Cancer-related cognitive impairment (CRCI) is increasingly recognized in patients with solid tumors and treated with immunotherapy but the mechanisms linking tumor immune status, systemic inflammation and neurocognitive dysfunction remain unclear. Here, we investigate in syngeneic immuno-desert (B16F10), immuno-excluded (B16F10 Ova) and immuno-inflamed (MC38) tumor-bearing immunocompetent male mice treated with anti-PD-1/anti-PD-L1 immune checkpoint inhibitors, behaviors, brain immune cells infiltration/homeostasis and neuroinflammation. Immuno-excluded and immuno-inflamed cancers impaired short-term memory as well as anxiety- and resignation-like behaviors, the anxiety-like behavior being correlated with an extended tumor “immunoscore”. Both immuno-desert and immuno-inflamed tumors evoked blood MCP-1/TNF- blood cytokines and meningeal STING-dependent transcriptional reprogramming with distinct B cell- and myeloid/T cell-dominated signatures. Immuno-inflamed MC38 tumors more specifically generated IL-6/IL-17 systemic inflammatory reaction associated with brain barriers permeability, ventriculomegaly, leptomeningeal myeloid cell accumulation, reactive hippocampal microglia and reduced neurogenesis. Anti-PD-1 and anti-PD-L1 did not affect behavior in cancer-naïve mice but exacerbated CRCI in a tumor-immune-status-dependent manner, increasing CD3+T cell infiltration, vascular inflammation, CCL19 expression and impacting progenitor proliferation in the dentate gyrus of the Hippocampus. Notably, anti-PD-L1 promoted BBB permeability, expanded circulating γδT cells and their accumulation at blood–brain barriers. γδT cell immunoneutralization prevented cognitive and anxiety-like deficits without impairing anti-PD-L1 efficacy. These findings identify barrier- and meningeal-centered mechanisms, and γδT cell-dependent pathways, as a central driver of immuno-inflamed- and PD-L1-related CRCI and provide new biomarkers and targets for neuroprotective strategies in cancer patients treated by immunotherapy.

Cerebellar extinction lesions can manifest themselves with cerebellar motor and cerebellar cognitive affective syndromes. For investigation of the functions of the cerebellum and the pathogenesis of cerebellar diseases, particularly hereditary neurodegenerative cerebellar ataxias, various cerebellar mutant mice are used. The Lurcher mouse is a model of selective olivocerebellar degeneration with early onset and rapid progress. These mice show both motor deficits as well as cognitive and behavioral changes i.e., pathological phenotype in the functional domains affected in cerebellar patients. Therefore, Lurcher mice might be considered as a tool to investigate the mechanisms of functional impairments caused by cerebellar degenerative diseases. There are, however, limitations due to the particular features of the neurodegenerative process and a lack of possibilities to examine some processes in mice. The main advantage of Lurcher mice would be the expected absence of significant neuropathologies outside the olivocerebellar system that modify the complex behavioral phenotype in less selective models. However, detailed examinations and further thorough validation of the model are needed to verify this assumption. Not applicable.

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.

Anxiety-related behaviors in mice are often assessed over short periods starting immediately after introducing the animals in a dedicated apparatus. In these usual conditions (5-10 min periods), the cerebellar Lurcher mutants showed disinhibited behaviors characterized by abnormally high exploration of the aversive areas in the elevated plus-maze test. We nevertheless observed that this disinhibition sharply weakened after 10 min. We therefore decided to further investigate the influence of the disinhibition on the intrinsic and anxiety-related exploratory behaviors in Lurcher mice, with a special focus on familiarization effects. To this end, we used an innovative apparatus, the Dual Maze, permitting to tune the familiarization level of animals to the experimental context before they are faced with more (open configuration of the device) or less (closed configuration of the device) aversive areas. Chlordiazepoxide administration in BALB/c mice in a preliminary experiment confirmed both the face and the predictive validity of our device as anxiety test and its ability to measure exploratory motivation. The results obtained with the Lurcher mice in the open configuration revealed that 20 min of familiarization to the experimental context abolished the behavioral abnormalities they exhibited when not familiarized with it. In addition, their exploratory motivation, as measured in the closed configuration, was comparable to that of their non-mutant littermates, whatever the level of familiarization applied. Exemplifying the interest of this innovative device, the results we obtained in the Lurcher mutants permitted to differentiate between the roles played by the cerebellum in exploratory motivation and stress-related behaviors.

Earth's gravity acts both as a mechanical stimulus on the body and as a sensory stimulus to the vestibular organ, which is transmitted into the brain. The vestibular system has been recently highlighted as the cornerstone of the multisensory cortex and of the dorsal hippocampus related to spatial cognition. Consequently, we have hypothesized that the vestibular sensory perception of gravity by the otoliths might also play a crucial role during the first stages of development in both sensorimotor and cognitive functions and the construction and perception of the 'self' and related functions of orientation and navigation. We have investigated an original mouse model (Head Tilted mice, B6Ei.GL-Nox3het/J) suffering from a selective congenital absence of vestibular otolithic gravisensors. We report that mouse pups suffered from a delay in the acquisition of sensorimotor reflexes, spatial olfactory guidance, path integration, and ultrasonic communication, while maternal care remained normal. We demonstrate that development has a critical period dependent on the vestibular otolithic sensory perception of gravity, probably temporally between the somesthetic and visual critical periods. The symptoms expressed by the congenital otolithic-deficient mice are similar to validated mouse models of autism and highlight the significance of vestibular graviception in the pathophysiology of development.

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.

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.

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.

The cerebellum is a structure of the central nervous system involved in balance, motor coordination, and voluntary movements. The elementary circuit implicated in the control of locomotion involves Purkinje cells, which receive excitatory inputs from parallel and climbing fibers, and are regulated by cerebellar interneurons. In mice as in human, the cerebellar cortex completes its development mainly after birth with the migration, differentiation, and synaptogenesis of granule cells. These cellular events are under the control of numerous extracellular matrix molecules including pleiotrophin (PTN). This cytokine has been shown to regulate the morphogenesis of Purkinje cells ex vivo and in vivo via its receptor PTPζ. Since Purkinje cells are the unique output of the cerebellar cortex, we explored the consequences of their PTN-induced atrophy on the function of the cerebellar neuronal circuit in mice. Behavioral experiments revealed that, despite a normal overall development, PTN-treated mice present a delay in the maturation of their flexion reflex. Moreover, patch clamp recording of Purkinje cells revealed a significant increase in the frequency of spontaneous excitatory postsynaptic currents in PTN-treated mice, associated with a decrease of climbing fiber innervations and an abnormal perisomatic localization of the parallel fiber contacts. At adulthood, PTN-treated mice exhibit coordination impairment on the rotarod test associated with an alteration of the synchronization gait. Altogether these histological, electrophysiological, and behavior data reveal that an early ECM disruption of PTN composition induces short- and long-term defaults in the establishment of proper functional cerebellar circuit.

The Lurcher mutant mice are characterized by massive cerebellar cortex degeneration. Besides their motor and cognitive disturbances, they exhibit both exaggerated blood corticosterone (CORT) level surge and behavioral disinhibition when confronted to anxiogenic conditions (i.e. to a potential threat). In this study, we assessed if such physiological and behavioral hyperactivity was also detectable in a fear-eliciting situation (actual threat). For this purpose, the behaviors and CORT level elevations in Lurcher mice were compared with those of littermate controls in the predator exposure test: mice were exposed either to a rat (exposure) or to a brief wave of the experimenter's hand (sham exposure). While the basal CORT concentrations (24h before testing) were not significantly different between mice of both genotypes, the post-exposure ones were higher in Lurcher than in control mice whatever the condition of the experimental design (exposure or sham exposure). Predator exposure did not provoke significant increase of CORT levels whatever the genotype. On the contrary, our data clearly showed that fear-related behaviors of cerebellar mutants facing a real threat were exacerbated in comparison to those of control mice. These results suggest that the cerebellar cortex not only participates to fear conditioning and anxiety but also actively contributes to the modulation of the innate fear-related behaviors.

In patients, cancer and treatments provoke cognitive impairments referred to "chemofog". Here a validated neurobehavioral animal model, the unique way to explore causal direct links between chemotherapy used in clinical practices and brain disorders, allowed investigation of the direct long-term impact of cob-rectal cancer chemotherapy on cognition and cerebral plasticity. Young and aged mice received three injections every 7 days during 2 weeks of 5-fluorouracil either alone (5-FU, 37.5 mg/kg) or in combination with oxaliplatin (3 mg/kg) or with glucose (5%). The long-term effects (from day 24 to day 60) of chemotherapy were tested on emotional reactivity, learning and memory, behavioral flexibility and hippocampal cell plasticity.5-FU (in saline)-treated aged and also young mice exhibited specific altered cognitive flexibility and behavioral hyper-reactivity to novelty, whereas the combination 5-FU (in saline)/oxaliplatin (in glucose) did not provoke any cognitive dysfunction. We thus observed that glucose counteracted 5-FU-induced altered executive functions and hippocampal cell proliferation in vivo, and protected neural stem cells in vitro from toxicity of 5-FU or oxaliplatin. In conclusion, these data suggest that the lasting chemotherapy-induced selective impairment of executive functions, whatever the age, and associated with a reduced number of hippocampal proliferating cells, can be counteracted by co-administration with glucose. (C) 2013 Elsevier Ltd. All rights reserved.

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.

Several studies show that a high proportion of women of childbearing age use drugs, including alcohol.The dangers of prenatal alcoholization have been particularly well studied, unlike those related to neonatal alcoholization, via breastfeeding.Epidemiological data and results obtained with animal models show that alcoholization via breastfeeding has a multifactorial impact which, in addition to causing neuronal losses, disrupts the physiology of the mother, including her hormonal balance, impacting on sleep, behavior and the children's development.Alcohol consumption is not formally contraindicated during lactation, while it is during pregnancy.

Stress is one of the prominent factors driving exploration showed by rodents in behavioural tests. Such an influence is exacerbated in mice like the Lurcher cerebellar mutants which are hyper reactive to experimental handling. In order to precisely delineate this influence of stress on explorative behaviours, we designed an innovative apparatus (the I maze) existing under two configurations (aversive and less aversive) and permitting to habituate animals more or less to experimental conditions before being tested. Exemplifying the interest of this device, the results we obtained in the Lurcher mutant mice permitted to differentiate between the roles played by the cerebellum in motivation for exploration proper and stress-related behaviours.