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Gema Martinez-Navarrete,1,2 Sergio Castaño-Castaño,3– 6 Miguel Morales-Navas,4 Francisco Nieto-Escámez,4,7 Fernando Sánchez-Santed,4 Eduardo Fernandez1,2 1Neuroprosthesis and Neuroengineering Research Group, Institute of Bioengineering (IB), University Miguel Hernández (UMH), Elche, 03020, Spain; 2Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain; 3Department Psychology, University of Oviedo, Plaza Feijoo S/N, Oviedo, 33003, Spain; 4Department of Psychology, University of Almería, Ctra. Sacramento S/N, La Cañada de San Urbano, Almería, 04120, Spain; 5Institute of Neurosciences of the Principality of Asturias (INEUROPA), Oviedo, Spain; 6Institute of Health Research of the Principality of Asturias (ISPA), Oviedo, Spain; 7Neuropsychological Evaluation and Rehabilitation Center (CERNEP), Ctra. Sacramento S/N, La Cañada de San Urbano, Almería, 04120, SpainCorrespondence: Gema Martinez-Navarrete, Department of Histology and Anatomy (Faculty of Medicine). Neuroengineering Biomedical Research Group, Institute of Bioengineering, University Miguel Hernandez, Elche, 03202, Spain, Email gema.martinezn@umh.es Sergio Castaño-Castaño, Department Psychology, University of Oviedo, Plaza Feijoo s/n, Asturias, 33003, Spain, Email castanosergio@uniovi.esPurpose: The impact of visual deprivation on retinal structure is widely debated. Experimental models, like monocular deprivation through lid suture, provide insights into the consequences of lacking visual experience during development. This deprivation delays primary visual cortex (CV1) maturation due to improper neural connection consolidation, which remains plastic beyond the critical period. However, few studies have used Optical Coherence Tomography (OCT) to investigate structural alterations in the retina of animal models following monocular deprivation. Instead, some studies have focused on the ganglion cell layer using post-mortem histological techniques in amblyopia models induced by monocular deprivation.Methods: In this study, we used Cliff test to assess stereoscopic vision and spectral domain optical coherence tomography (SD-OCT) to evaluate retinal changes in an in vivo model of visual deprivation treated with Transcranial Direct Current Stimulation (tDCS).Results: The depth perception test initially revealed differences between individuals with amblyopia and the control group. However, after 8 tDCS sessions, amblyopic subjects matched the control group’s performance, which remained stable Additionally, significant changes were observed in retinal structures post-tDCS treatment. Specifically, the thickness of the Nerve Fiber Layer + Ganglion Cell Layer + Inner Plexiform Layer (NFL+GCL+IPL) increased significantly in amblyopic eyes (p< 0.001). Moreover, significant retinal thickening, including the Nerve Fiber Layer + Ganglion Cell Layer + Inner Plexiform Layer (NFL+GCL+IPL) and the entire retina, was observed post-tDCS treatment (p< 0.05), highlighting the critical role of tDCS in ameliorating amblyopia. Additionally, treated animals exhibited reduced thickness in the Inner Nuclear Layer (INL) and Outer Nuclear Layer (ONL).Conclusion: tDCS treatment effectively restores amblyopic individuals’ stereoscopic vision, aligning their performance with controls, while impacting retinal structure, highlighting its potential in ameliorating amblyopia’s visual deficits. Keywords: amblyopia, monocular visual deprivation model, tDCS, stereoscopic vision, OCT

Introduction: In recent years, we are witnessing a crisis in diagnostic classification systems. Prevalence of mental health disorders has increased considerably, among various reasons, because traditional diagnostic criteria are not sensitive enough to detect their great heterogeneity. Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most prevalent mental health disorders, whose dimensional character has been pointed out. Objectives: The aim of this study was to improve ADHD diagnosis by identifying ADHD specific dimensional profiles. Methods: 100 adolescents (12-16 years old) were recruited from the local community, 45 ADHD and 55 controls, and were assessed with AULA Nesplora, a virtual-reality Continuous Performance test (CPT) specially designed for the assessment of attentional processes, impulsivity, processing speed and motor activity level. Hierarchical and non-hierarchical cluster analysis were performed to identify new homogeneous groups based on specific behavioural symptoms. One-wayANOVAwas used to compare between-group differences in performance. Results: Five dimensional profiles were obtained: two normative groups and three groupswith different impairments that don'tmatch with the traditional ADHD subtypes. These last three groups shared difficulties in selective and sustained attention but differed in the presence and severity of impulsive and/or hyperactive behaviours. Conclusions: These findings represent an advance in the understanding of ADHD symptoms, highlight the need to update diagnostic criteria and could be useful to design most effective intervention strategies based on specific behavioural dimensions. Funding: Ministerio de Ciencia, Innovación y Universidades and Fondo Europeo de Desarrollo Regional (MINECO-FEDER) [Grant numbers: PSI2017-86847-C2-1-R and PGC2018-099117-B-C21]. [ABSTRACT FROM AUTHOR]

Schedule‐induced polydipsia (SIP) is an animal model of compulsive drinking that selects for individual differences and varies across rat strains. The aim of this study was to investigate excessive habit formation by analyzing the SIP licking microstructure among rat strains, and to compare the brain areas activated by SIP in different populations. Wistar, Long Evans and Roman High‐ and Low‐Avoidance rat strains were compared using a cluster analysis of 2 main variables, that is, frequency of licking (percentage of interpellet intervals with drinking episodes) and intensity of licking (mean number of licks per interpellet interval), and were found to exhibit high intensity and frequent licking (compulsive drinkers, CD), low intensity but frequent licking (habitual drinkers, HD), and low intensity and low‐frequency licking (low drinkers, LD). The Wistar strain showed a higher frequency and intensity of licking, and had the largest group of CD rats when compared with the other strains. Regarding the acquisition of SIP, CD rats showed a higher intensity of licking when compared with the HD and LD rats. Moreover, c‐Fos quantification revealed that rats in the CD group showed hyperactivity in the lateral orbitofrontal cortex and basolateral amygdala when compared with the LD group. Analyzing the SIP microstructure could be a valuable tool for understanding the role of excessive habit formation in the development of compulsive drinking and its underpinning neurobiological mechanisms. Excessive habit formation measured by frequency and intensity of licking in schedule‐induce polydipsia among rat strains [ABSTRACT FROM AUTHOR]

Fmr1 (fragile X messenger ribonucleoprotein 1)-knockout (KO) rats, modeling the human Fragile X Syndrome (FXS), are of particular interest for exploring the ASD-like phenotype in preclinical studies. Gestational exposure to chlorpyrifos (CPF) has been associated with ASD diagnosis in humans and ASD-like behaviors in rodents and linked to the microbiota-gut-brain axis. In this study, we have used both Fmr1-KO and wild-type male rats (F2 generation) at postnatal days (PND) 7 and 40 obtained after F1 pregnant females were randomly exposed to 1 mg/kg/mL/day of CPF or vehicle. A nuclear magnetic resonance (NMR) metabolomics approach together with gene expression profiles of these F2 generation rats were employed to analyze different brain regions (such as prefrontal cortex, hippocampus, and cerebellum), whole large intestine (at PND7) and gut content (PND40). The statistical comparison of each matrix spectral profile unveiled tissue-specific metabolic fingerprints. Significant variations in some biomarker levels were detected among brain tissues of different genotypes, including taurine, myo-inositol, and 3-hydroxybutyric acid, and exposure to CPF induced distinct metabolic alterations, particularly in serine and myo-inositol. Additionally, this study provides a set of metabolites associated with gastrointestinal dysfunction in ASD, encompassing several amino acids, choline-derived compounds, bile acids, and sterol molecules. In terms of gene expression, genotype and gestational exposure to CPF had only minimal effects on decarboxylase 2 (gad2) and cholinergic receptor muscarinic 2 (chrm2) genes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In recent years, exposures to organophosphate pesticide have been highlighted as a possible cause or aggravating factor of autism spectrum disorder (ASD). The present study examined if Wistar rats prenatally exposed to chlorpyrifos (CPF) at a dose of 1 mg/kg in GD 12.5-15.5 could express similar behaviors to those exposed to valproic acid (VPA, 400 mg/kg) during the same administration window, which is an accepted animal model of autism. The 3-chambered test was employed to evaluate sociability and reaction to social novelty in two experiments, the first in adolescence and the second in adulthood. The results obtained in this study show that animals prenatally treated with CPF or VPA show a similar behavioral phenotype compared to the control group (CNT). In adolescence, the CPF animals showed a negative index in the reaction to social novelty, followed closely by the VPA, while both experimental groups showed a recovery in this aspect during adulthood. This study therefore provides evidence to suggest that prenatal exposure to CPF in rats could have similar effects on certain components of sociability to those seen in autistic models., (© 2024. The Author(s).)

Compulsivity is a core symptom in different psychopathological disorders, characterized by excessive behaviors and behavioral inflexibility. The selection of high drinker (HD) versus low drinker (LD) rats by schedule-induced polydipsia (SIP) is a valid model for studying the compulsive phenotype. The compulsive HD rats showed cognitive inflexibility and reduced serotonin 2A (5-HT2A) receptor binding levels in the frontal cortex (FC). According to that, we hypothesize that compulsive HD rats might have an alteration in the cognitive control domain regarding inflexibility, assessed by spatial memory on the Morris Water Maze (MWM), working and reference memory by the Radial Arm Maze, and behavioral deficits in stimulus processing by the Novel Object Recognition test. The possible underlying mechanisms might be linked to the brain gene expression of 5HT2A, 5HT2C, glutamate NMDA receptors, and brain-derived neurotrophic factor (BDNF) in FC, hippocampus, and amygdala. HD rats confirmed a cognitive inflexibility profile on the reversal condition in the MWM compared to LD rats, while no differences were observed on stimulus processing, spatial, and working memory. Moreover, HD rats showed a reduced expression of the Htr2a, Grin1, and Bdnf genes in FC. Furthermore, there was a negative correlation between the relative expression of the Htr2a, Grin1, and Bdnf genes in FC and the level of compulsive water intake in HD rats on SIP. These data reveal that cognitive inflexibility may not be associated with a memory or stimulus processing deficit in compulsive individuals but may result by a region-specific alteration of the Htr2a, Grin1, and Bdnf gene expression in FC., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Autism spectrum disorder (ASD) encompasses several neurodevelopmental conditions characterized by communication and social impairment, as well as repetitive patterns of behavior. However, it can co-occur with other mental conditions such as anxiety. The massive use of chlorpyrifos (CPF) has been linked to the increased prevalence of developmental disorders. Likewise, ASD has also been closely linked to a wide variety of genetic factors. The aims of the present investigation are to study how gestational CPF exposure and APOE polymorphism affects communication skills, early development and mid-term anxiety-like behaviors, as well as, changes in gene expression related to the cholinergic system. C57BL/6J and humanized apoE3 and apoE4 homozygous mice were exposed to 0 or 1 mg/kg/day of CPF through the diet, from gestational day (GD) 12-18. In addition, a group of C57BL/6J females were injected subcutaneously with 300 mg/kg/day of valproic acid (VPA) on GD 12 and 13. This group was used as a positive control for studying some core and associated autism-like behaviors. Communication skills by means of ultrasonic vocalizations and physical/motor development were assessed during the preweaning period, whereas locomotor activity, anxiety-like behaviors and the gene expression of cholinergic elements were evaluated during adolescence. Our results showed that C57BL/6J mice prenatally exposed to CPF or VPA showed a decrease in body weight and a delay in eye opening. Communication and anxiety behavior were affected differently depending on treatment, while gene expression was altered by sex and treatment. In addition, none of the parameters evaluated in apoE transgenic mice exposed to CPF were affected, but there were differences between genotypes. Therefore, we suggest that prenatal CPF exposure and VPA produce divergent effects on communication and anxiety., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Particulate matter (PM) is a major component of ambient air pollution (AAP), being widely associated with adverse health effects. Epidemiological and experimental studies point towards a clear implication of AAP on the development of central nervous system (CNS) diseases. In this sense, the period of most CNS susceptibility is early life, when the CNS is maturing. In humans the last trimester of gestation is crucial for brain maturation while in rodents, due to the shorter gestational period, the brain is still immature at birth, and early postnatal development plays a significant role. The present systematic review provides an updated overview and discusses the existing literature on the relationship between early exposure to PM and neurodevelopmental outcomes in experimental studies. We included 11 studies with postnatal exposure and 9 studies with both prenatal and postnatal exposure. Consistent results between studies suggest that PM exposure could alter normal development, triggering impairments in short-term memory, sociability, and impulsive-like behavior. This is also associated with alterations in synaptic plasticity and in the immune system. Interestingly, differences have been observed between sexes, although not all studies included females. Furthermore, the developmental window of exposure seems to be crucial for effects to be observed in the future. In summary, air pollution exposure during development affects subjects in a time- and sex-dependent manner, the postnatal period being more important and being males apparently more sensitive to exposure than females. Nevertheless, additional experimental investigations should prioritize the examination of learning, impulsivity, and biochemical parameters, with particular attention provided to disparities between sexes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Lipids are a major component of the brain, and are involved in structural and neurodevelopmental processes such as neurogenesis, synaptogenesis and signaling. Apolipoprotein E (apoE) is the main lipoprotein involved in lipid transport in the brain. The apoE isoforms can determine vulnerability to the toxic effects of the pesticide chlorpyrifos (CPF), which can interfere with normal neurodevelopment. We aimed to study the effects of postnatal exposure to CPF and of the APOE genotype on the lipid composition of the brain at early ages. For it, we used apoE3 and apoE4 targeted-replacement (TR) male mice, as well as wild-type C57BL/6. The mice were orally exposed to 1 mg/kg/day of CPF on postnatal days 10-15 and, four hours after the treatment, we obtained samples to assess the cerebral lipid composition. Differences between APOE genotypes were found in the cerebral lipid profile in the postnatal period. ApoE4-TR mice exhibited higher lipid concentrations compared to the other groups in most of the cases. CPF exposure led to a decrease in cholesteryl ester and triglyceride concentrations, while modulating the levels of phosphatidylcholine species based on the apoE isoform. Specifically, CPF treatment decreased the concentration of some species of this lipid (PC30:0, PC31:0, PC32:2, PC36:5, PC40:4 and PC40:5) in C57BL/6 mice exposed to CPF, increased (PC31:0 and PC37:6) in apoE3-TR exposed mice while exposed apoE4-TR mice remained unaltered. These results provide further insights into the lipid composition of the brain at early ages, and how it can be modulated by environmental and genetic factors., (© 2023. The Author(s).)

Air pollution plays, nowadays, a huge role in human's health and in the personal economy. Moreover, there has been a rise in the prevalence of neurodevelopmental disorders like the Autism Spectrum Disorder (ASD) in recent years. Current scientific studies have established a link between prenatal or perinatal exposure to environmental pollutants and ASD. This systematic review summarizes the current literature available about the relationship between exposure to air pollutants (particulate matter [PM], Second Organic Aerosols [SOA], Diesel Exhaust [DE], and Traffic Related Air Pollution [TRAP]) and neurodevelopmental disorders in preclinical models using rats and mice. The articles were selected and filtered using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, and bias-evaluated using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) tool. Overall, our findings suggest that air pollutants are associated with negative developmental outcomes characterized by ASD-like behaviors, abnormal biochemical patterns, and impaired achievement of developmental milestones in rodents. However, there is not sufficient information in certain domains to establish a clear relationship. Short phrases for indexing terms: Air pollution affects neurodevelopment; PM exposure modifies glutamate system; Prenatal exposure combined with postnatal affect more to behavioral / cognitive domain; Air pollution modifies social behavior in rodents; Cognitive deficits can be detected after gestational exposure to air pollution., Competing Interests: Declaration of Competing Interest All authors have declared that no financial or personal relationships have influenced in writing this article. No author claimed conflict of interest to disclose. No further affiliations with any organization that may have a financial or political interest in the subject matter discussed in this work are present. The present research was conducted solely for academic purposes and have not received any further support from any external sources that may have influenced our findings or conclusions., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The massive use of chlorpyrifos (CPF) has been associated with an increased prevalence of neurodevelopmental disorders. Some previous studies have shown that prenatal, but not postnatal, CPF exposure causes social behavior deficits in mice depending on sex while others have found that in transgenic mice models carrying the human apolipoprotein E (APOE) ε3 and ε4 allele confer different vulnerabilities to either behavioral or metabolic disorders after CPF exposure. This study aims to evaluate, in both sexes, how prenatal CPF exposure and APOE genotype impact on social behavior and its relation to changes in GABAergic and glutamatergic systems. For this purpose, apoE3 and apoE4 transgenic mice were exposed through the diet to 0 or 1 mg/kg/day of CPF, between gestational day 12 and 18. A three-chamber test was used to assess social behavior on postnatal day (PND) 45. Then, mice were sacrificed, and hippocampal samples were analyzed to study the gene expression of GABAergic and glutamatergic elements. Results showed that prenatal exposure to CPF impaired social novelty preference and increased the expression of GABA-A α1 subunit in females of both genotypes. In addition, the expression of GAD1, the ionic cotransporter KCC2 and the GABA-A α2 and α5 subunits were increased in apoE3 mice, whereas CPF treatment only accentuated the expression of GAD1 and KCC2. Nevertheless, future research is needed to evaluate whether the influences detected in the GABAergic system are present and functionally relevant in adults and old mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The balance between excitatory and inhibitory neurotransmitters is essential for proper brain development. An imbalance between these two systems has been associated with neurodevelopmental disorders. On the other hand, literature also associates the massive use of pesticides with the increase of these disorders, with a particular focus on chlorpyrifos (CPF) a world-wide used organophosphate pesticide. This study was aimed at assessing social autistic-like behaviors on mice pre or postnatally exposed to CPF (0 or 1 mg/kg/day), in both sexes. In prenatal exposure, C57BL/6J pregnant mice were exposed to CPF through the diet, between gestational days (GD) 12 and 18, while a positive control group for some autistic behaviors was exposed to valproic acid (VPA) on GD 12 and 13. To assess postnatal exposure, C57BL/6J mice were orally exposed to the vehicle (corn oil) or CPF, from postnatal days (PND) 10-15. Social behavior and gene expression analysis were assessed on PND 45. Results showed social alterations only in males prenatally treated. GABA system was upregulated in CPF-treated females, whereas an increase in both systems was observed in both treated males. These findings suggest that males are more sensitive to prenatal CPF exposure, favoring the sex bias observed in ASD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Based on previous reports, exposure to pesticides could be linked to the prevalence increase of autism spectrum disorders (ASD). Gestational exposure to chlorpyrifos (CPF) has been associated with ASD diagnosis in humans and ASD-like behaviors in rodents. However, ASD severity degree results from the complex relationship between genetic background and environmental factors. Thus, animals with a genetic vulnerability and prenatally exposed to CPF could have a more severe ASD-like phenotype. Fragile X syndrome is one of the most common monogenic causes of ASD, characterized by a mutation in the X chromosome which alters the expression of the fragile X mental retardation protein (FMRP). Based on this, some fmr1 knockout (KO) rodent models have been developed to study the physiological and genetic basis of ASD. Both fmr1-KO and wild-type male rats (F2 generation) were used in the present study. F1 pregnant females were randomly exposed to 1 mg/kg/mL/day of CPF (s.c.) from GD12.5-15.5 or vehicle. Different behavioral, developmental, and molecular variables were analyzed in F2 males. KO rats were heavier, emitted altered USVs, were socially inefficient, reacted more to a novel stimulus, were hyperactive when exploring a new context, but hypoactive when exploring anxiety-inducing environments, and had an upregulated hippocampal expression of the grin2c gene. When exposed to low doses of CPF during gestation, these KO rats showed decreased climbing capacity, dysfunctional social interaction, and increased hippocampal expression for kcc1 and 5ht2c genes. Gestational CPF exposure increased the ASD-like phenotype in those animals with a genetic vulnerability, although its effect was less generalized than expected. It is the first time that this additive effect of CPF exposure and the fmr1-KO genetic vulnerability model is explored concerning social traits or any other behavior., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)