Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin.

Malgorzata Lopatynska-Mazurek,Ewa Gibula-Tarlowska,Jolanta H Kotlinska,Lukasz Komsta

doi:10.3390/ijms22137083

Malgorzata Lopatynska-Mazurek, Ewa Gibula-Tarlowska + Show 2 more

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https://doi.org/10.3390/ijms22137083

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Abstract

Fetal alcohol spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces FASD development. The mammalian target of the Rapamycin (mTOR) signaling pathway that acts via two distinct multiprotein complexes, mTORC1 and mTORC2, can affect oxidative stress. We investigated whether mTOR-dependent or mTOR-independent mechanisms are engaged in this phenomenon. Thus, Rapamycin—a selective inhibitor of mTORC1, Torin-2—a non-selective mTORC1/mTORC2 inhibitor, and FK-506—a drug that impacts oxidative stress in an mTOR-independent manner were used. Behavioral tests were performed in adult (PND60-65) rats using a passive avoidance (PA) task (aversive learning and memory) and forced swimming test (FST) (depressive-like behaviors). In addition, the biochemical parameters of oxidative stress, such as lipid peroxidation (LPO), as well as apurinic/apyrimidinic (AP)-sites were determined in the hippocampus and prefrontal cortex in adult (PND65) rats. The rat FASD model was induced by intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4–9 (an equivalent to the third trimester of human pregnancy). All substances (3 mg/kg) were given 30 min before ethanol. Our results show that neonatal ethanol exposure leads to deficits in context-dependent fear learning and depressive-like behavior in adult rats that were associated with increased oxidative stress parameters in the hippocampus and prefrontal cortex. Because these effects were completely reversed by Rapamycin, an mTORC1 inhibitor, this outcome suggests its usefulness as a preventive therapy in disorders connected with prenatal ethanol exposure.

Highlights

Fetal alcohol spectrum disorder (FASD) is the most severe consequence of prenatal alcohol exposure (PAE) during pregnancy
The present study investigated the hypothesis that development of emotional learning deficits and depressive-like behaviors in adult rats exposed to ethanol during the neonatal period are a function of oxidative stress that, in turn, depends on the mammalian target of the Rapamycin (mTOR) signaling pathway
Our work reveals that mTORC1 inhibitors play an important role in depressive-like behaviors and learning functions in adult rats that received ethanol during the neonatal period and may be useful as a preventive therapy in disorders connected with prenatal ethanol exposure

Summary

Introduction

Fetal alcohol spectrum disorder (FASD) is the most severe consequence of prenatal alcohol exposure (PAE) during pregnancy. The most profound effects of PAE are neurobehavioral deficits, including physical and cognitive disabilities [1,2] These effects are long lasting and have possible lifelong implications [3]. A critical period of human pregnancy for brain development is the third trimester of human pregnancy (equivalent to the first 10 postnatal days (PND) in rodents) [5]. During this period, the prefrontal cortex and hippocampus, along with other brain regions, go through a transient period of mass neurodevelopment and rapid growth (growth spurt) [6,7,8]. Maternal alcohol consumption during this period leads, among other issues, to anatomical abnormalities, depressive-like behaviors, and learning and memory impairments in children [9]

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