Marc Jamon

Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice.

Several lines of evidence indicate an association between mitochondrial DNA (mtDNA) and the functioning of the nervous system. As neuronal development and structure as well as axonal and synaptic activity involve mitochondrial genes, it is not surprising that most mtDNA diseases are associated with brain disorders. Only one study has suggested an association between mtDNA and cognition, however. Here we provide direct evidence of mtDNA involvement in cognitive functioning. Total substitution of mtDNA was achieved by 20 repeated backcrosses in NZB/BlNJ (N) and CBA/H (H) mice with different mtDNA origins. All 13 mitochondrial genes were expressed in the brains of the congenic quartet. In interaction with nuclear DNA (nDNA), mtDNA modified learning, exploration, sensory development and the anatomy of the brain. The effects of mtDNA substitution persisted with age, increasing in magnitude as the mice got older. We observed different effects with input of mtDNA from N versus H mice, varying according to the phenotypes. Exchanges of mtDNA may produce phenotypes outside the range of scores observed in the original mitochondrial and nuclear combinations. These findings show that mitochondrial polymorphisms are not as neutral as was previously believed.

Role of gravity in the development of posture and locomotion in the neonatal rat

This report describes the early motor behaviour in the neonatal rat in relation with the maturation of sensory and motor elements of the central nervous system (CNS). The role of vestibular information during the week before (E14-21) and the 2 weeks after (P0-15) birth will be considered. There is a rostro-caudal gradient in the maturation of posture and locomotion with a control of the head and forelimbs during the first postnatal week and then a sudden acceleration in the functional maturation of the hindlimb. At birth, the neonatal rat is blinded and deaf; despite the immaturity of the other sensory systems, the animal uses its olfactory system to find the mother nipple. Vestibular development takes place between E8 and P15. Most descending pathways from the brainstem start to reach the lumbar enlargement of the spinal cord a few days before birth (reticulo-, vestibulospinal pathways as well as the serotonergic and noradrenergic projections); their development is not completed until the end of the second postnatal week. At birth, in an in vitro preparation, a locomotor activity can be evoked by perfusing excitatory amino acids and serotonin over the lumbar region. The descending pathways which trigger the activity of the CPG are also partly functional. At the same age both air stepping and swimming can be induced. Complex locomotion such as walking, trotting and galloping start later because it requires the maturation of the vestibular system, descending pathways and postural reflex regulation. The period around birth is critical to properly define how the vestibular information is essential for the structuring of the motor behaviour. Different types of experiments (hypergravity, microgravity) are planned to test this hypothesis.

Early olfactory-induced rhythmic limb activity in the newborn rat.

Locomotor-like rhythmic movements without postural constraints were elicited in newborn rats aged from a few hours to five days, using an olfactory stimulus provided by bedding materials. The rats were held in a sling with the front and the hind legs hanging on each side. The step frequency increased between postnatal days 0 and 4 (P0-P4); the step period was around 1 s at P0 and decreased during the following days. This decrease was larger in the forelimbs (650 ms at P4) than in the hindlimbs (750 ms at P4) and was mainly due to a decrease in stance duration. Both ipsilateral and contralateral legs moved in an alternating pattern. Analysis of the regulation of this pattern when a 1:1 or a 1:2 inter-leg coordination (with double steps) occurred showed that both anterior and posterior locomotion pattern generators were coupled very early. Results are discussed in relation to the locomotor activities studied at this early stage of life in other behavioral situations (swimming and air stepping), and in relation to fictive locomotion induced in vitro.

Behavioural profiling of a murine Charcot–Marie–Tooth disease type 1A model

Different features of motor behaviour were studied on a transgenic mouse model of Charcot–Marie–Tooths disease (CMT). Mutants with 4 or 7 copies of the human PMP22 gene leading to a phenotype significantly close to CMTs disease type 1A were compared with control animals. The aim of the study was to validate this transgenic model and to characterise the impairments occurring in the various lines. Three main types of analysis were performed in 2‐month‐old mice without any peculiar visible deficit: (i) a study of standardised clinical tests (SHIRPA protocol) demonstrated that only a few motor deficits were expressed; (ii) a measurement of general spontaneous activity by means of a commercial video‐tracking system was performed and revealed that the main spontaneous activities were identical in the three lines with, however, some slight localised modifications; and, (iii) by contrast, the three lines respond very differently to the footprints, grip strength, splay test and rotarod test. Even in lines with a significantly limited copy number of the transgene, we observed and quantified impairments. In conclusion, mutants of CMT1A seem to be a very pertinent model of this human pathology and will certainly be useful for therapeutic procedures and for theoretical studies on this disease.

Mice deficient for the close homologue of the neural adhesion cell L1 (CHL1) display alterations in emotional reactivity and motor coordination

Motor and cognitive phenotypes were assessed in mice deficient for the close homologue of the L1 adhesion molecule (CHL1). The CHL1-deficient mice displayed signs of decreased stress and a modification of exploratory behaviour. The mice also showed motor impairments on the Rotarod, but they were able to move as fast as controls in the alleys of a T-maze. The observed changes were assumed to be related to a deficit in attention. In addition, gender differences in CHL1 deficits were found and are discussed in view of a possible interaction with other cell adhesion molecules (CAMs) during development. The results are discussed in relation with motor and cognitive deficits in the human, caused by mutations of the distal part of the chromosome 3 which contains the CHL1 orthologue.

Stress response and humoral immune system alterations related to chronic hypergravity in mice

Spaceflights are known to induce stress and immune dysregulation. Centrifugation, as hindlimb unloading, is a good ground based-model to simulate altered gravity which occurs during space missions. The aim of this study was to investigate the consequences of a long-term exposure to different levels of hypergravity on the stress response and the humoral immunity in a mouse model. For this purpose, adult C57Bl/6J male mice were subjected for 21 days either to control conditions or to 2G or 3G acceleration gravity forces. Corticosterone level and anxiety behavior revealed a stress response which was associated with a decrease of body weight, after 21-day of centrifugation at 3G but not at 2G. Spleen lymphocyte lipopolysaccharide (LPS) responsiveness was diminished by 40% in the 2G group only, whereas a decrease was noted when cells were stimulated with concanavalin A for both 2G and 3G groups (about 25% and 20%, respectively) compared to controls. Pro-inflammatory chemokines (MCP-1 and IP-10) and Th1 cytokines (IFNγ and IL2) were slightly decreased in the 2G group and strongly decreased in the 3G mouse group. Regarding Th2 cytokines (IL4, IL5) no further significant modification was observed, whereas the immunosuppressive cytokine IL10 was slightly increased in the 3G mice. Finally, serum IgG concentration was twice higher whereas IgA concentration was slightly increased (about 30%) and IgM were unchanged in 2G mice compared to controls. No difference was observed in the 3G group with these isotypes. Consequently, functional immune dysregulations and stress responses were dependent of the gravity level.

Age-related changes in the motricity of the inbred mice strains 129/sv and C57BL/6j.

The development of motor skills was studied at different stages in the life of the mouse, focusing on three key aspects of motor development: early rhythmic motor activities prior to the acquisition of quadruped locomotion, motor skills in young adults, and the effect of aging on motor skills. The age-related development pattern was analysed and compared in two strains of major importance for genomic studies (C57Bl6/j and 129/sv). Early rhythmic air-stepping activities by l-dopa injected mice showed similar overall development in both strains; differences were observed with greater beating frequency and less inter-limb coordination in 129/sv, suggesting that 129/sv had a different maturation process. Performance on the rotarod by young adult C57Bl6/j gradually improved between 1 and 3 months, but then declined with age; performance on the treadmill also declined with an age-related increase in fatigability. Overall performance by 129/sv mice was lower than C57Bl6/j, and the age-related pattern of change was different, with 129/sv having relatively stable performance over time. Inter-strain differences and their possible causes, in particular the role of dopaminergic pathways, are discussed together with repercussions affecting mutant phenotyping procedures.

The adaptation of limb kinematics to increasing walking speeds in freely moving mice 129/Sv and C57BL/6.

The kinematics of locomotion was analyzed in two strains of great importance for the creation of mutated mice (C56BL/6 and 129/Sv). Different behavioral situations were used to trigger sequences of movement covering the whole range of velocities in the mice, and the variations of kinematic parameters were analyzed in relation with velocity. Both stride frequency and stride length contributed to the moving speed, but stride frequency was found to be the main contributor to the speed increase. A trot-gallop transition was detected at speed about 70 cm/s, in relation with a sharp shift in limb coordination. The results of this study were consistent with pieces of information previously published concerning the gait analyses of other strains, and provided an integrative view of the basic motor pattern of mice. On the other hand some qualitative differences were found in the movement characteristics of the two strains. The stride frequency showed a higher contribution to speed in 129/Sv than in C57BL/6. In addition, 129/Sv showed a phase shift in the forelimb and hindlimb, and a different position of the foot during the stance time that revealed a different gait and body position during walking. Overall, 129/Sv moved at a slower speed than C57BL/6 in any behavioral situation. This difference was related to a basal lower level of motor activity. The possibility that an alteration in the dopamine circuit was responsible for the different movement pattern in 129/Sv is discussed.

The development of vestibular system and related functions in mammals: impact of gravity

This chapter reviews the knowledge about the adaptation to Earth gravity during the development of mammals. The impact of early exposure to altered gravity is evaluated at the level of the functions related to the vestibular system, including postural control, homeostatic regulation, and spatial memory. The hypothesis of critical periods in the adaptation to gravity is discussed. Demonstrating a critical period requires removing the gravity stimulus during delimited time windows, what is impossible to do on Earth surface. The surgical destruction of the vestibular apparatus, and the use of mice strains with defective graviceptors have provided useful information on the consequences of missing gravity perception, and the possible compensatory mechanisms, but transitory suppression of the stimulus can only be operated during spatial flight. The rare studies on rat pups housed on board of space shuttle significantly contributed to this problem, but the use of hypergravity environment, produced by means of chronic centrifugation, is the only available tool when repeated experiments must be carried out on Earth. Even though hypergravity is sometimes considered as a mirror situation to microgravity, the two situations cannot be confused because a gravitational force is still present. The theoretical considerations that validate the paradigm of hypergravity to evaluate critical periods are discussed. The question of adaption of graviceptor is questioned from an evolutionary point of view. It is possible that graviception is hardwired, because life on Earth has evolved under the constant pressure of gravity. The rapid acquisition of motor programming by precocial mammals in minutes after birth is consistent with this hypothesis, but the slow development of motor skills in altricial species and the plasticity of vestibular perception in adults suggest that gravity experience is required for the tuning of graviceptors. The possible reasons for this dichotomy are discussed.

A reassessment of the random hypothesis in the ocean migration of Pacific salmon

The last stage in open-sea migration, in which Pacific salmon ( Oncorhynchus sp.) return toward their home stream mouth, was formalized as a random search model. The properties of this model were quantified by simulating migration situations where salmon homed either from a single place 1000 km from the coast or from several places randomly dispersed between 1000 and 2000 km from the coast. The accuracy of the timing predicted by this random model was good (the speed of travel averaged 42 km day −1 and 80% of the returns occurred within an interval of 18 days) and was consistent with actual recapture data. The homing success rate varied up to 15% depending mainly on the step length. Further incorporation of local reactions to environmental cues such as compass cues, current flows, or thermal preference into the model considerably increased the search performances, which makes random search a convincing candidate for explaining salmons homing. The possibility that they may return to their home stream by chance in the course of a Neills enviro-regulation migration process is discussed.