Decreased motivational properties of morphine in mouse models of cancerous- or inflammatory-chronic pain: implication of supraspinal neuropeptide FF(2) receptors.

Our main purpose was to evaluate the influence of cancer pain on the rewarding properties of morphine. Opioids are very addictive when used by healthy persons, conversely the occurrence of an opioid addiction seems very low when patients suffering from cancer are treated with morphine. We investigated the reinforcing properties of morphine in the place preference paradigm on a new model of mice suffering from a cancer pain induced by syngenic melanoma cells injected in the hind paw. These data were compared with mice suffering either from a short-term- or a chronic-inflammatory pain induced respectively by injection of carrageenan or complete Freund's adjuvant. Remarkably, mice suffering from cancer pain or chronic inflammatory pain did not develop any preference for the environment associated with the injection of morphine. In mice injected with melanoma cells, the specific binding of [(125)I]EYWSLAAPQRF-NH(2), an agonist of neuropeptide FF(2) receptors, was increased in several brain areas involved in the rewarding properties of opiates, including the shell of the nucleus accumbens, the major islands of Calleja, the ventral endopiriform nucleus and the amygdaloid area. Our study is the first to reveal a modification of morphine rewarding properties under cancer pain in rodents. We postulate that anti-opioid neuropeptides might contribute to the suppression of morphine rewarding effects in this murine model of cancer pain.

Two QTLs located on chromosomes 1 and 5 modulate different aspects of the performance of mice of the B x D Ty RI strain series in the Morris navigation task.

The Morris navigation task is widely used to study spatial abilities in rodents; namely, to analyze the effects of mutations in genetically engineered mice. Although quantitative and Mendelian genetic studies have shown that the variation of these abilities is partly under genetic control, little is known about these genetic factors. In order to analyze the genetic architecture of spatial navigation in mice, a wide genome scan was performed to map the QTLs that control various aspects of the performance, using the RI strain methodology. Latencies to locate the submerged platform across learning sessions and performance to the spatial probe test were analyzed in the 26 strains of the B x D RI series. Both cluster analysis of behavioral measurements and QTL mapping confirmed previous data showing that the escape latencies and the spatial bias rely on two distinct components of the task, controlled by different loci. A QTL on chromosome 1 influenced escape latencies during the four training sessions, whereas another QTL, located on chromosome 5, was shown to control spatial performance at the probe trial and also exhibited epistatic interactions with two other QTLs on chromosomes 2 and 13. The function of these QTLs is examined in the broader context of hippocampal-dependent learning processes and in relation to QTLs already found in similar positions in other behavioral traits.

Behavioral alterations associated with apoptosis and down-regulation of presenilin 1 in the brains of p53-deficient mice.

Presenilin 1 (PS1) expression is repressed by the p53 tumor suppressor. As shown herein, wild-type PS1 is an effective antiapoptotic molecule capable of significantly inhibiting p53-dependent and p53-independent cell death. We analyzed, at the functional and molecular levels, the brains of p53 knockout mice. Surprisingly, we found that lack of p53 expression induces apoptotic brain lesions, accompanied by learning deficiency and behavioral alterations. p53-deficient mice show an unexpected overexpression of p21(waf1) with subsequent down-regulation of PS1 in their brains. This process is progressive and age-dependent. These data indicate that the p53 pathway, besides affecting tumor suppression, may play a major role in regulating neurobehavioral function and cell survival in the brain.

Reversible inactivation of the hippocampal mossy fiber synapses in mice impairs spatial learning, but neither consolidation nor memory retrieval, in the Morris navigation task.

The role played by hippocampal mossy fibers in the learning and memory processes implemented in the Morris swimming navigation task has been studied in C57BL/6 mice by selective and reversible inactivation of mossy fiber synaptic fields by diethyldithiocarbamate. The functional integrity of the mossy fibers proved essential for the storage of the spatial representation on the modifiable synapses of the recurrent collaterals of the CA3 pyramidal cells, whereas it is not necessary for the consolidation and recall of spatial memories. The results suggest that mossy fibers are preferentially involved in new learning. They are consistent with the hypothesis that the hippocampal CA3 region might act as an autoassociation memory.

Radial maze learning using exclusively distant visual cues reveals learners and nonlearners among inbred mouse strains.

Spatial working memory on the radial maze was studied in 8 groups of isogenic mice. The device and procedure were specially designed to prevent the mice from using a response strategy or taking advantage of olfactory trails or other proximal cues. The results showed that the strains of mice were clearly split between those which succeeded (C57BL/6, DBA/2, CB6F1, B6D2F1) and those which failed (NZB, CBA, C3H/HE, BALB/c) to learn the task. A second experiment established that when more extended training was given, the four strains which had performed poorly in experiment 1 still did not improve their performance. In the conclusion, we discuss the possible reasons for the deficits of nonlearners and emphasize the importance of using proper tools to ensure the unambiguous assessment of the cognitive processes underlying behavioral adaptation.

Ontogeny of orientation and spatial learning on the radial maze in mice.

The development of the orientation capacities of C57BL/6 mice has been studied on the radial maze in several procedures allowed to dissociate the different types of cues used by the mouse for solving the task with two intersession delays (2 and 24 hr). The results of the first two studies show that performance is independent of intersession delay regardless of the age of the subject. Mice as early as 23 days old obtain good performances when they can develop an algorithmic strategy or when they dispose of both proximal and distal cues during learning. At 37 days of age, however, mice can efficiently solve the radial maze task with distal cues alone. However, in the third experiment, 23-day-old mice were able to use distal cues for orientation at the end of the learning session if, at the onset, they also had access to proximal cues. These results suggest that, on weaning, mice use several types of information for task performance and that, as they mature, they turn more often to distal cues for orientation.

Neurogenetic basis of cognition: Facts and hypotheses.

In the natural setting, cognitive processes direct behavioural adjustments and sometimes result in behavioural novelties which allow the organism to cope with environmental pressures. The resulting behavioural changes exhibit various forms which are dependent upon different causal factors and cognitive processes. Under long-lasting environmental changes, these behavioural adaptations can become hereditary either through the process of cultural transmission or through genetic mechanisms sensitive to selective forces acting on genotypes. In the last few years, neuroethology and behavioural neurosciences have produced an increasing amount of precise knowledge about brain-behaviour relationships, neurobiological bases of cognitive processes and their development. Unfortunately, the approach to these phenomena is basically normative and does not tell us much about non-pathological determinants of individual variation in cognitive and behavioural competences. In contrast, the differential approach has provided some cases of structural variations in the brain which are under genetic control and thus liable to evolve under selective pressures. Brain size, the ratio of various brain structures to the total brain, the number and density of neurons in various parts of the brain and the variations of neuronal circuitry are potential candidates. This paper reviews them and examines their possible behavioural and cognitive outcomes. The issue here is to examine if and where in the brain potential conditions occur that would allow the genetic evolution of cognitive processes.

Analysis of behavioral and hippocampal variation in congenic albino and pigmented BALB mice.

Mice of the BALB/c strain are widely used in behavioral research in spite of the albino condition, which can obscure brain-behavior relationships. We have developed a pigmented BALB strain, congenic to BALB/c, which could be more appropriate for neurogenetic studies that aim at identifying the effects of neurological mutations on behavior. Comparison of inbred albino and pigmented congenic BALB arising from the same litters provides a valuable tool for detecting the consequences of the albino mutation on behavioral performances. Preliminary results presented here show that the albino condition does not interfere with the development and patterns of connectivity of mossy fibers in the hippocampus. On the other hand, obvious coat color-linked differences appear for locomotor activity and defecation scores in the open field, pigmented mice being unexpectedly less active and more reactive than albino, as if better vision increased their reactions to a novel, anxiogenic environment. Finally, pigmented mice do not show better performances in the radial maze, which confirms that the inability of BALB mice for spatial learning in a highly demanding version of this task cannot be attributed to their inability to process visual information.

A study of behavioral and sensorial bases of radial maze learning in mice.

In order to analyze the various sensorial and behavioral modes implied in learning on a radial maze, three isogenic mice groups (BALB/C, C57BL/6, and CB6F1) were subjected to four different learning procedures, each ending with a probe test. These four procedures examined the use of radial strategies and allowed to dissociate the use of olfactory and spatial cues. Results showed that all mice preferred to use a radial strategy. When the confinement procedure rendered the use of a radial strategy impossible, BALB/C mice were incapable of establishing spatial orientation but were able to learn the task by using olfactory cues. C57BL/6 mice, on the other hand, seemed to use spatial cues exclusively, while the CB6F1 hybrids showed a high degree of plasticity, using either type of information. These strain-specific differences point out the heterogeneity of the processes called into play during radial maze learning and show that unless olfactory cues are carefully controlled they can account for choice accuracy in some mice.

Spontaneous exploration, response plus position learning and hippocampal mossy fibre distribution: A correlational study.

Forty-eight mice from twelve isogenic groups were tested in two different behavioral tests. The first test was a non-reinforced exploration of a Y-maze and the second was a response plus position learning followed by reversal learning in a T-maze. Behavioral results were correlated with the size of the area occupied by the various mossy fibre synaptic sub-fields in the hippocampus as revealed by Timm staining. The analysis of results showed that mice with a large suprapyramidal mossy fibre area tended to use a somewhat rigid motor response strategy during the initial exploration of the Y-maze, that they easily learned the response plus position task in the T-maze, but proved unable to quickly inhibit that learned response during the reversal task. On the other hand, mice with a large intra-infrapyramidal synaptic field displayed greater ability to cope with a situation including novelty or constraint elements.

Behavioural strategies, sensorial processes and hippocampal mossy fibre distribution in radial maze performance in mice.

Eight isogenic mice groups (6 inbred strains and 2 F1 hybrid generations) were tested on an eight-arm radial maze, using either a procedure of confinement (C) or a non-confinement (NC) to the central platform between trials, in order to control for the use of response strategies in learning. On the 6th day of training, the spatial surrounding was impoverished by removing the most salient visual cues of the room; thus allowing testing for the effective use of spatial cues during learning. Results showed that learning profiles and performance levels varied between strains within each procedure. These variations could correspond to a heterogeneity of the underlying perceptual processes involved in learning, since only some strains in each procedure were disturbed by the removal of spatial cues. Correlations between behavioural results and the distribution of mossy fibres in the hippocampus were analysed. The intercorrelation matrix revealed that correlations between the size of the infra-intrapyramidal synaptic field (IIP-MF) and some behavioural indices occurred only during the first trial on the maze, whatever the procedure. Learning performances on the 5th day of training did not correlate with any hippocampal measure. When the spatial surrounding was impoverished, on the 6th day of training, correlations with mossy fibres appeared only in the confinement procedure.

Hybrid vigour and maternal environment in mice. I. Body and brain growth.

Ovarian grafting and surrogate fostering were used to manipulate the pre- and postnatal maternal environments, respectively, in order that the inbred mouse strains BALB/c and C57BL/6J and their reciprocal F1 hybrids experienced either an inbred or an F1 hybrid environment pre- and/or postnatally. Results revealed sizeable heteroric as well as maternal environmental effects on birth, weaning and 100-day body weights as well as on brain weight at 100 days. The maternal environmental effect on brain weight was mediated by its effect on body weight, but there was heterosis for brain weights even when body weight was taken into account. At birth and weaning, inbreds appeared to benefit more from the hybrid maternal environment than did hybrids, but we found no evidence of increased variability of inbreds compared to hybrids (homeostasis) within experimental conditions.

Hybrid vigour and maternal environment in mice. II. Water escape learning, open-field activity and spatial memory.

A combination of ovarian grafting and fostering was used to study the effects of pre- and postnatal maternal factors on adult behaviour. Inbred mice (BALB/c and C57BL/6) and F1 hybrids were compared to assess differential sensitivity to early maternal effects. In addition to the peculiar behavioural profile of BALB mice, results revealed the existence of a cognitive process in mice and confirmed the greater ability of F1 mice to adopt efficient escape strategies. Only postnatal maternal factors were shown to exert long lasting effects on behaviour, appearing to affect the general ability to react to a new situation rather than specific psychological functions. F1 hybrids proved less sensitive to such effects than inbred mice.

Hybrid vigour and maternal environment in mice. III. Hippocampal mossy fibres and behaviour.

Inbred BALB/c and C57BL/6 mice as well as their F1 hybrids were reared in either an inbred or hybrid maternal environment prenatally and/or postnatally, and were later tested for several behaviours prior to histological study of the brain at 100 days after birth. Whereas measures of spatial memory showed hybrid vigour or overdominance, measures of hippocampal mossy fibres showed intermediate inheritance. Brain-behaviour correlations within a strain were generally very small, and effects of maternal environment on hippocampal morphology were not significant.

Genetic variation, hippocampal mossy fibres distribution, novelty reactions and spatial representation in mice.

It is now well established that variation in hippocampal circuitry correlates with various behavioural measures. In order to formulate more precise hypotheses about the functional role of the supra (SP-MF) and intra-infra mossy fibres (IIP-MF) layers, we investigated their covariation with a large number of behavioural measures in the classic and the spatial open-field taken from a genetically heterogeneous population composed of subjects from 12 isogenic mice groups (9 inbred strains and 3 F1's). The hippocampus-behaviour intercorrelation matrix reveals that behavioural reactions and inferred psychological processes only correlate with IIP-MF. Detailed analysis of correlates shows that IIP-MF positively correlate with locomotor activity, rearings and central sector crossings in the classic open-field and correlate negatively with the short-term habituation index to the objects in the spatial open-field. Surprisingly the memory of the spatial arrangement of a set of objects does not correlate with any hippocampal measure.

Mise en evidence d'effects grand-maternels sur les conduites maternelles de la souris.

Continuous recording of locomotor activity and time spent in the nest were performed on mice during the five first days postpartum. We compared mice of the C57BL/6 inbred strain to mice of the two reciprocal F2's derived from the C57BL/6 and BALB/c parental strains. All animals reared foster pups of the C57BL/6 strain. The results did not show any difference between the three groups for the total amount of time spent in the nest ; this parameter decreases with days. No difference appeared between the C57BL/6 group and the F2 B6CxCB6 group (having a grandmother of the C57BL/6 strain), whereas each of these groups differed significantly from F2 CB6xB6C group (having a grandmother of the BALB/c strain) for the following indices : locomotor activity, mean duration of a stay in the nest, mean duration of an absence from the nest and percentage of nocturnal activity. These results are discussed in terms of grandmaternal effects as far as the variation in the strain of the grandmother is the only factor which can account for these differences in behavior.

Measurements of the behavioral effects of albino mutation in mice (Mus musculus): comparisons of coisogenic inbred and hybrid lines.

The effects of the albino gene on mouse behavior were examined, in particular its possible interactions with nonallelic genes (epistasis). More generally, the possible effects of genetic background (inbreeding depression or hybrid vigor) on the effects of the mutation were also considered. Tasks requiring either predominantly motor or predominantly cognitive capacity were studied for coisogenic albino and pigmented mice from either an inbred strain (C57BL/6 c/c vs. C57BL/6 +/c) or an F1 heterozygous generation (F1 c/c vs. F1 +/c) from a BALB/c X C57BL/6 +/c cross. The results showed a clear albino gene effect in the two lines and provide further evidence that the gene is the effective factor. On the other hand, there was no significant interaction between the mutation and the genotypic group (C57BL/6 or F1), which indicates that the effects of the mutation act approximately in an additive fashion between loci in these groups.