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Amblyopia or lazy eye is a dysfunction of the visual system that appears during childhood and traditionally has been considered untreatable in adults. Its main consequences are the loss of visual acuity and contrast sensitivity of the amblyopic eye and binocular vision impairments. During the last years videogames have been used as a therapeutic tool for amblyopia with the inconclusive results. The present work has assessed the effectiveness of a virtual reality videogame (AmbliOK®) in the neurorehabilitation of four adult clinical cases with anisometropic amblyopia. Visual acuity, contrast sensitivity, stereopsis and interocular suppression were assessed before, during, immediately after, one month and one year (in one patient) after the training. The intervention was conducted along four weeks (10 h) and yielded the variable results. In general, all patients showed an improvement in visual functions although not all ameliorated in the same way. Visual acuity measures improved in all patients, falling outside the amblyopia criterion at the end of the treatment. However, the improvement was not maintained one month later in two patients. Contrast sensitivity progressively improved for the amblyopic and the fellow eyes with all patients showing better results one month after the treatment. The patient assessed one year after still showed better results than in the baseline. Patients showing bad stereopsis in the baseline reached a performance considered normal one month and even one year after the treatment. The effectiveness of the treatment seems to be related to the characteristics of patients.

The molecular and behavioral effects of the developmental exposure to low doses of Chlorpyrifos (CPF) have been intensively studied in young (neonates and adolescents), and adult animals. However, no study examined influences of developmental CPF exposure in older adult or geriatric rats. This is relevant as such ages are generally linked to cognitive decline and the onset of specific neurodegenerative disorders, some of them previously associated with CPF exposure in both preclinical and human studies. 1 mg/kg/mL of CPF was orally administered to both male and female Wistar rats from Postnatal day 10 to 15. Animals' spatial memory, learning, compulsivity, motricity, and anxiety were analyzed with Morris Water Maze (15-16 months of age) and the Plus-maze (at 18 months of age). Results showed that postnatal CPF exposure did not alter either spatial memory, compulsive-like behaviors, or anxiety levels in late-adult rats. However, CPF exposed rats were hyposensitive to brief disruptions (Probe stage) following the learning phase and showed a general decrease in locomotor activity in both paradigms. These data are relevant as it is the first time that developmental exposure to CPF has been studied at such a late age, observing important effects in locomotor activity that could be linked to specific pathologies previously associated with CPF effects in people. Future studies should extend these findings to other behaviors and molecular outcomes.

In recent years, the worldwide prevalence of overweight and obesity among adults and children has dramatically increased. The conventional model regarding the onset of obesity is based on an imbalance between energy intake and expenditure. However, other possible environmental factors involved, such as the exposure to chemicals like pesticides, cannot be discarded. These compounds could act as endocrine-disrupting chemicals (EDC) that may interfere with hormone activity related to several mechanisms involved in body weight control. The main objective of this study was to systematically review the data provided in the scientific literature for a possible association between prenatal and postnatal exposure to pesticides and obesity in offspring. A total of 25 human and 9 animal studies were analyzed. The prenatal, perinatal, and postnatal exposure to organophosphate, organochlorine, pyrethroid, neonicotinoid, and carbamate, as well as a combined pesticide exposure was reviewed. This systematic review reveals that the effects of pesticide exposure on body weight are mostly inconclusive, finding conflicting results in both humans and experimental animals. The outcomes reviewed are dependent on many factors, including dosage and route of administration, species, sex, and treatment duration. More research is needed to effectively evaluate the impact of the combined effects of different pesticides on human health. This study was supported by grants from the Spanish Government (Ministerio de Economía y Competitividad and Instituto Mixto de Investigación-Escuela Nacional de Sanidad (IMIENS)) and the Fondo Europeo de Desarrollo Regional (MINECO-FEDER) Grant numbers: PSI2017-90806-REDT, PSI2017-83038-P, PSI2017-83893-R, PSI2017-86396-P, PSI2017-86847-C2-2-R MINECO-FEDER, and IMIENS: PIC-IMIENS-2018-003. Sí

Autism spectrum disorder (ASD) is a complex set of neurodevelopmental pathologies characterized by impoverished social and communicative abilities and stereotyped behaviors. Although its genetic basis is unquestionable, the involvement of environmental factors such as exposure to pesticides has also been proposed. Despite the systematic analyses of this relationship in humans, there are no specific reviews including both human and preclinical models. The present systematic review summarizes, analyzes, and discusses recent advances in preclinical and epidemiological studies. We included 45 human and 16 preclinical studies. These studies focused on Organophosphates (OP), Organochlorine (OC), Pyrethroid (PT), Neonicotinoid (NN), Carbamate (CM), and mixed exposures. Preclinical studies, where the OP Chlorpyrifos (CPF) compound is the one most studied, pointed to an association between gestational exposure and increased ASD-like behaviors, although the data are inconclusive with regard to other ages or pesticides. Studies in humans focused on prenatal exposure to OP and OC agents, and report cognitive and behavioral alterations related to ASD symptomatology. The results of both suggest that gestational exposure to certain OP agents could be linked to the clinical signs of ASD. Future experimental studies should focus on extending the analysis of ASD-like behaviors in preclinical models and include exposure patterns similar to those observed in human studies. The study was supported by grants from the Spanish Goverment (Ministerio de Economía y Competitividad, Ministerio de Ciencia, Innovación y Universidades and Instituto Mixto de Investigación-Escuela Nacional de Sanidad (IMIENS)) and the Fondo Europeo de Desarrollo Regional (MINECO-FEDER) [Grant numbers: PSI2017-86847-C2-1-R MINECO-FEDER, PSI2017-86847-C2-2-R, PSI2017-86396-P, PSI2017-90806-REDT, PSI2013-45924-P, PSI2017-83038-P, PSI2017-83893-R, MINECO PSI2017-86396-P and IMIENS: PIC-IMIENS-2018-003]. Sí

Rationale Compulsive behaviour, present in different psychiatric disorders such as obsessive-compulsive disorder, schizophrenia and drug abuse, is associated with altered levels of serotonin (5-hydroxytryptamine, 5-HT). The gut microbiota regulates tryptophan (TRP) metabolism and may affect global 5-H synthesis in the enteric and central nervous systems, suggesting a possible involvement of gut microbiota in compulsive spectrum disorders. Objectives The present study investigated whether chronic TRP depletion by diet alters the faecal bacterial community profiles of compulsive versus non-compulsive rats in schedule-induced polydipsia (SIP). Peripheral plasma 5-HT and brain-derived neurotrophic factor (BDNF) levels were evaluated. Methods Wistar rats were selected as High Drinkers (HD) or Low Drinkers (LD) according to their SIP behaviour and were fed for 14 days with either a TRP-free diet (T-) or a TRP-supplemented diet (T+). The faecal bacterial community structure was investigated with 16S rRNA gene-targeted denaturing gradient gel electrophoresis (DGGE) fingerprinting analysis. Results Compulsive HD rats showed a lower bacterial diversity than LD rats, irrespectively of the diet. The TRP-depleted HD rats, the only group increasing compulsive licking in SIP, showed a reduction of bacterial evenness and a highly functionally organized community compared with the other groups, indicating that this bacterial community is more fragile to external changes due to the dominance of a low number of species. The chronic TRP depletion by diet effectively reduced peripheral plasma 5-HT levels in both HD and LD rats, while plasma BDNF levels were not altered. Conclusions These results highlight the possible implication of reduced microbial diversity in compulsive behaviour and the involvement of the serotonergic system in modulating the gut brain-axis in compulsive spectrum disorders.

Background: In recent years, ultrasonic vocalizations (USV) in pups has become established as a good tool for evaluating behaviors related to communication deficits and emotional states observed in autism spectrum disorder (ASD). Prenatal valproic acid (VPA) exposure leads to impairments and social behavior deficits associated with autism, with the effects of VPA being considered as a reliable animal model of ASD. Some studies also suggest that prenatal exposure to chlorpyrifos (CPF) could enhance autistic-like behaviors. Methods: In order to explore these similarities, in the present study we tested whether prenatal exposure to CPF at GD12.5&ndash, 14.5 produces effects that are comparable to those produced by prenatal VPA exposure at GD12.5 in infant Wistar rats. Using Deep Squeek software, we evaluated total number of USVs, latency to the first call, mean call duration, principal frequency peak, high frequency peak, and type of calls. Results: Consistent with our hypothesis, we found that exposure to both CPF and VPA leads to a significantly smaller number of calls along with a longer latency to produce the first call. No significant effects were found for the remaining dependent variables. Conclusions: These results suggest that prenatal exposure to CPF could produce certain behaviors that are reminiscent of those observed in ASD patients.

Organophosphorus pesticides – and in particular chlorpyrifos (CPF) – are extensively used worldwide. They mainly exert their toxicity by targeting the cholinergic system. Several studies suggested that the gene coding for apolipoprotein E (apoE), which is a risk factor for several diseases, can also confer different vulnerability to toxic insults. This study was aimed at assessing the long-term effects of postnatal exposure to CPF on learning and memory as well as the expression levels of several genes involved in cholinergic neurotransmission in mice. Both male and female apoE4-TR and C57BL/6 mice were exposed to either 0 or 1 mg/kg/day of CPF by oral gavage using a micropipette on postnatal days 10–15. At 9 months, they were tested in a Morris Water Maze (MWM) and the gene expression in the frontal cortex and hippocampus was evaluated. Our results show that, in males, CPF had an effect on the spatial retention, while in females, it altered the expression levels of nicotinic receptors. Furthermore, apoE4-TR mice performed the worst during the MWM retention and presented low expression levels in a considerable number of cholinergic genes. Taken together, the current results reveal long-term effects in mice nine months after postnatal exposure to CPF, which are modulated by sex and apoE4 genotype.

The present review collects the most relevant empirical evidence available in the literature until date regarding the effects of transcranial direct current stimulation (tDCS) on the human motor function. tDCS in a non-invasive neurostimulation technique that delivers a weak current through the brain scalp altering the cortical excitability on the target brain area. The electrical current modulates the resting membrane potential of a variety of neuronal population (as pyramidal and gabaergic neurons); raising or dropping the firing rate up or down, depending on the nature of the electrode and the applied intensity. These local changes additionally have shown long-lasting effects, evidenced by its promotion of the brain-derived neurotrophic factor. Due to its easy and safe application and its neuromodulatory effects, tDCS has attracted a big attention in the motor neurorehabilitation field among the last years. Therefore, the present manuscript updates the knowledge available about the main concept of tDCS, its practical use, safety considerations, and its underlying mechanisms of action. Moreover, we will focus on the empirical data obtained by studies regarding the application of tDCS on the motor function of healthy and clinical population, comprising motor deficiencies of a variety of pathologies as Parkinson’s disease, stroke, multiple sclerosis and cerebral palsy, among others. Finally, we will discuss the main current issues and future directions of tDCS as a motor neurorehabilitation tool. Electronic supplementary material The online version of this article (doi:10.1186/s12938-017-0361-8) contains supplementary material, which is available to authorized users.

Many adolescents use amphetamines which are the second most common abused illegal drugs. Methamphetamine (Meth), as a potent amphetamine affects attentional functions. However, the most significant factor for susceptibility to Meth is the age of exposure, most studies have examined the effects of Meth after early adolescence stage. The present experiment was aimed to investigate some possible short- and long-term effects of Meth at two distinct points of adolescence stage (early versus late) on 1) locomotor activity in adolescent rats and 2) attentional functions in their adulthood. Rats received Meth (5 mg/kg, i.p., for consecutive 10 days) during early adolescence (postnatal days (PND) 30–39) or late adolescence (PND 50–59). Locomotor activity was assessed after the first and tenth injections. Then, in adulthood, rats were trained and tested on the Five-choice serial reaction time task (5-CSRTT) to display possible attentional impairments. The first Meth administration in early exposed adolescent (EEA) group produced the highest level of activity, compared with the first exposure in late exposed adolescent (LEA) group and tenth administrations in both groups. In adulthood, LEA group significantly delayed learning the 5-CSRTT and exhibited attentional impairments, as demonstrated by significant reduced response accuracy and increased omission errors under pharmacological challenge, compared with control group. The susceptibility to Meth depends on the age of exposure and Meth administration during late adolescence stage may cause prolonged attentional deficits in adulthood.

Autism spectrum disorder (ASD) is a complex neurodevelopmental pathology characterized by altered verbalizations, reduced social interaction behavior, and stereotypies. Environmental factors have been associated with its development. Some researchers have focused on pesticide exposure. Chlorpyrifos (CPF) is the most used Organophosphate. Previous developmental studies with CPF showed decreased, enhanced or no effect on social outcomes eminently in mice. The study of CPF exposure during preweaning stages on social behavior is sparse in mice and non-existent in rats. d stressors could be at the basis of ASD development, and around postnatal day 10 in the rat is equivalent to the human birthday in neurodevelopmental terms. We explored the effects of exposure to low doses (1mg/kg/mL/day) of CPF during this stage regarding: sociability, dominance gut microbiome and plasma metabolomic profile, since alterations in these systems have also been linked to ASD. There was a modest influence of CPF on social behavior in adulthood, with null effects during adolescence. Dominance and hierarchical status were not affected by exposure. Dominance status explained the significant reduction in reaction to social novelty observed on the sociability test. CPF induced a significant gut microbiome dysbiosis and triggered a hyperlipidemic, hypoglycemic/hypogluconeogenesis and a general altered cell energy production in females. These behavioral results in rats extend and complement previous studies with mice and show novel influences on gut metagenomics and plasma lipid profile and metabolomics, but do not stablish a relation between the exposure to CPF and the ASD phenotype. The effects of dominance status on reaction to social novelty have an important methodological meaning for future research on sociability.

Background: Impulsive and compulsive traits represent a variety of maladaptive behaviors defined by the difficulties to stop an improper response and the control of a repeated behavioral pattern without sensitivity to changing contingencies, respectively. Otherwise, human beings are continuously exposed to plenty neurotoxicological agents which have been systematically linked to attentional, learning, and memory dysfunctions, both preclinical and clinical studies. Interestingly, the link between both impulsive and compulsive behaviors and the exposure to the most important xenobiotic compounds have been extensively developed; although the information has been rarely summarized. For this, the present systematic review schedule and analyze in depth the most important works relating different subtypes of the above-mentioned behaviors with 4 of the most important xenobiotic compounds: Lead (Pb), Methylmercury (MeHg), Polychlorinated biphenyls (PCB), and Organophosphates (OP) in both preclinical and clinical models. Methods: Systematic search strategy on PubMed databases was developed, and the most important information was structured both in text and in separate tables based on rigorous methodological quality assessment. Results: For Lead, Methylmercury, Polychlorinated biphenyls and organophosphates, a total of 44 (31 preclinical), 34 (21), 38 (23), and 30 (17) studies were accepted for systematic synthesis, respectively. All the compounds showed an important empirical support on their role in the modulation of impulsive and, in lesser degree, compulsive traits, stronger and more solid in animal models with inconclusive results in humans in some cases (i.e., MeHg). However, preclinical and clinical studies have systematically focused on different subtypes of the above-mentioned behaviors, as well as impulsive choice or habit conformations have been rarely studied. Discussion: The strong empirical support in preclinical studies contrasts with the lack of connection between preclinical and clinical models, as well as the different methodologies used. Further research should be focused on dissipate these differences as well as deeply study impulsive choice, decision making, risk taking, and cognitive flexibility, both in experimental animals and humans.

Developmental exposure to toxicants and diet can interact with an individual&rsquo, s genetics and produce long-lasting metabolic adaptations. The different isoforms of the apolipoprotein E (APOE) are an important source of variability in metabolic disorders and influence the response to the pesticide chlorpyrifos (CPF). We aimed to study the epigenetic regulation on feeding control genes and the influence of postnatal CPF exposure, APOE genotype, and sex, and how these modifications impact on the metabolic response to a high-fat diet (HFD). Both male and female apoE3- and apoE4-TR mice were exposed to CPF on postnatal days 10&ndash, 15. The DNA methylation pattern of proopiomelanocortin, neuropeptide Y, leptin receptor, and insulin-like growth factor 2 was studied in the hypothalamus. At adulthood, the mice were given a HFD for eight weeks. The results highlight the importance of sex in the epigenetic regulation and the implication of CPF treatment and APOE genotype. The body weight progression exhibited sex-dimorphic differences, apoE4-TR males being the most susceptible to the effects induced by CPF and HFD. Overall, these results underscore the pivotal role of sex, APOE genotype, and developmental exposure to CPF on subsequent metabolic disturbances later in life and show that sex is a key variable in epigenetic regulation.

Alterations in attention and inhibitory control are common features in several neurological disorders. Environmental factors such as exposure to pesticides have been linked to their appearance. Chlorpyrifos (CPF) is one of the most widely used organophosphate compounds in the world. CPF exposure during development seems to be critical for later behavioral and molecular disruptions during adult ages, although this depends on the specific period of development, where the preweaning period is one of the least studied. Despite the abundant empirical work made in the last decades on developmental CPF exposure, the systematic study of this on attention is sparse, and nonexistent concerning inhibitory control, without a single study on preweaning developmental stages. The present research explored the effects of the exposure to low doses of CPF that do not elicit a significant inhibition of the Cholinesterases during this developmental period on rats' behavior in the five-choice serial reaction time task. Behavioral manipulations (inter-trial interval and stimulus duration), pharmacological manipulations (cholinergic and GABAergic drugs) and brain gene expression analyses were also conducted. Exposure to CPF decreased the locomotor activity and enhanced the learning profile of the female rats, increased the impulsive rates, unmasked by a longer inter-trial interval, hypo-sensitized the cholinergic system and down-regulated the mRNA expression levels of the brain-derived neurotrophic factor in the dorsal striatum of the male rats. This happened without significant inhibition of the brain Acetylcholinesterase. All this new information corroborates that the exposure to a common pesticide at low doses during a key, but under-explored developmental period importantly affects different behaviors, neurotransmitter systems, and molecules that are altered in the main neurological disorders observed nowadays.

Development is especially sensitive to Chlorpyrifos (CPF) toxicity, associated with several neurodegenerative and neurodevelopmental disorders where motor function dysfunction is a core symptom. Amongst the alternative molecular targets to cholinesterases inhibition, developmental CPF alters different components in the most important neurotransmitter systems, although this depends on the exposure period. Exposure during the late postnatal preweaning stage is the least studied by far. This period includes essential neurodevelopmental processes and has an important translational meaning. The present study analyzed the influence of low doses of CPF on this developmental window on locomotor activity and the state of the different neurotransmitter systems by pharmacological challenges. Brain gene expression and microbiome modulation following CPF were also analyzed. CPF exposure long-term increased spontaneous vertical activity, female's activity following acute stress, hyposensitized the cholinergic system and hypersensitized the GABAergic system, up-regulated both muscarinic 2 receptor and GABA-A-α2 receptor subunit in the dorsal striatum and the frontal cortex, respectively and induced gut microbiota dysbiosis at both genus and species levels. The present study supports alternative molecular targets than the ChEs following late postnatal, preweaning exposure to low doses of CPF, focusing on both cholinergic and GABAergic systems and the gut microbiome as an important factor.

The gut microbiota comprises a large number of microorganisms, whose composition can be modified by genetic and environmental factors. The host's genetic background, including the different isoforms of the apolipoprotein E (APOE) gene, can exert an influence over microbiota composition. Exposure to the widely-used pesticide chlorpyrifos (CPF), can lead to dysbiosis and alter the levels of metabolites produced by the microbiota, such as short-chain fatty acids (SCFAs). This study was aimed at assessing the contribution of the APOE genotype and early exposure to CPF on gut microbiota and SCFA in brain. For it, C57BL/6, apoE3-and apoE4-TR mice were orally exposed to CPF from postnatal day (PND) 10 to PND 15. Microbiota in the gut and SCFA in the brain were assessed at PND 15 after CPF exposure. Differences between genotypes at different taxonomic levels were found, A. muciniphila presented greater abundance in APOE4 genotype, but was reduced by CPF exposure. APOE and CPF influenced cerebral SCFAs, with APOE3 genotype showing the highest levels of acetic, propionic and butyric acids and CPF exposure inducing the highest levels of isovaleric and 4-methylvaleric acids. These results provide further knowledge about gut microbiota and cerebral SCFAs composition at early ages and their modulation by APOE and postnatal CPF exposure.

Lack of inhibitory control is present in impulsive and compulsive personality traits. The Go/No-Go task is one of the most effective means to assess response inhibition measured by the ability to appropriately withhold responding to No-Go stimuli. The aim of this work was to study whether differences in performance of Go/No-Go task predicts differences in personality traits related to inhibitory control. For this purpose 63 healthy participants divided into two groups based on the median split of false alarms on the Go/No-Go task completed Barratt Impulsiveness Scale (BIS-11) and the Maudsley Obsessional Compulsive Questionnaire (MOCI). Results showed that participants with high false alarms (H-FA) displayed a high-risk strategy of responding, and higher scores in the MOCI Total and MOCI Checking subscale compared to participants with low false alarms (L-FA). The results show for the first time a relation between the execution of the Go/No-Go task and the MOCI scale. Surprisingly, no relation was found between the Go/No-Go task and the BIS-11 scale. Further studies are needed to define the heterogeneous constructs of compulsivity and impulsivity, and to improve the convergence of the clinical scales and the behavioral measures of these two personality traits.