range of cognitive deficiencies. We previously found that gestational exposure to moderate levels of alcohol in mice throughout the 1st-2nd human trimester-equivalents for brain development results in profound impairment of the hippocampal neurogenic response to enriched environment (EE) in adulthood, without altering baseline neurogenesis rate under standard housing (SH). However, the functional and structural consequences of impaired EE-mediated neurogenesis in the context of prenatal alcohol exposure (PAE) have not been determined. Here, we demonstrate that PAE-EE mice display impaired performance on a neurogenesis-dependent pattern discrimination task, broadened behavioral activation of the dentate gyrus, as assessed by expression of the immediate early gene, c-Fos, and impaired dendritic branching of adult-generated dentate granule cells (aDGCs). These studies further underscore the impact of moderate gestational alcohol exposure on adult hippocampal plasticity and support adult hippocampal neurogenesis as a potential therapeutic target to remediate certain neurological outcomes in FASD.

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Resistance of Postnatal Hippocampal Neurogenesis to Alcohol Toxicity in a Third Trimester‐Equivalent Mouse Model of Gestational Alcohol Exposure

Cited by 3 publications

References 85 publications

Persistent myelin abnormalities in a third trimester‐equivalent mouse model of fetal alcohol spectrum disorder

Persistent myelin abnormalities in a third trimester‐equivalent mouse model of fetal alcohol spectrum disorder

Early Ethanol Exposure Inhibits the Differentiation of Hippocampal Dentate Gyrus Granule Cells in a Mouse Model of Fetal Alcohol Spectrum Disorders

Functional and Structural Correlates of Impaired Enrichment-Mediated Adult Hippocampal Neurogenesis in a Mouse Model of Prenatal Alcohol Exposure

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