CB1 receptor deficiency decreases wheel-running activity: consequences on emotional behaviours and hippocampal neurogenesis.

Chronic voluntary wheel-running activity has been reported to hypersensitise central CB1 receptors in mice. On the other hand, pharmacological findings suggest that the CB1 receptor could be involved in wheel-running behaviour and in running-induced neurogenesis in the hippocampus. We analysed wheel-running behaviour for 6 weeks and measured its consequences on hippocampal neurogenesis in CB1 knockout (CB1(-/-)) animals, compared to wild-type (CB1(+/+)) littermates. Because wheel running has been shown to affect locomotor reactivity in novel environments, memory for aversive events and depression-like behaviours, we also assessed these behaviours in control and running CB1(+/+) and CB1(-/-) mice. When compared with running CB1(+/+) mice, the distance covered weekly by CB1(-/-) mice was decreased by 30-40%, an observation accounted for by decreased time spent and maximal velocity on the wheels. Analyses of running distances with respect to the light/dark cycle revealed that mutant covered less distance throughout both the inactive and the active phases of that cycle. Locomotion in an activity cage, exploration in an open field, and immobility time in the forced swim test proved insensitive to chronic wheel running in either genotype. Wheel running, per se, did not influence the expression and extinction of cued fear memory but counteracted in a time-dependent manner the deficiency of extinction measured in CB1(-/-) mice. Hippocampal neurogenesis, assessed by doublecortin labelling of immature neurons in the dentate gyrus, was lowered by 40% in control CB1(-/-) mice, compared to control CB1(+/+) mice. Although CB1(-/-) mice ran less than their wild-type littermates, the 6-week running protocol increased neurogenesis to similar extents (37-39%) in both genotypes. This study suggests that mouse CB1 receptors control wheel running but not its neurogenic consequences in the hippocampus.

Dubreucq S ，Koehl M ，Abrous DN ，Marsicano G ，Chaouloff F ... -  《-》

Voluntary exercise induces anxiety-like behavior in adult C57BL/6J mice correlating with hippocampal neurogenesis.

Fuss J ，Ben Abdallah NM ，Vogt MA ，Touma C ，Pacifici PG ，Palme R ，Witzemann V ，Hellweg R ，Gass P ... -  《-》

Prolonged voluntary wheel-running stimulates neural precursors in the hippocampus and forebrain of adult CD1 mice.

Voluntary wheel-running induces a rapid increase in proliferation and neurogenesis by neural precursors present in the adult rodent hippocampus. In contrast, the responses of hippocampal and other central nervous system neural precursors following longer periods of voluntary physical activity are unclear and are an issue of potential relevance to physical rehabilitation programs. We investigated the effects of a prolonged, 6-week voluntary wheel-running paradigm on neural precursors of the CD1 mouse hippocampus and forebrain. Examination of the hippocampus following 6 weeks of running revealed two to three times as many newly born neurons and 60% more proliferating cells when compared with standard-housed control mice. Among running mice, the number of newly born neurons correlated with the total running distance. To establish the effects of wheel-running on hippocampal precursors dividing during later stages of the prolonged running regime, BrdU was administered after 3 weeks of running and the BrdU-retaining cells were analyzed 18 days later. Quantifications revealed that the effects of wheel-running were maintained in late-stage proliferating cells, as running mice had two to three times as many BrdU-retaining cells within the hippocampal dentate gyrus, and these yielded greater proportions of both mature neurons and proliferative cells. The effects of prolonged wheel-running were also detected beyond the hippocampus. Unlike short-term wheel-running, prolonged wheel-running was associated with higher numbers of proliferating cells within the ventral forebrain subventricular region, a site of age-associated decreases in neural precursor proliferation and neurogenesis. Collectively, these findings indicate that (i) prolonged voluntary wheel-running maintains an increased level of hippocampal neurogenesis whose magnitude is linked to total running performance, and (ii) that it influences multiple neural precursor populations of the adult mouse brain.

Bednarczyk MR ，Aumont A ，Décary S ，Bergeron R ，Fernandes KJ ... -  《-》

Running increases neurogenesis without retinoic acid receptor activation in the adult mouse dentate gyrus.

Both vitamin A deficiency and high doses of retinoids can result in learning and memory impairments, depression as well as decreases in cell proliferation, neurogenesis and cell survival. Physical activity enhances hippocampal neurogenesis and can also exert an antidepressant effect. Here we elucidate a putative link between running, retinoid signaling, and neurogenesis in hippocampus. Adult transgenic reporter mice designed to detect ligand-activated retinoic acid receptors (RAR) or retinoid X receptors (RXR) were used to localize the distribution of activated RAR or RXR at the single-cell level in the brain. Two months of voluntary wheel-running induced an increase in hippocampal neurogenesis as indicated by an almost two-fold increase in doublecortin-immunoreactive cells. Running activity was correlated with neurogenesis. Under basal conditions a distinct pattern of RAR-activated cells was detected in the granule cell layer of the dentate gyrus (DG), thalamus, and cerebral cortex layers 3-4 and to a lesser extent in hippocampal pyramidal cell layers CA1-CA3. Running did not change the number of RAR-activated cells in the DG. There was no correlation between running and RAR activation or between RAR activation and neurogenesis in the DG of hippocampus. Only a few scattered activated retinoid X receptors were found in the DG under basal conditions and after wheel-running, but RXR was detected in other areas such as in the hilus region of hippocampus and in layer VI of cortex cerebri. RAR agonists affect mood in humans and reduce neurogenesis, learning and memory in animal models. In our study, long-term running increased neurogenesis but did not alter RAR ligand activation in the DG in individually housed mice. Thus, our data suggest that the effects of exercise on neurogenesis and other plasticity changes in the hippocampal formation are mediated by mechanisms that do not involve retinoid receptor activation.

Aberg E ，Perlmann T ，Olson L ，Brené S ... -  《-》

Physical exercise leads to rapid adaptations in hippocampal vasculature: temporal dynamics and relationship to cell proliferation and neurogenesis.

Increased levels of angiogenesis and neurogenesis possibly mediate the beneficial effects of physical activity on hippocampal plasticity. This study was designed to investigate the temporal dynamics of exercise-induced changes in hippocampal angiogenesis and cell proliferation. Mice were housed with a running wheel for 1, 3, or 10 days. Analysis of glucose transporter Glut1-positive vessel density showed a significant increase after 3 days of wheel running. Cell proliferation in the dentate gyrus showed a trend towards an increase after 3 days of running and was significantly elevated after 10 days of physical exercise. Ten days of wheel running resulted in a near-significant increase in the number of immature neurons, as determined by a doublecortin (DCX) staining. In the second part of the study, the persistence of the exercise-induced changes in angiogenesis and cell proliferation was determined. The running wheel was removed from the cage after 10 days of physical activity. Glut-1 positive vessel density and hippocampal cell proliferation were determined 1 and 6 days after removal of the wheel. Both parameters had returned to baseline 24 h after cessation of physical activity. The near-significant increase in the number of DCX-positive immature neurons persisted for at least 6 days, indicating that new neurons formed during the period of increased physical activity had survived. Together these experiments show that the hippocampus displays a remarkable angiogenic and neurogenic plasticity and rapidly responds to changes in physical activity.

Van der Borght K ，Kóbor-Nyakas DE ，Klauke K ，Eggen BJ ，Nyakas C ，Van der Zee EA ，Meerlo P ... -  《-》