Yves Lamberty

Investigation into sex-related differences in locomotor activity, place learning and passive avoidance responding in NMRI mice

Learning abilities of young adult (5-6 weeks) male and female NMRI mice were compared in two tasks involving cognitive functions, namely spatial learning in a water maze and passive avoidance responding. Locomotor activity was also monitored as a putative bias for the results obtained in these learning tests. No sex-related difference was observed either in avoidance responding or in spatial learning using a procedure with the same point of departure throughout testing in the water maze. However, in this test, using a procedure with 3 different points of departure in randomized order day after day, female mice performed better than male mice. The difference was statistically significant on the last acquisition day but was not sustained during a retention trial 72 hr later. Since no sex differences in locomotor activity were observed, the learning effects cannot be attributed to a difference in general activity level.

Spatial processing and emotionality in aged NMRI mice: A multivariate analysis

The goal of this study was to investigate possible relationships between different aspects of behavioural decline in aged (17 months) NMRI mice by a multivariate analysis. These mice presented defects in spatial processing both in place learning in a Morris-type water maze and in spontaneous alternation in a Y-maze, as well as showing changes in their behaviour in the elevated plus maze test of fear/anxiety and open-field ambulation. Data were first factor analysed and then correlated on the basis of variable factor scores. The results showed clearly that age-related behavioural changes were independent of each other except between open-field activity measured over 6 min and spatial learning indices in the Morris-type water maze, in that mice performing poorly in the latter were more active in the open field, and between the ratio open/total arms visited in the elevated plus maze task and locomotor activity during the first 2 min of the open-field test. It is proposed that the notion of an allocentric or locale system cannot be applied unitarily to both spatial learning and spontaneous alternation defects, and that activity levels in the aged mice are task dependent and reflect different underlying factors.

Scopolamine effects on juvenile conspecific recognition in rats: Possible interaction with olfactory sensitivity

The social recognition of a juvenile conspecific by an adult male rat was evaluated as the decrease in investigation time when the same juvenile individual was reintroduced 30min after the first exposure period. The results showed that scopolamine impaired this transient individual recognition. A drop in investigation time was also observed in both tests (first and second exposure), with the same and with different juvenile individuals, in scopolamine treated animals. A second experiment showed that scopolamine disturbed the chemosensory preference for familiar odour observed in the control group. In the light of these two experiments, and according to the chemosensory mediation of social recognition in the rat, it is impossible to rule out a lack of odour discrimination in the absence of social recognition after scopolamine injection.

Simplifying environmental cues in a Morris-type water maze improves place learning in old NMRI mice

Old virgin female NMRI mice aged 17 months were compared with mice aged 3 months for their spatial learning abilities in two versions of the Morris water maze. The first one was a simplified version with a salient configuration of cues comparable to a black/white discrimination and the second one was the classical version of the Morris test with many distal cues surrounding the maze. In the simplified version, old mice presented a slower rate of acquisition and a transient poorer retention compared to young mice. However, old mice achieved a final level of performance statistically comparable to their young counterparts as assessed by latencies to escape onto the concealed platform and by the spatial bias measured in probe trials at intervals during testing. When subsequently subjected to classical Morris maze learning, the same old animals showed marked learning deficits and were persistently impaired in their latencies to escape onto the platform. They presented no spatial bias for the location of the platform in the different probe trials. When the goal was cued at the end of the experiment, the performances of old mice rapidly improved, showing that motivation, motor disabilities, or fatigue and ability to use proximal cues cannot explain the place learning deficit. Our results were discussed in terms of cognitive versus sensory/perceptual disabilities in aged rats and mice.

Scopolamine disrupts visual reversal without affecting the first discrimination

The effect of scopolamine (0.5 mg/kg) was determined in a brightness discrimination test (Y maze) motivated by electrical shocks (escape avoidance). Male adult Sprague Dawley rats were used. Results show that scopolamine impairs significantly the visual reversal without affecting the first brightness discrimination. The qualitative analysis reveals that the anticholinergic drug-induced deficit involves both perseveration, i.e. failure to suppress inappropriate response, and a tendency to adopt a position habit. A parallelism with hippocampal and frontal lobe damage symptoms is discussed and an interpretation in terms of disinhibition and incapacity to solve a more difficult problem is proposed.

Anxiolytic profile of the antiepileptic drug levetiracetam in the Vogel conflict test in the rat.

The novel antiepileptic drug levetiracetam has been shown to reverse anxiogenic effects of benzodiazepine withdrawal in mice tested in an elevated plus-maze without altering the behaviour of normal mice in this model. This could suggest that the effect of levetiracetam is dependent upon the level of stress/anxiety of the animals. Levetiracetam was therefore further examined in another widely used animal model of anxiety, the Vogel conflict test. In the first experiment, water-deprived rats were submitted to a free drinking period (habituation) in a chamber equipped with a bottle of water. Twenty-four hours later, animals were returned to the same chamber but the licks to the water bottle were then punished with a foot shock (0.5 mA, 90 ms). In the second experiment, the procedure was modified by administering a foot shock at the end of the habituation period in order to induce a state of stress/anxiety (conditioned fear/ anticipatory anxiety) for subsequent testing. Levetiracetam (17 and 54 mg/kg) and chlordiazepoxide (5 mg/kg) were administered via the intraperitoneal route. The results indicated that in the first experiment only chlordiazepoxide showed a statistically significant anxiolytic effect. In contrast, in the second experiment, where the shock was given at the end of the habituation period, levetiracetam (54 mg/kg) revealed significant anxiolytic activity similar to chlordiazepoxide. This suggests that levetiracetam may have potential anxiolytic effects and may provide therapeutic benefits to individual with anxiety spectrum disorders.

Lack of synaptic vesicle protein SV2B protects against amyloid-β25–35-induced oxidative stress, cholinergic deficit and cognitive impairment in mice

SV2B is a synaptic protein widely distributed throughout the brain, which is part of the complex vesicle protein machinery involved in the regulation of synaptic vesicle endocytosis and exocytosis, and therefore in neurotransmitters release. The aims of the present work were twofold: (1) phenotype SV2B knockout mice (SV2B KO) in a battery of cognitive tests; and (2) examine their vulnerability to amyloid-β25-35 (Aβ25-35) peptide-induced toxicity. SV2B KO mice showed normal learning and memory abilities in absence of Aβ25-35 injection. SV2B KO mice were protected against the learning deficits induced after icv injection of an oligomeric preparation of amyloid-β25-35 peptide, as compared to wild-type littermates (SV2B WT). These mice failed to show Aβ25-35-induced impairments in a number of cognitive domains: working memory measured by a spontaneous alternation procedure, recognition memory measured by a novel object recognition task, spatial reference memory assessed in a Morris water-maze, and long-term contextual memory assessed in a inhibitory avoidance task. In addition, SV2B KO mice were protected against Aβ25-35-induced oxidative stress and decrease in ChAT activity in the hippocampus. These data suggest that SV2B could be a key modulator of amyloid toxicity at the synaptic site.

Brain catechol-O-methyltransferase (COMT) inhibition by tolcapone counteracts recognition memory deficits in normal and chronic phencyclidine-treated rats and in COMT-Val transgenic mice.

The critical involvement of dopamine in cognitive processes has been well established, suggesting that therapies targeting dopamine metabolism may alleviate cognitive dysfunction. Catechol-O-methyl transferase (COMT) is a catecholamine-degrading enzyme, the substrates of which include dopamine, epinephrine, and norepinephrine. The present work illustrates the potential therapeutic efficacy of COMT inhibition in alleviating cognitive impairment. A brain-penetrant COMT inhibitor, tolcapone, was tested in normal and phencyclidine-treated rats and COMT-Val transgenic mice. In a novel object recognition procedure, tolcapone counteracted a 24-h-dependent forgetting of a familiar object as well as phencyclidine-induced recognition deficits in the rats at doses ranging from 7.5 to 30u2009mg/kg. In contrast, entacapone, a COMT inhibitor that does not readily cross the blood–brain barrier, failed to show efficacy at doses up to 30u2009mg/kg. Tolcapone at a dose of 30u2009mg/kg also improved novel object recognition performance in transgenic mice, which showed clear recognition deficits. Complementing earlier studies, our results indicate that central inhibition of COMT positively impacts recognition memory processes and might constitute an appealing treatment for cognitive dysfunction related to neuropsychiatric disorders.

Difference in scopolamine sensitivity during ageing in rats: dichotomy between behavioural repertoire and learning performances

The effects of different doses of scopolamine in adult and aged rats were compared in two behavioural experiments. The first experiment involved visual reversal learning, while the second experiment investigated individual and social behavioural patterns. Results showed that the same dose of scopolamine was more effective in impairing the reverse discrimination in aged than in adult rats. In contrast, low doses which were effective in modifying behavioural patterns in adults, were inactive in aged rats. This difference in scopolamine sensitivity (supersensitivity versus hyposensitivity), observed between the two types of behaviour, is discussed in relation to age-related functional receptor adaptation, selective changes in muscarinic receptors in the different brain areas and dopaminergic- cholinergic interactions.