Mohamed Bennis

Sensorimotor cortex projections to the ventrolateral and the dorsomedial medulla oblongata in the rat

After small pressure injections of Fluorogold (FG), and Dextran-tetramethylrodamine (DR) into the dorsal motor nucleus of the vagus/nucleus of the solitary tract (DMV/NTS) and the rostral ventrolateral medulla (RVLM), respectively, retrograde FG-labelled cells were found mainly in the sensorimotor cortex; retrograde DR-labelled cells were located in the same cortical areas and in the prefrontal cortex. Double-labelled cells were also found in the sensorimotor cortical areas. These results provide evidence of direct projections from the sensorimotor cortex to the DMV/NTS and RVLM and suggest that somatic cortical areas directly control cardiovascular output during sensory and somatic processes.

Evaluation of the developmental toxicity of the aqueous extract from Trigonella foenum-graecum (L.) in mice.

AIM OF THE STUDY The use of medicinal plant products to treat various ailments is a common practice in many developing countries. However, a lack of information on the adverse effects of these plants raises questions on their safety and possible adverse side effects. This study was undertaken to evaluate the potential toxic effects of fenugreek seeds on pregnant mice and foetal development. MATERIALS AND METHODS Lyophilized aqueous extract from fenugreek seeds (LAE-FS) was administered to mated female mice during the entire period of pregnancy, at doses of 500 and 1000 mg/kg/day. Females were examined for standard parameters of reproductive performance. Foetuses were weighed and examined for externally visible malformations. RESULTS In pregnant females, there were no obvious symptoms of toxicity, LAE-FS-related deaths or macroscopic abnormalities. Developmental toxicity in offspring included an increase in the foetal death rate, a decrease in the litter size, and a reduction in the foetal body weight. In addition there was an increase in the incidence of morphological abnormalities. CONCLUSIONS Based on these results, it was concluded that fenugreek seeds extract may have deleterious toxic effects on reproductive performance and potential teratogenic effects in foetuses.

The developmental neurobehavioral effects of fenugreek seeds on prenatally exposed mice.

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.

Behavioral and cognitive changes after early postnatal lesions of the rat mediodorsal thalamus.

Highlights • Early insult of the mediodorsal thalamus (MD) disturbed cognitive behaviors.• Early MD damage decreased locomotor activity, and reduced social interactions.• Early insult of the MD disturbed postnatal maturation of affective behavior.• The MD is important for prefrontal cortex function during brain maturation.

Haloperidol treatment at pre-exposure phase reduces the disturbance of latent inhibition in rats with neonatal ventral hippocampus lesions

Animals with neonatal ventral hippocampal lesions develop during or after adolescence abnormal behaviors related to schizophrenia such as anxiety and latent inhibition disruption. The aim of this study was to test whether haloperidol injection prior to pre-exposure session in the latent inhibition test would facilitate latent inhibition. Lesioned animals showed a significant decrease in the number and duration of social interactions, a decrease in the marbles buried, a significant increase in locomotor activity, and a disruption of latent inhibition. In the conditioned taste aversion test, injection of haloperidol produced the recovery of latent inhibition. These findings demonstrate that neonatal lidocaine lesion of the ventral hippocampus can induce behavioral changes related to schizophrenia, and injection of haloperidol, when restricted only to a three-day pre-exposure, is sufficient to facilitate latent inhibition.

Clock genes and behavioral responses to light are altered in a mouse model of diabetic retinopathy.

There is increasing evidence that melanopsin-expressing ganglion cells (ipRGCs) are altered in retinal pathologies. Using a streptozotocin-induced (STZ) model of diabetes, we investigated the impact of diabetic retinopathy on non-visual functions by analyzing ipRGCs morphology and light-induced c-Fos and Period 1–2 clock genes in the central clock (SCN). The ability of STZ-diabetic mice to entrain to light was challenged by exposure animals to 1) successive light/dark (LD) cycle of decreasing or increasing light intensities during the light phase and 2) 6-h advance of the LD cycle. Our results show that diabetes induces morphological changes of ipRGCs, including soma swelling and dendritic varicosities, with no reduction in their total number, associated with decreased c-Fos and clock genes induction by light in the SCN at 12 weeks post-onset of diabetes. In addition, STZ-diabetic mice exhibited a reduction of overall locomotor activity, a decrease of circadian sensitivity to light at low intensities, and a delay in the time to re-entrain after a phase advance of the LD cycle. These novel findings demonstrate that diabetes alters clock genes and behavioral responses of the circadian timing system to light and suggest that diabetic patients may show an increased propensity for circadian disturbances, in particular when they are exposed to chronobiological challenges.

Prenatal exposure to fenugreek impairs sensorimotor development and the operation of spinal cord networks in mice.

Fenugreek is a medicinal plant whose seeds are widely used in traditional medicine, mainly for its laxative, galactagogue and antidiabetic effects. However, consumption of fenugreek seeds during pregnancy has been associated with a range of congenital malformations, including hydrocephalus, anencephaly and spina bifida in humans. The present study was conducted to evaluate the effects of prenatal treatment of fenugreek seeds on the development of sensorimotor functions from birth to young adults. Pregnant mice were treated by gavage with 1g/kg/day of lyophilized fenugreek seeds aqueous extract (FSAE) or distilled water during the gestational period. Behavioral tests revealed in prenatally treated mice a significant delay in righting, cliff avoidance, negative geotaxis responses and the swimming development. In addition, extracellular recording of motor output in spinal cord isolated from neonatal mice showed that the frequency of spontaneous activity and fictive locomotion was reduced in FSAE-exposed mice. On the other hand, the cross-correlation coefficient in control mice was significantly more negative than in treated animals indicating that alternating patterns are deteriorated in FSAE-treated animals. At advanced age, prenatally treated mice displayed altered locomotor coordination in the rotarod test and also changes in static and dynamic parameters assessed by the CatWalk automated gait analysis system. We conclude that FSAE impairs sensorimotor and coordination functions not only in neonates but also in adult mice. Moreover, spinal neuronal networks are less excitable in prenatally FSAE-exposed mice suggesting that modifications within the central nervous system are responsible, at least in part, for the motor impairments.

Glyphosate based- herbicide exposure affects gut microbiota, anxiety and depression-like behaviors in mice

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.

Behavioral and Immunohistochemical Study of the Effects of Subchronic and Chronic Exposure to Glyphosate in Mice

Many epidemiological studies have described an adolescent-related psychiatric illness and sensorimotor deficits after Glyphosate based herbicide (GBH) exposure. GBH exposure in animal models of various ages suggests that it may be neurotoxic and could impact brain development and subsequently, behavior in adulthood. However, its neurotoxic effects on adolescent brain remain unclear and the results are limited. The present study was conducted to evaluate the neurobehavioral effects of GBH following acute, subchronic (6 weeks) and chronic (12 weeks) exposure (250 or 500 mg/kg/day) in mice treated from juvenile age until adulthood. Mice were subjected to behavioral testing with the open field (OF), the elevated plus maze, the tail suspension and Splash tests (STs). Their behaviors related to exploratory activity, anxiety and depression-like were recorded. After completion of the behavioral testing, adult mice were sacrificed and the expression of tyrosine hydroxylase (TH) in the substantia nigra pars compacta (SNc) and serotonin (5-HT) in the dorsal raphe nucleus (DRN), the basolateral amygdala (BLA) and the ventral medial prefrontal cortex (mPFC) was evaluated using immunohistochemical procedure. Our results indicate that unlike acute exposure, both subchronic and chronic exposure to GBH induced a decrease in body weight gain and locomotor activity, and an increase of anxiety and depression-like behavior levels. In addition, the immunohistochemical findings showed that only the chronic treatment induced a reduction of TH-immunoreactivity. However, both subchronic and chronic exposure produced a reduction of 5-HT-immunoreactivity in the DRN, BLA and ventral mPFC. Taken together, our data suggest that exposure to GBH from juvenile age through adulthood in mice leads to neurobehavioral changes that stem from the impairment of neuronal developmental processes.

Neonatal 6-OHDA lesion model in mouse induces Attention-Deficit/ Hyperactivity Disorder (ADHD)-like behaviour

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.