Prenatal Environment That Affects Neuronal Migration

Hwang, Hye Mee; Ku, Ray Yueh; Hashimoto-Torii, Kazue

doi:10.3389/fcell.2019.00138

Cited by 24 publications

(20 citation statements)

References 111 publications

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“…To further explore this phenomenon of increased neurogenesis at lower EtOH doses as it relates to neuroimmune systems in the brain, we focused here on the pro‐inflammatory chemokine Cxcl12 (also known as SDF‐1) and its primary receptor Cxcr4, which are shown to have a major role in processes of neurogenesis, influencing the proliferation, differentiation, and migration of neurons from neuroprogenitor cells shown predominantly in vitro (Hwang et al, 2019). In adult human subjects, EtOH and beer are found to stimulate Cxcr4 expression in peripheral tissue and increase circulating levels of Cxcl12 (Chiva‐Blanch et al, 2014; Poulsen et al, 2019), while prolonged withdrawal or abstinence causes a decrease in Cxcl12 plasma levels (Garcia‐Marchena et al, 2016).…”

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confidence: 99%

Involvement of Cxcl12a/Cxcr4b Chemokine System in Mediating the Stimulatory Effect of Embryonic Ethanol Exposure on Neuronal Density in Zebrafish Hypothalamus

Collier

Khalizova

Chang

et al. 2020

Alcoholism Clin & Exp Res

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Background: Embryonic exposure to ethanol (EtOH) produces marked disturbances in neuronal development and alcohol-related behaviors, with low-moderate EtOH doses stimulating neurogenesis without producing apoptosis and high doses having major cytotoxic effects while causing gross morphological abnormalities. With the pro-inflammatory chemokine system, Cxcl12, and its main receptor Cxcr4, known to promote processes of neurogenesis, we examined here this neuroimmune system in the embryonic hypothalamus to test directly if it mediates the stimulatory effects low-moderate EtOH doses have on neuronal development. Methods: We used the zebrafish (Danio rerio) model, which develops externally and allows one to investigate the developing brain in vivo with precise control of dose and timing of EtOH delivery in the absence of maternal influence. Zebrafish were exposed to low-moderate EtOH doses (0.1, 0.25, 0.5% v/ v), specifically during a period of peak hypothalamic development from 22 to 24 hours postfertilization, and in some tests were pretreated from 2 to 22 hpf with the Cxcr4 receptor antagonist, AMD3100. Measurements in the hypothalamus at 26 hpf were taken of cxcl12a and cxcr4b transcription, signaling, and neuronal density using qRT-PCR, RNAscope, and live imaging of transgenic zebrafish. Results: Embryonic EtOH exposure, particularly at the 0.5% dose, significantly increased levels of cxcl12a and cxcr4b mRNA in whole embryos, number of cxcl12a and cxcr4b transcripts in developing hypothalamus, and internalization of Cxcr4b receptors in hypothalamic cells. Embryonic EtOH also caused an increase in the number of hypothalamic neurons and coexpression of cxcl12a and cxcr4b transcripts within these neurons. Each of these stimulatory effects of EtOH in the embryo was blocked by pretreatment with the Cxcr4 antagonist AMD3100. Conclusions: These results provide clear evidence that EtOH's stimulatory effects at low-moderate doses on the number of hypothalamic neurons early in development are mediated, in part, by increased transcription and intracellular activation of this chemokine system, likely due to autocrine signaling of Cxcl12a at its Cxcr4b receptor within the neurons.

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confidence: 99%

Involvement of Cxcl12a/Cxcr4b Chemokine System in Mediating the Stimulatory Effect of Embryonic Ethanol Exposure on Neuronal Density in Zebrafish Hypothalamus

Collier

Khalizova

Chang

et al. 2020

Alcoholism Clin & Exp Res

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“…Impaired maternal cardiovascular function and maternal anemia can deprive the fetus of an adequate blood supply and result in intrauterine hypoxia. Chronic hypoxia during brain development can affect neuronal migration and profoundly affect brain development [ 39 ].…”

Section: Main Textmentioning

confidence: 99%

“…Exogenous chemical exposures during pregnancy can also impact the developing embryo through molecular changes in the female, or can cross the placenta to directly affect fetal development. Substances such as alcohol and valproic acid have been associated with behavior impairments, transcriptional alterations, congenital malformation, and neuropsychiatric and neurodevelopmental disorders [ 39 , 49 , 50 ].…”

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confidence: 99%

Controlling litter effects to enhance rigor and reproducibility with rodent models of neurodevelopmental disorders

Jiménez

Zylka

2021

J Neurodevelop Disord

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Research with rodents is crucial for expanding our understanding of genetic and environmental risk factors for neurodevelopmental disorders (NDD). However, there is growing concern about the number of animal studies that are difficult to replicate, potentially undermining the validity of results. These concerns have prompted funding agencies and academic journals to implement more rigorous standards in an effort to increase reproducibility in research. However, these standards fail to address a major source of variability in rodent research brought on by the “litter effect,” the fact that rodents from the same litter are phenotypically more similar to one other than rodents from different litters of the same strain. We show that the litter effect accounts for 30–60% of the variability associated with commonly studied phenotypes, including brain, placenta, and body weight. Moreover, we show how failure to control for litter-to-litter variation can mask a phenotype in Chd8V986*/+ mice that model haploinsufficiency of CHD8, a high-confidence autism gene. Thus, if not properly controlled, the litter effect has the potential to negatively influence rigor and reproducibility of NDD research. While efforts have been made to educate scientists on the importance of controlling for litter effects in previous publications, our analysis of the recent literature (2015–2020) shows that the vast majority of NDD studies focused on genetic risks, including mutant mouse studies, and environmental risks, such as air pollution and valproic acid exposure, do not correct for litter effects or report information on the number of litters used. We outline best practices to help scientists minimize the impact of litter-to-litter variability and to enhance rigor and reproducibility in future NDD studies using rodent models.

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“…In the reporter transgenic mice, we observed RFP reporter expression, which reflects prior activation of HS signaling, in both neurons and glial cells broadly in the postnatal brain. The affected brain regions include the cerebral cortex and hypothalamus, in which the impact of early exposure to alcohol and arsenic has been suspected to contribute to cognitive and behavioral deficits [31][32][33][34][35].…”

Section: Tracing the Lineage Of Cells Prenatally Affected By Environmmentioning

confidence: 99%

Long-term spatial tracking of cells affected by environmental insults

Mohammad

Page

Sasaki

et al. 2020

J Neurodevelop Disord

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Background Harsh environments surrounding fetuses and children can induce cellular damage in the developing brain, increasing the risk of intellectual disability and other neurodevelopmental disorders such as schizophrenia. However, the mechanisms by which early damage leads to disease manifestation in later life remain largely unknown. Previously, we demonstrated that the activation of heat shock (HS) signaling can be utilized as a unique reporter to label the cells that undergo specific molecular/cellular changes upon exposure to environmental insults throughout the body. Since the activation of HS signaling is an acute and transient event, this approach was not intended for long-term tracing of affected cells after the activation has diminished. In the present study, we generated new reporter transgenic mouse lines as a novel tool to achieve systemic and long-term tracking of affected cells and their progeny. Methods The reporter transgenic mouse system was designed so that the activation of HS signaling through HS response element (HSE) drives flippase (FLPo)-flippase recognition target (FRT) recombination-mediated permanent expression of the red fluorescent protein (RFP), tdTomato. With a priority on consistent and efficient assessment of the reporter system, we focused on intraperitoneal (i.p.) injection models of high-dose, short prenatal exposure to alcohol (ethanol) and sodium arsenite (ethanol at 4.0 g/kg/day and sodium arsenite at 5.0 mg/kg/day, at embryonic day (E) 12 and 13). Long-term reporter expression was examined in the brain of reporter mice that were prenatally exposed to these insults. Electrophysiological properties were compared between RFP+ and RFP− cortical neurons in animals prenatally exposed to arsenite. Results We detected RFP+ neurons and glia in the brains of postnatal mice that had been prenatally exposed to alcohol or sodium arsenite. In animals prenatally exposed to sodium arsenite, we also detected reduced excitability in RFP+ cortical neurons. Conclusion The reporter transgenic mice allowed us to trace the cells that once responded to prenatal environmental stress and the progeny derived from these cells long after the exposure in postnatal animals. Tracing of these cells indicates that the impact of prenatal exposure on neural progenitor cells can lead to functional abnormalities in their progeny cells in the postnatal brain. Further studies using more clinically relevant exposure models are warranted to explore this mechanism.

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Prenatal Environment That Affects Neuronal Migration

Cited by 24 publications

References 111 publications

Involvement of Cxcl12a/Cxcr4b Chemokine System in Mediating the Stimulatory Effect of Embryonic Ethanol Exposure on Neuronal Density in Zebrafish Hypothalamus

Involvement of Cxcl12a/Cxcr4b Chemokine System in Mediating the Stimulatory Effect of Embryonic Ethanol Exposure on Neuronal Density in Zebrafish Hypothalamus

Controlling litter effects to enhance rigor and reproducibility with rodent models of neurodevelopmental disorders

Long-term spatial tracking of cells affected by environmental insults

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