Feeding mice with diets containing mercury-contaminated fish flesh from French Guiana: a model for the mercurial intoxication of the Wayana Amerindians

International audienc

Advancing schizophrenia drug discovery : optimizing rodent models to bridge the translational gap

Although our knowledge of the pathophysiology of schizophrenia has increased, treatments for this devastating illness remain inadequate. Here, we critically assess rodent models and behavioural end points used in schizophrenia drug discovery and discuss why these have not led to improved treatments. We provide a perspective on how new models, based on recent advances in the understanding of the genetics and neural circuitry underlying schizophrenia, can bridge the translational gap and lead to the development of more effective drugs. We conclude that previous serendipitous approaches should be replaced with rational strategies for drug discovery in integrated preclinical and clinical programmes. Validation of drug targets in disease-based models that are integrated with translationally relevant end point assessments will reduce the current attrition rate in schizophrenia drug discovery and ultimately lead to therapies that tackle the disease process

The effects of cytotoxic entorhinal lesions and electrolytic medial septal lesions on the acquisition and retention of a spatial working memory task.

Rats with lesions either of medial septal nucleus (MSN) or the entorhinal cortex (ECx) were compared postoperatively with unoperated controls in a discrete-trial, delayed matching-to-position (DMTP) task, conducted on an elevated T-maze. A DMTP trial consisted of two consecutive visits to the maze: an information run and a choice run. The animals were first forced to visit a randomly selected choice arm in the information run. In the choice run, the correct response was to match the choice arm that had been visited on the information run, regardless of whether the information run itself had been rewarded or not. MSN animals failed to succeed in this task, performing at close to chance level throughout training. On the other hand, ECx rats consistently perform at a level comparable with that of unoperated controls; both groups attained more than 90% correct after 192 trials. Long-term retention testing was carried out after an intermission of 4 weeks, when the same task was re-administered to the ECx and unoperated control animals. ECx animals showed significantly less saving than controls in the retention test. In contrast, when the retention interval within a DMTP trial was increased by the imposition of a 20-s delay between the information and choice runs, the ECx group was not selectively affected by this manipulation

Cytosolic hippocampal PKC and aging: Correlation with discrimination performance

Adult and aged mice were submitted to a discrimination task in a radial maze (regular trials), and then to probe trials requiring them to form relational representations. Three weeks later, animals were again tested for regular and probe trials. Following another interval of 3 weeks, individual hippocampal cytosolic calcium-dependent and -independent PKC activities were measured. Performance of aged animals was impaired on probe but not regular trials and aged mice had lower hippocampal cytosolic calcium-dependent and - independent PKC activities than adults. Performance on probe trials was specifically correlated with calcium-dependent PKC activity. This suggests a specific relationship between the ability to form relational representations and hippocampal cytosolic calcium-dependent PKC activity

Knowing which and knowing what: a potential mouse model for age-related human declarative memory decline.

The present study was built on the original report of Eichenbaum et al. [Eichenbaum, H., Fagan, A., Mathews, P. and Cohen, N.J. (1988), Behav. Neurosci., 102, 3531-3542] on the contrasting effects of fornix lesion in different versions of an odour-guided discrimination task in rats, and attempted to extend this into a mouse model for the preferential loss of declarative memory seen in human senescence. Each of the two experiments reported here consisted of a two-stage paradigm, with an initial learning phase followed by a test phase. The information acquired in the first stage was identical in both experiments, i.e. the valence or reward contingency associated with six (three positive and three negative) arms of a radial maze. The only parameter which was varied between Experiment A and B, and also between the two successive stages within each experiment, was the way of presenting the arms to the mice, i.e. either in pairs (simultaneous discriminations) or one at a time (successive go : no-go discrimination). Performance in the first stage demonstrated that our aged mice were impaired in learning concurrent simultaneous discriminations but not successive go/no-go discrimination, thereby resembling that reported in rats with hippocampal damage. Most importantly, our present set of data supports the conclusion that two forms of memory expression for the same piece of acquired experience can be assessed in the same subjects by manipulating the way of presenting two arms that were previously experienced separately. These two forms of memory expressions are differentially affected in aged mice, thereby demonstrating the highly selective and specific deleterious effect of ageing

Cytosolic hippocampal PKC and aging: Correlation with discrimination performance

Adult and aged mice were submitted to a discrimination task in a radial maze (regular trials), and then to probe trials requiring them to form relational representations. Three weeks later, animals were again tested for regular and probe trials. Following another interval of 3 weeks, individual hippocampal cytosolic calcium-dependent and -independent PKC activities were measured. Performance of aged animals was impaired on probe but not regular trials and aged mice had lower hippocampal cytosolic calcium-dependent and - independent PKC activities than adults. Performance on probe trials was specifically correlated with calcium-dependent PKC activity. This suggests a specific relationship between the ability to form relational representations and hippocampal cytosolic calcium-dependent PKC activity

Glucocorticoids can induce PTSD-like memory impairments in mice

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PAI-1 protein is a key molecular effector in the transition from normal to PTSD-like fear memory

International audienceAbstract Moderate stress increases memory and facilitates adaptation. In contrast, intense stress can induce pathological memories as observed in post-traumatic stress disorders (PTSD). A shift in the balance between the expression of tPA and PAI-1 proteins is responsible for this transition. In conditions of moderate stress, glucocorticoid hormones increase the expression of the tPA protein in the hippocampal brain region which by triggering the Erk1/2 MAPK signaling cascade strengthens memory. When stress is particularly intense, very high levels of glucocorticoid hormones then increase the production of PAI-1 protein, which by blocking the activity of tPA induces PTSD-like memories. PAI-1 levels after trauma could be a predictive biomarker of the subsequent appearance of PTSD and pharmacological inhibition of PAI-1 activity a new therapeutic approach to this debilitating condition