RESUMEN

Opioid use by women during pregnancy has risen dramatically since 2004, accompanied by a striking increase in the prevalence of neonatal opioid withdrawal syndrome (NOWS) and other long-term neurological deficits. However, the mechanisms underlying the impact of prenatal opioid exposure on fetal neurodevelopment are largely unknown. To translate from the clinical presentation, we developed a novel mouse model to study the neurodevelopmental consequences of maternal opioid use and management. Female mice were treated with oxycodone (OXY) before mating to mimic opioid use disorder (OUD) in humans. Following pregnancy confirmation, dams were switched to buprenorphine (BUP) via oral administration, simulating medication management of OUD (MOUD) in pregnant women. Here, we document critical changes in fetal brain development including reduced cortical thickness, altered corticogenesis, and ventriculomegaly in embryos from dams that were treated with opioids before and throughout pregnancy. Maternal care giving behavior was slightly altered without affecting gross growth of offspring. However, adolescent offspring exposed to maternal opioid use during pregnancy exhibited hyperactivity in late adolescence. Remarkably, we also show increased generation of dopaminergic neurons within the ventral tegmental area (VTA) of mice exposed to prenatal opioids. These data provide critical evidence of teratogenic effects of opioid use during pregnancy and suggest a causal relationship between maternal opioid use and neurodevelopmental/behavioral anomalies in adolescence.

Asunto(s)

RESUMEN

[This corrects the article DOI: 10.1371/journal.pntd.0008413.].

RESUMEN

Global Zika virus (ZIKV) outbreaks and their link to microcephaly have raised major public health concerns. However, the mechanism of maternal-fetal transmission remains largely unknown. In this study, we determined the role of yolk sac (YS) microglial progenitors in a mouse model of ZIKV vertical transmission. We found that embryonic (E) days 6.5-E8.5 were a critical window for ZIKV infection that resulted in fetal demise and microcephaly, and YS microglial progenitors were susceptible to ZIKV infection. Ablation of YS microglial progenitors significantly reduced the viral load in both the YS and the embryonic brain. Taken together, these results support the hypothesis that YS microglial progenitors serve as "Trojan horses," contributing to ZIKV fetal brain dissemination and congenital brain defects.

Asunto(s)

RESUMEN

Many advancements have been made over the years looking at the individual and combined effects of drugs of abuse on the brain, with one key area of research focusing on the effects on neurogenesis. An integral part of fetal brain development and, later, maintenance in the adult brain, neurogenesis occurs in three main regions: subventricularzone of the lateral ventricles (SVZ), subgranularzone of the dentate gyrus (SGZ), and the tanycyte layer in the hypothalamus (TL). We will review current literature on combined drugs of abuse and their effect on adult neurogenesis. More specifically, this review will focus on the effect of combining cocaine and alcohol. Additionally, the tanycyte layer will be explored in more depth and probed to look at the neurogenic properties of tanycytes and their role in neurogenesis.

RESUMEN

Cocaine and ethanol are two commonly co-abused substances; however, the neuropathology following chronic dual consumption is poorly understood. Neural stem cells (NSCs) are a subpopulation of cells within the adult brain that are integral to brain maintenance and repair making them an appealing target to reverse neurodegeneration associated with abused substances. Yet, knowledge about NSC response to chronic poly-drug administration of ethanol and cocaine is minimal. Here, we developed a novel chronic poly-drug administration paradigm of ethanol and cocaine using a transgenic mouse model to trace endogenous NSC survival and differentiation in three brain regions from both male and female mice. We report significant and distinct patterns of NSC survival and differentiation among brain regions, as well as between sexes. Additionally, poly-drug administration had synergistic effects on NSC survival. Altered cognitive and hedonic behaviors were also observed, however the extent of these behavioral changes was not proportional to the NSC changes. With this mouse model we can effectively examine cognitive and behavioral changes and correlate them with pathological changes in the brain in response to chronic poly-drug administration, which is of great value in understanding the progression of neurodegeneration in polysubstance use disorders and evaluation potential therapeutics on neuroregeneration.

Asunto(s)

RESUMEN

Human neural stem cells (hNSCs) can differentiate into an oligodendrocyte lineage to facilitate remyelination in patients. Molecular mechanisms underlying oligodendrocyte fate specification remains unknown, hindering the development of efficient methods to generate oligodendrocytes from hNSCs. We have found that Neurobasal-A medium (NB) is capable of inducing hNSCs to oligodendrocyte progenitor cells (OPCs). We identified several signaling molecules are altered after cultivation in NB medium, including Akt, ERK1/2 and c-Src. While sustained activation of Akt and ERK1/2 during both NB induction and subsequent differentiation was required for OPC differentiation, c-Src phosphorylation was increased temporally during the period of NB induction. Both pharmacological inhibition and RNA interference confirmed that a transient elevation of phospho-c-Src is critical for OPC induction. Furthermore, inactivation of c-Src inhibited phosphorylation of Akt and ERK1/2. In summary, we identified a novel and critical role of c-Src in guiding hNSC differentiation to an oligodendrocyte lineage.

Asunto(s)