Cytoskeleton Protein EB3 Contributes to Dendritic Spines Enlargement and Enhances Their Resilience to Toxic Effects of Beta-Amyloid

EB3 protein is expressed abundantly in the nervous system and transiently enters the dendritic spines at the tip of the growing microtubule, which leads to spine enlargement. Nevertheless, the role of dynamic microtubules, and particularly EB3 protein, in synapse function is still elusive. By manipulating the EB3 expression level, we have shown that this protein is required for a normal dendritogenesis. Nonetheless, EB3 overexpression also reduces hippocampal neurons dendritic branching and total dendritic length. This effect likely occurs due to the speeding neuronal development cycle from dendrite outgrowth to the step when dendritic spines are forming. Implementing direct morphometric characterization of dendritic spines, we showed that EB3 overexpression leads to a dramatic increase in the dendritic spine head area. EB3 knockout oppositely reduces spine head area and increases spine neck length and spine neck/spine length ratio. The same effect is observed in conditions of amyloid-beta toxicity, modeling Alzheimer`s disease. Neck elongation is supposed to be a common detrimental effect on the spine’s shape, which makes them biochemically and electrically less connected to the dendrite. EB3 also potentiates the formation of presynaptic protein Synapsin clusters and CaMKII-alpha preferential localization in spines rather than in dendrites of hippocampal neurons, while its downregulation has an opposite effect and reduces the size of presynaptic protein clusters Synapsin and PSD95. EB3′s role in spine development and maturation determines its neuroprotective effect. EB3 overexpression makes dendritic spines resilient to amyloid-beta toxicity, restores altered PSD95 clustering, and reduces CaMKII-alpha localization in spines observed in this pathological state.     

Epigallocatechin Gallate Ameliorates the Effects of Prenatal Alcohol Exposure in a Fetal Alcohol Spectrum Disorder-Like Mouse Model

Fetal alcohol spectrum disorder is the main preventable cause of intellectual disability in the Western world. Although binge drinking is the most studied prenatal alcohol exposure pattern, other types of exposure, such as the Mediterranean, are common in specific geographic areas. In this study, we analyze the effects of prenatal alcohol exposure in binge and Mediterranean human drinking patterns on placenta and brain development in C57BL/6J mice. We also assess the impact of prenatal treatment with the epigallocatechin-3-gallate antioxidant in both groups. Study experimental groups for Mediterranean or binge patterns: (1) control; (2) ethanol; (3) ethanol + epigallocatechin-3-gallate. Brain and placental tissue were collected on gestational Day 19. The molecular pathways studied were fetal and placental growth, placental angiogenesis (VEGF-A, PLGF, VEGF-R), oxidative stress (Nrf2), and neurodevelopmental processes including maturation (NeuN, DCX), differentiation (GFAP) and neural plasticity (BDNF). Prenatal alcohol exposure resulted in fetal growth restriction and produced imbalances of placental angiogenic factors. Moreover, prenatal alcohol exposure increased oxidative stress and caused significant alterations in neuronal maturation and astrocyte differentiation. Epigallocatechin-3-gallate therapy ameliorated fetal growth restriction, attenuated alcohol-induced changes in placental angiogenic factors, and partially rescued neuronal nuclear antigen (NeuN), (doublecortin) DCX, and (glial fibrillary acidic protein) GFAP levels. Any alcohol consumption (Mediterranean or binge) during pregnancy may generate a fetal alcohol spectrum disorder phenotype and the consequences may be partially attenuated by a prenatal treatment with epigallocatechin-3-gallate.     

C57BL/6 Background Attenuates mHTT Toxicity in the Striatum of YAC128 Mice

Mouse models are frequently used to study Huntington’s disease (HD). The onset and severity of neuronal and behavioral pathologies vary greatly between HD mouse models, which results from different huntingtin expression levels and different CAG repeat length. HD pathology appears to depend also on the strain background of mouse models. Thus, behavioral deficits of HD mice are more severe in the FVB than in the C57BL/6 background. Alterations in medium spiny neuron (MSN) morphology and function have been well documented in young YAC128 mice in the FVB background. Here, we tested the relevance of strain background for mutant huntingtin (mHTT) toxicity on the cellular level by investigating HD pathologies in YAC128 mice in the C57BL/6 background (YAC128/BL6). Morphology, spine density, synapse function and membrane properties were not or only subtly altered in MSNs of 12-month-old YAC128/BL6 mice. Despite the mild cellular phenotype, YAC128/BL6 mice showed deficits in motor performance. More pronounced alterations in MSN function were found in the HdhQ150 mouse model in the C57BL/6 background (HdhQ150/BL6). Consistent with the differences in HD pathology, the number of inclusion bodies was considerably lower in YAC128/BL6 mice than HdhQ150/BL6 mice. This study highlights the relevance of strain background for mHTT toxicity in HD mouse models.     

Single Cell Analysis of Reversibility of the Cell Death Program in Ethanol-Treated Neuronal PC12 Cells

Neurodegenerative diseases are generally characterized clinically by the selective loss of a distinct subset of neurons and a slow progressive course. Mounting evidence in vivo indicates that large numbers of neurons pass through a long period of injury and dysfunction before the actual death of the cells. Whether these dying neurons can be rescued and return to a normal, functional state is uncertain. In the present study, we explored the reversibility of the neuronal cell death pathway at various stages by monitoring the dynamics of single cells with high-resolution live-cell spinning disk confocal microscopy in an in vitro neuronal cell death model. We exposed differentiated neuronal PC12 cells to ethanol as our cell death model. Results showed that exposure to 5% ethanol for 24 h induced cell death in >70% of the cells. Ethanol treatment for 3 h already induced cellular changes and damage such as reactive oxygen species generation, elevation of intracellular Ca²⁺ level, phosphatidylserine exposure, nuclear shrinkage, DNA damage, mitochondrial fragmentation and membrane potential loss, and retraction of neurites. These phenomena are often associated with programmed cell death. Importantly, after removing ethanol and further culturing these damaged cells in fresh culture medium, cells recovered from all these cell injuries and generated new neurites. Moreover, results indicated that this recovery was not dependent on exogenous NGF and other growth factors in the cell culture medium. Overall, our results suggest that targeting dying neurons can be an effective therapeutic strategy in neurodegenerative diseases.     

Mesoporous silica nanoparticles functionalized with a redox-responsive biopolymer

A redox-responsive delivery system has been formulated for cancer therapy using mesoporous silica nanoparticles (MSNs). The silica surface is modified with carboxylic acid groups prior to loading with 5-fluorouracil (5-FU). Subsequently, the pores of the MSNs are sealed by reacting cystamine-modified carboxymethyl cellulose (CMC), which contains disulfide bonds, with the surface of the MSNs via carbodiimide chemistry. Because these bonds are the sites of cleavage, cells overexpressing reducing agents should be able to cleave Cystamine-modified CMC and release the encapsulated drug. Characterization of the resulting nanoparticles shows a decrease in surface area and pore volume, which suggests that the pores of MSNs has been sealed by the attachment of Cystamine-modified CMC. Transmission electron microscopy confirms these results and shows a coating of Cystamine-modified CMC on the surface of the MSNs. The release of 5-FU can be triggered in the presence of dithiothreitol (DDT), a reducing agent. The breast cancer cells (MCF-7) show the positive uptake of Redox-responsive MSNs Moreover, these nanoparticles exhibit higher cytotoxicity when the breast cancer cells are preincubated with DTT compared to the control nanoparticles or 5-FU loaded MSNs in the absence of DTT. These results show that MSNs crosslinked with Cystamine-modified CMC are redox-responsive and can be developed further for cancer therapy.     

Solid Lipid Curcumin Particles Protect Medium Spiny Neuronal Morphology,and Reduce Learning and Memory Deficits in the YAC128 Mouse Model of Huntington’s Disease

Huntington’s disease (HD) is a genetic neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms, accompanied by massive neuronal degeneration in the striatum. In this study, we utilized solid lipid curcumin particles (SLCPs) and solid lipid particles (SLPs) to test their efficacy in reducing deficits in YAC128 HD mice. Eleven-month-old YAC128 male and female mice were treated orally with SLCPs (100 mg/kg) or equivalent volumes of SLPs or vehicle (phosphate-buffered saline) every other day for eight weeks. Learning and memory performance was assessed using an active-avoidance task on week eight. The mice were euthanized, and their brains were processed using Golgi-Cox staining to study the morphology of medium spiny neurons (MSNs) and Western blots to quantify amounts of DARPP-32, brain-derived neurotrophic factor (BDNF), TrkB, synaptophysin, and PSD-95. We found that both SLCPs and SLPs improved learning and memory in HD mice, as measured by the active avoidance task. We also found that SLCP and SLP treatments preserved MSNs arborization and spinal density and modulated synaptic proteins. Our study shows that SLCPs, as well as the lipid particles, can have therapeutic effects in old YAC128 HD mice in terms of recovering from HD brain pathology and cognitive deficits.     

Systematic study of dye loaded small mesoporous silica nanoparticles for detecting latent fingerprints on various substrates

Uniform mesoporous silica nanoparticles (MSNs) with small particle size of ca. 50 nm were fabricated and used as a novel developing agent for latent fingerprints detection. Methylene blue (MB) molecules as a representative dye were loaded in the mesopore of MSNs in order to increase the contrast of the developed latent fingerprints. Both powder and suspension methods composed of MSNs and MSNs@MB were investigated on various substrates, and both of them were able to realize the latent fingerprints development. Moreover, powder method can successfully achieve the detection of the sweat pores (i.e., the typical feature of tertiary structure) of the latent fingerprint, and it has a better effect (i.e., contrast, selectivity and resolution) of latent fingerprints development than suspension methods. In addition, trimethylsilyl (TMS) groups were grafted on the surface of MSNs to increase the hydrophobic nature of particles, but MSNs-TMS@MB had the worse effect of latent fingerprint development than MSNs@MB.     

Phenolic Compounds Protect Cultured Hippocampal Neurons against Ethanol-Withdrawal Induced Oxidative Stress

Ethanol withdrawal is linked to elevated oxidative damage to neurons. Here we report our findings on the contribution of phenolic antioxidants (17β-estradiol, p-octyl-phenol and 2,6-di-tert-butyl-4-methylphenol) to counterbalance sudden ethanol withdrawal-initiated oxidative events in hippocampus-derived cultured HT-22 cells. We showed that ethanol withdrawal for 4 h after 24-h ethanol treatment provoked greater levels of oxidative damage than the preceding ethanol exposure. Phenolic antioxidant treatment either during ethanol exposure or ethanol withdrawal only, however, dose-dependently reversed cellular oxidative damage, as demonstrated by the significantly enhanced cell viability, reduced malondialdehyde production and protein carbonylation, compared to untreated cells. Interestingly, the antioxidant treatment schedule had no significant impact on the observed neuroprotection. In addition, the efficacy of the three phenolic compounds was practically equipotent in protecting HT-22 cells in spite of predictions based on an in silico study and a cell free assay of lipid peroxidation. This finding implies that free-radical scavenging may not be the sole factor responsible for the observed neuroprotection and warrants further studies to establish, whether the HT-22 line is indeed a suitable model for in vitro screening of antioxidants against EW-related neuronal damage.     

Size-controlled synthesis of monodispersed mesoporous silica nano-spheres under a neutral condition

Under a neutral condition, monodispersed mesoporous silica nano-spheres (MSNs) with controllable size were synthesized. The effects of temperature, structure-directing agent (SDA), co-surfactant/co-solvent propanetriol (PT) and multistep addition modes on particle size and the dispersivity of MSNs were studied. The results showed that MSNs became bigger and more uniform in size with the increase of the temperature. Compared with single surfactant, the use of cationic–nonionic composite surfactants of CTAB and Brij-56 as SDA resulted in the improved dispersivity and regularity of spherical shape, and the decreased particle size of MSNs. PT as additive effectively improved the monodispersivity of MSNs. With the gradual increase of the PT concentration, PT played a role of co-surfactant at first and then of co-solvent, resulting in an unusual dependence of the particle size of MSNs on the PT concentration. Multistep addition modes further contributed to the uniformity and bigger size of MSNs.     

Adolescent Intermittent Ethanol (AIE) Enhances the Dopaminergic Response to Ethanol within the Mesolimbic Pathway during Adulthood: Alterations in Cholinergic/Dopaminergic Genes Expression in the Nucleus Accumbens Shell

A consistent preclinical finding is that exposure to alcohol during adolescence produces a persistent hyperdopaminergic state during adulthood. The current experiments determine that effects of Adolescent Intermittent Ethanol (AIE) on the adult neurochemical response to EtOH administered directly into the mesolimbic dopamine system, alterations in dendritic spine and gene expression within the nucleus accumbens shell (AcbSh), and if treatment with the HDACII inhibitor TSA could normalize the consequences of AIE. Rats were exposed to the AIE (4 g/kg ig; 3 days a week) or water (CON) during adolescence, and all testing occurred during adulthood. CON and AIE rats were microinjected with EtOH directly into the posterior VTA and dopamine and glutamate levels were recorded in the AcbSh. Separate groups of AIE and CON rats were sacrificed during adulthood and Taqman arrays and dendritic spine morphology assessments were performed. The data indicated that exposure to AIE resulted in a significant leftward and upward shift in the dose-response curve for an increase in dopamine in the AcbSh following EtOH microinjection into the posterior VTA. Taqman array indicated that AIE exposure affected the expression of target genes (Chrna7, Impact, Chrna5). The data indicated no alterations in dendritic spine morphology in the AcbSh or any alteration in AIE effects by TSA administration. Binge-like EtOH exposure during adolescence enhances the response to acute ethanol challenge in adulthood, demonstrating that AIE produces a hyperdopaminergic mesolimbic system in both male and female Wistar rats. The neuroadaptations induced by AIE in the AcbSh could be part of the biological basis of the observed negative consequences of adolescent binge-like alcohol exposure on adult drug self-administration behaviors.     

Multifunctional mesoporous silica nanocomposite nanoparticles for theranostic applications

Clever combinations of different types of functional nanostructured materials will enable the development of multifunctional nanomedical platforms for multimodal imaging or simultaneous diagnosis and therapy. Mesoporous silica nanoparticles (MSNs) possess unique structural features such as their large surface areas, tunable nanometer-scale pore sizes, and well-defined surface properties. Therefore, they are ideal platforms for constructing multifunctional materials that incorporate a variety of functional nanostructured materials. In this Account, we discuss recent progress by our group and other researchers in the design and fabrication of multifunctional nanocomposite nanoparticles based on mesoporous silica nanostructures for applications to simultaneous diagnosis and therapy. Versatile mesoporous silica-based nanocomposite nanoparticles were fabricated using various methods. Here, we highlight two synthetic approaches: the encapsulation of functional nanoparticles within a mesoporous silica shell and the assembly of nanoparticles on the surface of silica nanostructures. Various nanoparticles were encapsulated in MSNs using surfactants as both phase transfer agents and pore-generating templates. Using MSNs as a scaffold, functional components such as magnetic nanoparticles and fluorescent dyes have been integrated within these systems to generate multifunctional nanocomposite systems that maintain their individual functional characteristics. For example, uniform mesoporous dye-doped silica nanoparticles immobilized with multiple magnetite nanocrystals on their surfaces have been fabricated for their use as a vehicle capable of simultaneous magnetic resonance (MR) and fluorescence imaging and drug delivery. The resulting nanoparticle-incorporated MSNs were then tested in mice with tumors. These in vivo experiments revealed that these multifunctional nanocomposite nanoparticles were delivered to the tumor sites via passive targeting. These nanocomposite nanoparticles served as successful multimodal imaging probes and also delivered anticancer drugs to the tumor site. With innumerable combinations of imaging modalities and drug delivery available within these vehicles, multifunctional nanocomposite nanoparticles provide new opportunities for clinical diagnostics and therapeutics.     

Does Bisphenol A Confer Risk of Neurodevelopmental Disorders? What We Have Learned from Developmental Neurotoxicity Studies in Animal Models

Substantial evidence indicates that bisphenol A (BPA), a ubiquitous environmental chemical used in the synthesis of polycarbonate plastics and epoxy resins, can impair brain development. Clinical and epidemiological studies exploring potential connections between BPA and neurodevelopmental disorders in humans have repeatedly identified correlations between early BPA exposure and developmental disorders, such as attention deficit/hyperactivity disorder and autism spectrum disorder. Investigations using invertebrate and vertebrate animal models have revealed that developmental exposure to BPA can impair multiple aspects of neuronal development, including neural stem cell proliferation and differentiation, synapse formation, and synaptic plasticity—neuronal phenotypes that are thought to underpin the fundamental changes in behavior-associated neurodevelopmental disorders. Consistent with neuronal phenotypes caused by BPA, behavioral analyses of BPA-treated animals have shown significant impacts on behavioral endophenotypes related to neurodevelopmental disorders, including altered locomotor activity, learning and memory deficits, and anxiety-like behavior. To contextualize the correlations between BPA and neurodevelopmental disorders in humans, this review summarizes the current literature on the developmental neurotoxicity of BPA in laboratory animals with an emphasis on neuronal phenotypes, molecular mechanisms, and behavioral outcomes. The collective works described here predominantly support the notion that gestational exposure to BPA should be regarded as a risk factor for neurodevelopmental disorders.     

Synthesis of poly(N‐isopropylacrylamide) by distillation precipitation polymerization and quantitative grafting on mesoporous silica

In this work, syntheses of thermoresponsive poly(N‐isopropylacrylamide) (PNIPAM) with different molecular weights were carried out in ethanol by distillation precipitation polymerization (DPP) technique. The synthesized polymers were fully characterized by attenuated total reflection Fourier‐transform infrared (ATR‐FTIR) spectroscopy, nuclear magnetic resonance spectroscopy, and size exclusion chromatography techniques. The lower critical solution temperatures of the polymers were determined with differential scanning calorimetry. A simple and versatile method for the in situ synthesis and grafting of PNIPAM on mesoporus silica nanoparticles (MSNs) with improved control over quantitative grafting is devised. The PNIPAM grafted MSNs were characterized with ATR‐FTIR, thermogravimetric analysis, transmission electron microscopy, and dynamic light scattering analyses. From the results obtained it is showed that quantitative grafting of PNIPAM on MSNs from 1 to 20% by weight can be tuned by manipulating the in situ DPP reaction conditions. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 44181.     

Kinetics studies and characterization of poly(furfuryl alcohol) for use as bio‐based furan novolacs

Poly(furfuryl alcohol) (PFA) is an attractive target for the development of bio‐based novolac resins. However, control of the polycondensation reaction is not well understood and side reactions are an important factor for PFA and the development of new resins. The polymerization reactions and kinetics of furfuryl alcohol and 2‐furyl ethanol into polymeric resins are detailed in this work. Nuclear magnetic resonance spectroscopy analysis of reaction kinetics, molecular weight analysis, and rheology analysis confirm that the polymerization reaction rate of 2‐furyl ethanol is much faster than that of furfuryl alcohol because the addition of this methyl group serves to stabilize the carbocation transition state. Side reactions, such as Diels–Alder crosslinking and in particular branching, are quantified and were found to be much more prevalent in the polymerization of PFA. The glass transition temperature was measured to be 376 K for PFA and only 294 K for poly(2‐furyl ethanol). Molecular dynamics simulations showed that the alternative structure that forms in PFA that causes branching results in greater backbone rigidity causing its higher glass transition temperature. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46608.     

The chemistry and development of branched PRF wood adhesives of low resorcinol content

Phenol–Resorcinol–Formaldehyde (PRF) resins of good adhesive performance, and of resorcinol content much lower than in traditional PRF cold-setting adhesives, were prepared by introducing small amounts of urea as a branching unit during preparation of the resin. Resorcinol contents as low as 10.6% were obtained by this method while still maintaining an acceptable pot-life of the resin. Resorcinol contents as low as 8%, still with a good adhesive performance, were obtained, although the pot-life obtained was too short. GPC, FT–IR and C¹³ NMR indicated that the small amount of urea branching unit used leads to the reduction of resorcinol content mostly by rapid doubling of the average linear length of the PF intermediates and of the final PF oligomers. Tridimensional branching in the liquid resin, contrary to what was previously thought, does not appear to be an important contributory factor and better adhesives are often prepared when branching is totally, or almost totally, absent. Reduction of resorcinol content is achieved simultaneously by two mechanisms: (i) the decrease of resorcinol percentage on resin solids due to the rapid lengthening (doubling) of average oligomers length and (ii) the need for these resins to operate at lower solids content, due to the increased viscosity obtained during their preparation. © 1993 John Wiley & Sons, Inc.     

In Situ Loading of Basic Fibroblast Growth Factor Within Porous Silica Nanoparticles for a Prolonged Release

Basic fibroblast growth factor (bFGF), a protein, plays a key role in wound healing and blood vessel regeneration. However, bFGF is easily degraded in biologic systems. Mesoporous silica nanoparticles (MSNs) with well-tailored porous structure have been used for hosting guest molecules for drug delivery. Here, we report an in situ route to load bFGF in MSNs for a prolonged release. The average diameter (d) of bFGF-loaded MSNs is 57 ± 8 nm produced by a water-in-oil microemulsion method. The in vitro releasing profile of bFGF from MSNs in phosphate buffer saline has been monitored for 20 days through a colorimetric enzyme linked immunosorbent assay. The loading efficiency of bFGF in MSNs is estimated at 72.5 ± 3%. In addition, the cytotoxicity test indicates that the MSNs are not toxic, even at a concentration of 50 μg/mL. It is expected that the in situ loading method makes the MSNs a new delivery system to deliver protein drugs, e.g. growth factors, to help blood vessel regeneration and potentiate greater angiogenesis.     

PEG-templated mesoporous silica nanoparticles exclusively target cancer cells

Mesoporous silica nanoparticles (MSNs) have been proposed as DNA and drug delivery carriers, as well as efficient tools for fluorescent cell tracking. The major limitation is that MSNs enter cells regardless of a target-specific functionalization. Here we show that non functionalized MSNs, synthesized using a PEG surfactant-based interfacial synthesis procedure, do not enter cells, while a highly specific, receptor mediated, cellular internalization of folic acid (FOL) grafted MSNs (MSN-FOL), occurs exclusively in folate receptor (FR) expressing cells. Neither the classical clathrin pathway nor macropinocytosis is involved in the MSN endocytic process, while fluorescent MSNs (MSN-FITC) enter cells through aspecific, caveolae-mediated, endocytosis. Moreover, internalized particles seem to be mostly exocytosed from cells within 96 h. Finally, cisplatin (Cp) loaded MSN-FOL were tested on cancerous FR-positive (HeLa) or normal FR-negative (HEK293) cells. A strong growth arrest was observed only in HeLa cells treated with MSN-FOL-Cp. The results presented here show that our mesoporous nanoparticles do not enter cells unless opportunely functionalized, suggesting that they could represent a promising vehicle for drug targeting applications.     

非粮乙醇的生产及应用研究

全球经济快速发展,能源危机日益严峻,非粮乙醇燃料成为全球关注焦点。综述了国内能源现状,分别介绍了煤基乙醇和生物质乙醇的生产工艺及最新进展,并进行分析对比。提出了燃料乙醇在实际应用中面临的困难和问题,并给出意见和建议。     

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

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.