A Panax quinquefolius-Based Preparation Prevents the Impact of 5-FU on Activity/Exploration Behaviors and Not on Cognitive Functions Mitigating Gut Microbiota and Inflammation in Mice.

Chemotherapy-related cognitive impairment (CRCI) and fatigue constitute common complaints among cancer patient survivors. Panax quinquefolius has been shown to be effective against fatigue in treated cancer patients. We developed a behavioral C57Bl/6j mouse model to study the role of a Panax quinquefolius-based solution containing vitamin C (Qiseng®) or vitamin C alone in activity/fatigue, emotional reactivity and cognitive functions impacted by 5-Fluorouracil (5-FU) chemotherapy. 5-FU significantly reduces the locomotor/exploration activity potentially associated with fatigue, evokes spatial cognitive impairments and leads to a decreased neurogenesis within the hippocampus (Hp). Qiseng® fully prevents the impact of chemotherapy on activity/fatigue and on neurogenesis, specifically in the ventral Hp. We observed that the chemotherapy treatment induces intestinal damage and inflammation associated with increased levels of Lactobacilli in mouse gut microbiota and increased expression of plasma pro-inflammatory cytokines, notably IL-6 and MCP-1. We demonstrated that Qiseng® prevents the 5-FU-induced increase in Lactobacilli levels and further compensates the 5-FU-induced cytokine release. Concomitantly, in the brains of 5-FU-treated mice, Qiseng® partially attenuates the IL-6 receptor gp130 expression associated with a decreased proliferation of neural stem cells in the Hp. In conclusion, Qiseng® prevents the symptoms of fatigue, reduced chemotherapy-induced neuroinflammation and altered neurogenesis, while regulating the mouse gut microbiota composition, thus protecting against intestinal and systemic inflammation.

The Role of the Cerebellar and Vestibular Networks in Anxiety Disorders and Depression: the Internal Model Hypothesis.

Clinical data and animal studies confirmed that the cerebellum and the vestibular system are involved in emotions. Nowadays, no real consensus has really emerged to explain the clinical symptoms in humans and behavioral deficits in the animal models. We envisage here that the cerebellum and the vestibular system play complementary roles in emotional reactivity. The cerebellum integrates a large variety of exteroceptive and proprioceptive information necessary to elaborate and to update the internal model: in emotion, as in motor processes, it helps our body and self to adapt to the environment, and to anticipate any changes in such environment in order to produce a time-adapted response. The vestibular system provides relevant environmental stimuli (i.e., gravity, self-position, and movement) and is involved in self-perception. Consequently, cerebellar or vestibular disorders could generate « internal fake news¼ (due to lack or false sensory information and/or integration) that could, in turn, generate potential internal model deficiencies. In this case, the alterations provoke false anticipation of motor command and external sensory feedback, associated with unsuited behaviors. As a result, the individual becomes progressively unable to cope with the environmental solicitation. We postulate that chronically unsuited, and potentially inefficient, behavioral and visceral responses to environmental solicitations lead to stressful situations. Furthermore, this inability to adapt to the context of the situation generates chronic anxiety which could precede depressive states.

Cooperation of the vestibular and cerebellar networks in anxiety disorders and depression.

The discipline of affective neuroscience is concerned with the neural bases of emotion and mood. The past decades have witnessed an explosion of research in affective neuroscience, increasing our knowledge of the brain areas involved in fear and anxiety. Besides the brain areas that are classically associated with emotional reactivity, accumulating evidence indicates that both the vestibular and cerebellar systems are involved not only in motor coordination but also influence both cognition and emotional regulation in humans and animal models. The cerebellar and the vestibular systems show the reciprocal connection with a myriad of anxiety and fear brain areas. Perception anticipation and action are also major centers of interest in cognitive neurosciences. The cerebellum is crucial for the development of an internal model of action and the vestibular system is relevant for perception, gravity-related balance, navigation and motor decision-making. Furthermore, there are close relationships between these two systems. With regard to the cooperation between the vestibular and cerebellar systems for the elaboration and the coordination of emotional cognitive and visceral responses, we propose that altering the function of one of the systems could provoke internal model disturbances and, as a result, anxiety disorders followed potentially with depressive states.

Aluminium oxide nanoparticles compromise spatial learning and memory performance in rats.

Recently, the biosafety and potential influences of nanoparticles on central nervous system have received more attention. In the present study, we assessed the effect of aluminium oxide nanoparticles (Al2O3-NPs) on spatial cognition. Male Wistar rats were intravenously administered Al2O3-NP suspension (20 mg/kg body weight/day) for four consecutive days, after which they were assessed. The results indicated that Al2O3-NPs impaired spatial learning and memory ability. An increment in malondialdehyde levels with a concomitant decrease in superoxide dismutase activity confirmed the induction of oxidative stress in the hippocampus. Additionally, our findings showed that exposure to Al2O3-NPs resulted in decreased acetylcholinesterase activity in the hippocampus. Furthermore, Al2O3-NPs enhanced aluminium (Al) accumulation and disrupted mineral element homoeostasis in the hippocampus. However, they did not change the morphology of the hippocampus. Our results show a connection among oxidative stress, disruption of mineral element homoeostasis, and Al accumulation in the hippocampus, which leads to spatial memory deficit in rats treated with Al2O3-NPs.

Impaired spatial performance in cerebellar-deficient Lurcher mice is not associated with their abnormal stress response.

Both humans and laboratory animals suffering from cerebellar lesions exhibit cognitive as well as many emotional and behavioral abnormalities. These latter have been already observed in the cerebellar mutant mice currently used to highlight some aspect of autism spectrum disorders. The aim of this study was to investigate the influence of cerebellar-related stress response abnormalities on spatial learning and memory. Cerebellar-deficient Lurcher mutant mice were exposed to water environment without active escape possibility and then tested for spatial learning in the Morris water maze. As a marker of stress intensity we measured corticosterone in urine. Finally, the volumes of individual components of the adrenal gland were estimated. Though having spatial navigation deficit in the water maze, Lurcher mice preserved a substantial residuum of learning capacity. Lurcher mutants had a higher increase of corticosterone level after exposure to the water environment than wild type mice. We did not observe any decrease of this physiological stress marker between the start and the end of the spatial navigation task, despite significant improvement of behavioral performances. Furthermore, zona fasciculata and zona reticularis of the adrenal cortex as well as the adrenal medulla were larger in Lurcher mice, reflecting high stress reactivity. We conclude that for both genotypes water exposure was a strong stressor and that there was no habituation to the experiment independently to the increasing controllability of the stressor (e.g. ability to find the escape platform). Based on these findings, we suggest that the enhanced stress response to water exposure is not the main factor explaining the spatial deficits in these cerebellar mutant mice.

Evaluation of the impact of the cancer therapy everolimus on the central nervous system in mice.

Cancer and treatments may induce cognitive impairments in cancer patients, and the causal link between chemotherapy and cognitive dysfunctions was recently validated in animal models. New cancer targeted therapies have become widely used, and their impact on brain functions and quality of life needs to be explored. We evaluated the impact of everolimus, an anticancer agent targeting the mTOR pathway, on cognitive functions, cerebral metabolism, and hippocampal cell proliferation/vascular density in mice. Adult mice received everolimus daily for 2 weeks, and behavioral tests were performed from 1 week after the last treatment. Everolimus-treated mice displayed a marked reduction in weight gain from the last day of the treatment period. Ex vivo analysis showed altered cytochrome oxidase activity in selective cerebral regions involved in energy balance, food intake, reward, learning and memory modulation, sleep/wake cycle regulation, and arousal. Like chemotherapy, everolimus did not alter emotional reactivity, learning and memory performances, but in contrast to chemotherapy, did not affect behavioral flexibility or reactivity to novelty. In vivo hippocampal neural cell proliferation and vascular density were also unchanged after everolimus treatments. In conclusion, two weeks daily everolimus treatment at the clinical dose did not evoke alteration of cognitive performances evaluated in hippocampal- and prefrontal cortex-dependent tasks that would persist at one to four weeks after the end of the treatment completion. However, acute everolimus treatment caused selective CO modifications without altering the mTOR effector P70S6 kinase in cerebral regions involved in feeding behavior and/or the sleep/wake cycle, at least in part under control of the solitary nucleus and the parasubthalamic region of the hypothalamus. Thus, this area may represent a key target for everolimus-mediating peripheral modifications, which has been previously associated with symptoms such as weight loss and fatigue.

Effects of corticosterone synthesis inhibitor metyrapone on anxiety-related behaviors in Lurcher mutant mice.

Beyond their motor impairments, the cerebellar Lurcher mutant mice show an alteration of the anxiety-related behaviors we called "behavioral disinhibition". This is characterized by a low avoidance towards the open arms of the elevated plus-maze device paradoxically combined with a dramatic blood corticosterone level rise induced by the exposure to the experimental conditions. The present study was aimed at determining if the disinhibition of the mutants could be caused by their stress-induced high corticosterone rate. For this purpose, we compared the behaviors of Lurcher and control mice in the elevated plus-maze test after injection of either 2-methyl-1.2-di-3-pyridil-1-propanone (metyrapone; 75 mg/kg), a corticosterone synthesis inhibitor, or vehicle alone (Tween 80, 5%). Our results showed that metyrapone, although efficiently reducing their blood corticosterone rate, provoked only modest modifications of the anxiety-related behaviors in mice of both genotypes. As a result, the behavioral distance between the Lurcher and control mice slightly decreased, without being totally abolished. Thus, it seems that the behavioral disinhibition of the mutants is caused only in part by their stress-provoked high corticosterone level. As a complementary hypothesis, we propose that the behavioral disturbances observed in the Lurcher mice also might arise from dysfunctions of the neural pathways connecting the cerebellum with some limbic structures known to be highly involved in the regulation of emotions.

Effects of chlordiazepoxide on the emotional reactivity and motor capacities in the cerebellar Lurcher mutant mice.

It is now well accepted that besides its roles in motor control, the cerebellum is involved in non-motor functions with emotional aspects. Consistent with this view, several studies highlighted that the cerebellar Lurcher mutant mice (+/Lc), with motor impairments, also exhibited altered emotional reactivity, previously interpreted in term of behavioural disinhibition. In this study, we investigated the effects of a classical anxiolytic on such disinhibition. For that, behaviours of +/Lc and control (+/+) mice injected with NaCl or chlordiazepoxide (CDP 5 and 7.5mg/kg) were evaluated in the elevated plus-maze test. The motor impact of the drug (7.5mg/kg only) was also evaluated in the hole-board and unstable platform tests. Our results showed that, compared to the +/+ mice, CDP injection greatly influenced the anxious-related behaviours in the +/Lc mice by reducing their preference to the open areas in the elevated plus-maze test. Furthermore, we found that injection of CDP at the dose of 7.5mg/kg aggravated motor coordination deficit, altered motor learning capabilities in the mutants and provoked equilibrium disturbances in the non-mutant mice in the unstable platform test. These results indicated that CDP was able to reduce behavioural disinhibition in the cerebellar +/Lc mice and were discussed in term of implication of the cerebellar connections into CDP-sensitive neural circuitries involved in both emotional and motor processes.

Effects of harmaline on anxiety-related behavior in mice.

Harmaline (HA) is a beta-carboline commonly known to provoke motor alterations through activation of cells in the inferior olive. In addition, this pharmacological agent also induces cognitive disturbances such as motor and spatial learning impairments. In order to complete and extend these data, we examined the effects of this drug on state anxiety in mice, employing elevated plus maze test. We report here that lower doses of harmaline (5-10 mg/kg) have anxiogenic since higher doses (20 mg/kg) have anxiolytic-like properties. Overall pattern of our behavioral results provides evidence that harmaline also acts on emotional reactivity in mice by influencing their decision making when placed in an anxiogenic situation.

Stress and anxious-related behaviors in Lurcher mutant mice.

Blood corticosterone levels (CORT) were measured before and after the completion of the elevated +-maze test in cerebellar Lurcher mutant and control mice. Consistent with the existence of a much more pronounced activation of the hypothalamo-pituitary-adrenal (HPA) system in the mutants, our results showed that while basal CORT were similar in mutants and controls, the surge of this stress indicator was enhanced in the Lurcher mice after completion of a behavioral test of anxiety. In contrast, at the behavioral level, we also observed that Lurcher exhibited significantly reduced anxiety related indices; they spent a significant greater amount of time in the aversive places of the apparatus and entered them more frequently than non mutant mice. It is proposed that rather than less anxious, the Lurcher mice are less inhibited than controls when placed in anxiogenic situation and that such poor inhibition could be causally related to changes in HPA system regulation. The overall patterns of our behavioral and endocrinological results thereby provided the evidence that cerebellar circuitry is involved in producing changes in physiological and behavioral stress-related emotional responses.