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Early life low-level lead (Pb) exposure is still an alarming child health issue. To date, animal studies investigating the effects of low doses of Pb since early stages of life to adulthood are scarce. We investigated in a mouse model the behavioral effects of developmental exposure to low-level Pb yielding blood levels similar to those observed in child clinical literature. CD1 outbred mouse dams received Pb (25- or 100-ppm) via drinking water from two weeks pre-mating until the end of lactation. Offspring of both sexes underwent a longitudinal assessment of motor, socio-emotional, and cognitive endpoints from neonatal to adult stage. Pb levels were determined in several matrices (blood, brain and bone) up to six months after the end of exposure. We found that new born pups exposed to Pb have slightly altered motor patterns and reduced preference for the nest odor. Offspring of both sexes exposed to the lowest Pb dose showed diminished interest for social novelty stimuli as adults. Moreover, sex-dependent effects of Pb exposure were observed in the spatial learning and memory task, where males were selectively impaired. Finally, blood, brain and bone Pb levels were elevated in a dose dependent fashion up to six months after termination of exposure. We observed marked accumulation of Pb in bones, with higher Pb levels in 100-ppm exposed females than in males at 7 months of age. In conclusion, developmental Pb exposure caused mild alterations in early- and late-life behavioral domains, particularly involving olfactory and cognitive responses. These findings confirm the importance of animal models to understand how early chronic low-level lead exposure impacts on health in a life-course perspective., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Prenatal viral/bacterial infections are considered risk factors for autism spectrum disorders (ASD) and rodent models of maternal immune activation (MIA) have been developed and extensively used in preclinical studies. Poly inosinic-cytidylic acid (Poly I:C) was injected in C57BL6/J dams to mimic a viral infection on gestational day 12.5; the experimental design includes 10/12 litters in each treatment group and data were analysed always considering the litter-effect; neonatal (spontaneous motor behaviour and ultrasonic vocalizations) and adult [open field, marble burying, social approach, fear conditioning, prepulse inhibition (PPI)] offspring of both sexes were tested. In vivo magnetic resonance imaging/spectroscopy (MRI-MRS) and high-performance liquid chromatography (HPLC) to quantify both aminoacid and/or neurotransmitter concentration in cortical and striatal regions were also carried out. In both sexes high levels of repetitive motor responses and sensory gating deficits in PPI were the more striking effects of Poly I:C, whereas no alteration of social responses were evidenced. Poly I:C treatment did not affect mean values, but, intriguingly, increased variability in the levels of four aminoacids (aspartate glycine and GABA) selectively in males. As a whole prenatal Poly I:C induced relevant long-term alterations in explorative-stereotyped motor responses and in sensory gating, sparing cognitive and social competences. When systematically assessing differences between male and female siblings within each litter, no significant sex differences were evident except for increased variability of four aminoacid levels in male brains. As a whole, prenatal Poly I:C paradigms appear to be a useful tool to investigate the profound and translationally-relevant effects of developmental immune activation on brain and behavioural development, not necessarily recapitulating the full ASD symptomatology., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by social communication deficits and repetitive/stereotyped behaviours. We evaluated the effects of a chronic treatment with the immunomodulator drug Fingolimod (FTY720 - a non-selective Sphingosine 1-Phosphate Receptor ligand) in an ASD model, the BTBR T + tf/J (BTBR) mouse strain. In adult BTBR males, chronic FTY720 treatment (4 weeks) increased social and vocal response during a male-female interaction and hippocampal expression of BDNF and Neuregulin 1, two trophic factors reduced in BTBR when compared to control C57 mice. FTY720 also re-established the expression of IL-1β and MnSOD in the hippocampus, whereas it did not modify IL-6 mRNA content. In addition to its central effect, FTY720 modulated the activation state of peripheral macrophages in the BTBR model, both in basal conditions and after stimulation with an immune challenge. Furthermore, IL-6 mRNA colonic content of BTBR mice, reduced when compared with C57 mice, was normalized by chronic treatment with FTY720. Our study, while indicating FTY720 as a tool to attenuate relevant alterations of the BTBR neurobehavioural phenotype, emphasizes the importance of gut mucosal immune evaluation as an additional target that deserve to be investigated in preclinical studies of anti-inflammatory therapeutic approaches in ASD., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

In hypertensive retinopathy, the retinal damage due to high blood pressure is accompanied by increased expression of Glial Fibrillary Acidic Protein (GFAP), which indicates a role of neuroinflammatory processes in such a retinopathy. Proteins belonging to the Rho GTPase family, particularly Rac1, are involved in the activation of Müller glia and in the progression of photoreceptor degeneration, and may thus represent a novel candidate for therapeutic intervention following central nervous system inflammation. In this paper, we have observed that topical administration as eye drops of Cytotoxic Necrotizing Factor 1 (CNF1), a Rho GTPase modulator, surprisingly improves electrophysiological and behavioral visual performances in aged spontaneously hypertensive rats. Furthermore, such functional improvement is accompanied by a reduction of Rac1 activity and retinal GFAP expression. Our results suggest that Rac1 inhibition through CNF1 topical administration may represent a new strategy to target retinal gliosis., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly caused by mutations in the X-linked MECP2 gene associated with severe intellectual disability, movement disorders, and autistic-like behaviors. Its pathogenesis remains mostly not understood and no effective therapy is available. High circulating levels of oxidative stress markers in patients and the occurrence of oxidative brain damage in MeCP2-deficient mouse models suggest the involvement of oxidative stress in RTT pathogenesis. However, the molecular mechanism and the origin of the oxidative stress have not been elucidated. Here we demonstrate that a redox imbalance arises from aberrant mitochondrial functionality in the brain of MeCP2-308 heterozygous female mice, a condition that more closely recapitulates that of RTT patients. The marked increase in the rate of hydrogen peroxide generation in the brain of RTT mice seems mainly produced by the dysfunctional complex II of the mitochondrial respiratory chain. In addition, both membrane potential generation and mitochondrial ATP synthesis are decreased in RTT mouse brains when succinate, the complex II respiratory substrate, is used as an energy source. Respiratory chain impairment is brain area specific, owing to a decrease in either cAMP-dependent phosphorylation or protein levels of specific complex subunits. Further, we investigated whether the treatment of RTT mice with the bacterial protein CNF1, previously reported to ameliorate the neurobehavioral phenotype and brain bioenergetic markers in an RTT mouse model, exerts specific effects on brain mitochondrial function and consequently on hydrogen peroxide production. In RTT brains treated with CNF1, we observed the reactivation of respiratory chain complexes, the rescue of mitochondrial functionality, and the prevention of brain hydrogen peroxide overproduction. These results provide definitive evidence of mitochondrial reactive oxygen species overproduction in RTT mouse brain and highlight CNF1 efficacy in counteracting RTT-related mitochondrial defects., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The complexity of the neuroendocrine level of investigation requires the assessment of behavioral patterns that extend beyond the reproductive functions, which are age- and sex-specific in rodents, described by defined clusters of behavioral items regulated by genetic, hormonal, and epigenetic factors. The study of social behavior in laboratory rodents reveals sex-dimorphic effects of environmental chemicals that may be undetected either by a traditional neurotoxicological approach or referring to the classical definition of endocrine disrupting chemicals. Here we review data on the neurobehavioral effects of developmental exposure to the non-persistent organophosphorus insecticide chlorpyrifos, whose neurotoxic activity at low doses is currently a matter of concern for children's health. In mice exposed to chlorpyrifos in utero and/or in early development social/emotional responses are differently affected in the two sexes in parallel with sex-dependent interference on hypothalamic neuroendocrine pathways regulating social behaviors (vasopressin, oxytocin, and steroid regulated systems). Through the analysis of complex sex-dimorphic behavioral patterns we show that neurotoxic and endocrine disrupting activities of CPF overlap. This widely diffused organophosphorus pesticide might thus be considered as a neuroendocrine disruptor possibly representing a risk factor for sex-biased neurodevelopmental disorders in children., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The present studies investigate the effects of early nerve growth factor (NGF) administration on the ontogenetic profile of learning and retention capacities in mice. The learning paradigm used required the animals to withhold an escape response from a vibrating platform to avoid a punishment (step-down passive avoidance). In Experiment 1, acquisition of step-down passive avoidance was essentially the same in 11- and 15-day-old mice whereas only the latter showed significant retention after 24 h. In younger animals, data pointed to a facilitating effect of familiarization with the test environment. In Experiment 2 ICV NGF treatment on postnatal day 9 increased step-down latencies in both reinforced and nonreinforced pups on day 11. Moreover, NGF mice exposed in nonreinforcement condition on day 11 failed to acquire the avoidance response 24 h later, suggesting that the treatment anticipated the appearance of latent inhibition. Results of Experiment 3, investigating the effects of different durations of preexposure to the test apparatus on passive avoidance acquisition 24 h later, supported the specificity of NGF effects on the emergence of latent inhibition. These findings suggest that neural populations responsive to NGF trophic effect are involved in the maturation of early learning and retention capacities in rodents.

This study was aimed at investigating the behavioral effects of ozone (O3) exposure in CD-1 mice. Pairs of same-sex adult male and female mice were continuously exposed for 13 days to either 0, 0.4, 0.8, or 1.2 ppm O3. The exposure apparatus consisted of a system for O3 production and delivery into four stainless-steel chambers, each equipped to contain up to 24 home cages, with continuous monitoring and recording of concentrations. Acute behavioral changes were assessed during the first hour of O3 exposure without removing animals from the chambers. The onset of exposure produced remarkable behavioral disturbances consisting of a sharp increase of several responses (rearing, sniffing, grooming, feeding, and social interactions) paralleled by a reduction of bar-holding. These changes were rapidly reversed within 1 hour, suggesting that they constituted a response to strong novel stimulation followed by habituation. Subsequently, brief sessions of videorecording of the animals' activities in freshly cleaned cages (identical to the home cages) were performed outside the chambers after 3, 7, and 10 days of exposure. These tests showed a significant concentration-dependent increase of grooming and rearing and a decrease of crossing and wall climbing. Both food and water intake showed a nonmonotonic trend over time consisting of a concentration-dependent depression (for about 3 and 7 days, respectively) followed by recovery; body weight followed a similar trend. The detailed study of various components of the animal's behavioral repertoire, showing concentration-dependent and time-dependent changes in different directions, appears to be a sensitive tool in the analysis of pollutants' effects.

CD-1 outbred mice were exposed to oxazepam on fetal days 12-16 by maternal administration (per os of 15 mg/kg twice daily at 8 a.m. and 8 p.m.) and fostered at birth to untreated dams, while control mice received vehicle solution. Mice were then tested on postnatal day 14 and 15 in a passive avoidance apparatus for their ability to withhold a step-down response from a vibrating platform. The step-down response was punished with a mild footshock. Each animal was subjected to a maximum of 15 trials. Mice prenatally treated with oxazepam showed an impairment in the acquisition of the task as indicated by shorter latencies to step-down throughout the 15 trials in both sessions (days 14 and 15). As control nonreinforced animals prenatally treated with oxazepam did not show a similar alteration in latency to step-down, these data suggest that prenatal exposure to oxazepam influences behavioral performance of preweaning mice in an aversively motivated task.