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Topiramate, an antiepileptic drug, has been found to be useful for the treatment of aggression in clinical populations as well as in animal models of aggression. However, increases in aggression were also observed under lower doses of Topiramate. Subsequently, Topiramate produced an inverted U-shaped dose response curve, with increases in aggression at low doses, whereas higher doses engendered anti-aggressive effects. In our previous study, we demonstrated that Topiramate modulates brain activity in the prefrontal areas involved in the modulation of the subcortical circuit mediating aggression, and we found indirect evidence that the anterior cingulate cortex (ACC) could be a key site where Topiramate may exert its dose-response effects on aggression. In this study, we performed site-directed injections of Topiramate (0.1 and 0.3 mM) into the ACC on offensive behaviors in isolation-inducedaggression paradigm. By using the resident-intruder test, we demonstrated that Topiramate microinfusion into the ACC at low doses produced increases in aggression, as evidenced by shorter attack latencies (p < 0.01) and increased attack duration (p < 0.01), without affecting the social behavior. In contrast, higher doses engendered anti-aggressive effects, by increasing the attack latencies (p < 0.001), decreasing attack number (p < 0.001) and decreasing attack duration (p < 0.001), as well as an increase in the social behavior. Our findings supported that Topiramate at higher concentrations appeared more efficient to decrease aggression in treated mice. Therefore, we suggest that the ACC is a key brain region in which Topiramate may exert its dose-response effects on aggressive and antisocial behaviors observed in populations with psychotic disorders., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by impaired attention, impulsivity and hyperactivity. The "neonatal 6-hydroxydopamine" (6-OHDA) lesion is a commonly used model of ADHD in rat. However, a comprehensive assessment of ADHD-like symptoms is still missing, and data in mouse remain largely unavailable. Our aim was to analyse symptoms of ADHD in the mouse neonatal 6-OHDA model. 6-OHDA mice exhibited the major ADHD-like symptoms, i.e. hyperactivity (open field), attention deficit and impulsivity (five-choice serial reaction time task). Further, the model revealed discrete co-existing symptoms, i.e. anxiety-like (elevated plus maze test) and antisocial (social interaction) behaviours and decreased cognitive functioning (novel object recognition). The efficacy of methylphenidate, a classical psychostimulant used in the treatment of ADHD, was also evaluated. A histological analysis further supports the model validity by indicating dopamine depletion, changes in cortical thickness and abnormalities in anterior cingulate cortex neurons. A principal component analysis of the behaviour profile confirms that the 6-OHDA mouse model displayed good face and predictive validity. We conclude that neonatal dopamine depletion results in behavioural and morphological changes similar to those seen in patients and therefore could be used as a model for studying ADHD pathophysiological mechanisms and identifying therapeutic targets.

Thinners are organic solvents widely used in industrial applications, but they have also been subject to abuse by inhalation for their psychoactive and rewarding properties. In spite of the prevalence of inhalant abuse, the addictive potential and pathways mediating their reinforcing effects are not yet fully understood and thus still subject of further investigations. Here, we assessed in mice the locomotor activity and the ability of paint thinner to reinforce the conditioning in the place preference paradigm following acute (1 day), subchronic (6 weeks) and chronic (12 weeks) exposures to 300 and 600 ppm of thinner vapor. While locomotor activity was unaffected by the different thinner treatments, a positive conditioned place preference to inhaled thinner was found upon subchronic and chronic exposures. To investigate the activated brain structures underlying such behavioural changes, we analyzed the distribution of c-Fos immunoreactivity, a marker for neuronal activation, following acute and repeated exposures to 600 ppm of thinner. Notably, thinner exposure increased the number of c-Fos immunoreactive neurons with increasing duration of exposure in the majority of structures examined; including those typically involved in the processing of rewarding or emotionally stimuli (e.g., ventral tegmental area, core and shell of nucleus accumbens, amygdala, bed nucleus of the stria terminalis, and cingulate cortex), and olfactory stimuli (e.g., piriform cortex and olfactory tubercle). Moreover, prolonged, but not acute thinner inhalation significantly increased c-Fos immunoreactivity in all hippocampal subregions. Taken together, the expanded distribution of thinner-induced c-Fos expression may underlie the observed positive reinforcement upon long-term thinner inhalation., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Recently, a number of studies have demonstrated the profound relationship between gut microbiota (GM) alterations and behavioral changes. Glyphosate-based herbicides (GBH) have been shown to induce behavioral impairments, and it is possible that they mediate the effects through an altered GM. In this study, we investigated the toxic effects of GBH on GM and its subsequent effects on the neurobehavioral functions in mice following acute, subchronic and chronic exposure to 250 or 500 mg/kg/day. The effect of these acute and repeated treatments was assessed at the behavioral level using the open field, the elevated plus maze, the tail suspension and splash tests. Then, mice were sacrificed and the intestinal samples were collected for GM analysis. Subchronic and chronic exposure to GBH induced an increase of anxiety and depression-like behaviors. In addition, GBH significantly altered the GM composition in terms of relative abundance and phylogenic diversity of the key microbes. Indeed, it decreased more specifically, Corynebacterium, Firmicutes, Bacteroidetes and Lactobacillus in treated mice. These data reinforce the essential link between GM and GBH toxicity in mice and suggest that observed intestinal dysbiosis could increase the prevalence of neurobehavioral alterations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Early postnatal damage to the mediodorsal thalamus (MD) produces deficits in cognition and behavior believed to be associated with early prefrontal cortical maldevelopment. We assessed the role of MD afferents during development on the morphological and functional maturation of the prefrontal cortex (PFC) and the basolateral amygdala (BLA). Sprague-Dawley rat pups (n = 56) received a bilateral electrolytic lesion of the MD or a MD Sham lesion on postnatal day 4. 7 weeks later, all rats were tested in anxiety-related and cognitive paradigms using the elevated plus maze and novel object recognition tests. Following behavioral testing (P70), rats were killed and the baseline expression of C-Fos protein and the number of GABAergic neurons were evaluated in the PFC and the BLA. The dendritic morphology and spine density in the PFC using Golgi-Cox staining was also evaluated. Adult rats with early postnatal bilateral MD damage exhibited disrupted recognition memory and increased anxiety-like behaviors. The lesion also caused a significant diminution of C-Fos immunolabeling and an increase of the number of GABAergic neurons in the PFC. In the BLA, the number of GABAergic neurons was significantly reduced, associated with an increase in C-Fos immunolabeling. Furthermore, in the PFC the lesion induced a significant reduction in dendritic branching and spine density. Our data are consistent with the hypothesis that the MD plays a role in the development of the PFC and, therefore, may be a good animal model to investigate cognitive symptoms associated with schizophrenia.

In the present work, we investigated developmental toxicity of Paraquat (PQ), from the 1st or 6th day of mating and throughout the gestation period. We have examined several parameters, including toxicity indices, reproductive performance, sensorimotor development, as well as anxiety and cognitive performance of the offspring. Our results showed that exposure to 20mg/kg of Paraquat during the first days of pregnancy completely prevents pregnancy in treated mice, but from the 6th day of pregnancy, an alteration in fertility and reproductive parameters was observed. In offspring, the PQ was responsible for an overall delay of innate reflexes and a deficit in motor development. All exposed animals showed a decrease in the level of locomotor activity, increased levels of anxiety-like behavior and pronounced cognitive impairment in adulthood. These results demonstrated that Paraquat led to the onset of many behavioral changes that stem from the impairment of neuronal developmental processes in prenatally exposed mice., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The circadian clock is thought to adjust retinal sensitivity to ambient light levels, yet the involvement of specific clock genes is poorly understood. We explored the potential role of the nuclear receptor subfamily 1, group D, member 1 (REV-ERBα; or NR1D1) in this respect. In light-evoked behavioral tests, compared with wild-type littermates, Rev-Erbα -/- mice showed enhanced negative masking at low light levels (0.1 lx). Rev-Erbα -/- mouse retinas displayed significantly higher numbers of intrinsically photosensitive retinal ganglion cells (ipRGCs; 62% more compared with wild-type) and more intense melanopsin immunostaining of individual ipRGCs. In agreement with a pivotal role for melanopsin, negative masking at low light intensities was abolished in Rev-Erbα -/- Opn4 -/- (melanopsin gene) double-null mice. Rev-Erbα -/- mice showed shortened latencies of both a and b electroretinogram waves, modified scotopic and photopic b-wave and scotopic threshold responses, and increased pupillary constriction, all of which suggested increased light sensitivity. However, wild-type and Rev-Erbα -/- mice displayed no detectable differences by in vivo fundus imaging, retinal histology, or expression of cell type-specific markers for major retinal cell populations. We conclude that REV-ERBα plays a major role in retinal information processing, and we speculate that REV-ERBα and melanopsin set sensitivity levels of the rod-mediated ipRGC pathway to coordinate activity with ambient light.-Ait-Hmyed Hakkari, O., Acar, N., Savier, E., Spinnhirny, P., Bennis, M., Felder-Schmittbuhl, M.-P., Mendoza, J., Hicks, D. Rev-Erbα modulates retinal visual processing and behavioral responses to light., (© FASEB.)

Early insults to the thalamus result in functional and/or structural abnormalities in the cerebral cortex. However, differences in behavioral and cognitive changes after early insult are not well characterized. The present study assessed whether early postnatal damage to mediodorsal nucleus of the thalamus (MD), reciprocally interconnected with the prefrontal cortex, causes behavioral and cognitive alterations in young adult rats. Rat pups at postnatal day 4 received bilateral electrolytic lesion of MD, or a MD Sham lesion or were anesthetized controls; on recovery they were returned to their mothers until weaning. Seven weeks later, all rats were tested with the following behavioral and cognitive paradigms: T-maze test, open field test, actimetry, elevated plus maze test, social interactions test and passive avoidance test. Rats with bilateral MD damage presented with disrupted recognition memory, deficits in shifting response rules, significant hypoactivity, increased anxiety-like behavior, deficits in learning associations as well as decreased locomotor activity, and reduced social interactions compared to MD Sham lesion and anesthetized Control rats. The lesion also caused significant decreases in pyramidal cell density in three frontal cortex regions: medial infralimbic cortex, dorsolateral anterior cortex, and cingulate Cg1 cortex. The present findings suggest a functional role for MD in the postnatal maturation of affective behavior. Further some of the behavioral and cognitive alterations observed in these young adult rats after early MD lesion are reminiscent of those present in major psycho-affective disorders, such as schizophrenia in humans., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Fenugreek (Trigonella foenum graecum (L.)), is a medicinal plant whose seeds and leaves are widely used in Moroccan traditional medicine. Consumption of fenugreek seeds during pregnancy has been associated with a range of congenital malformations, including hydrocephalus, anencephaly and spina bifida. In previous work we have shown that exposure of pregnant mice to aqueous extract of fenugreek seeds (AEFS) leads to reduced litter size, intrauterine growth retardation, and malformations. However, there have been no studies to date of its longer-term neurobehavioral effects. We investigated these effects in prenatally exposed mice., Materials and Methods: Pregnant females were exposed to 0, 500 or 1000 mg/kg/day AEFS, by gavage, for the whole period of gestation. Pups body weight was measured at 1, 7, 14, 21 and 28 day of age. Behavior of progeny was evaluated three weeks after birth using the open field, the rotarod test and the continuous alternation task by the T-maze. At 28 postnatal day age, brain of progeny was removed and cut for histological evaluation., Results: The progeny of exposed mice displayed reduced body weight at birth (1000 mg/kg group: 27%; 500 mg/kg group: 32%) and reduced brain weight (10% in both treated groups). Both males and females mice prenatally exposed to AEFS displayed a significant decrease in the locomotor activity, in the boli deposits during the open field test and in motor coordination. These results seem to show that exposure to AEFS induces a depressive effect in the offspring. Assessment on a continuous alternation T-maze test showed a significant reduction in successful spontaneous alternations in males and females but only in the 1000 mg/kg group., Conclusion: These results suggest that prenatal exposure of mice to high dose of fenugreek seeds causes growth retardation and altered neurobehavioral performance in the post-weaning period in both male and female., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)