Effects of dietary resveratrol on the sleep-wake cycle in the non-human primate gray mouse lemur (Microcebus murinus)

Converging evidence shows that the non-human primate gray mouse lemur (Microcebus murinus) is ideal for the study of the aging process and for testing the effects of new therapies and dietary interventions on age-associated pathologies. One such dietary supplement is resveratrol (RSV), a dietary polyphenolic compound with several positive effects on metabolic functions and longevity. However, little is known about the effect of RSV on the lemur sleep-wake cycle, which reflects mammalian brain function and health. In the present study, the authors investigated this effect by comparing sleep-wake cycles in adult lemurs based on electroencephalographic (EEG) rhythms. The effect of short-term RSV supplementation on the sleep-wake cycle of mouse lemurs was evaluated in entrained conditions (long-day photoperiods, light:dark 14:10). After 3 wks of RSV supplementation, the animals exhibited a significantly increased proportion of active-wake time, occurring mainly during the resting phase of the sleep-wake cycle (+163%). The increase in active-wake time with RSV supplementation was accompanied by a significant reduction of both paradoxical sleep (-95%) and slow-wave sleep (-38%). These changes mainly occurred during the resting phase of the sleep-wake cycle (RSV supplementation induced negligible changes in active-wake time during the active phase of the sleep-wake cycle). The present data suggest that RSV may be a potent regulator of sleep-wake rhythms and could be of major interest in the study of sleep perturbations associated with aging and neuropathology.     

Cognitive performances are selectively enhanced during chronic caloric restriction or resveratrol supplementation in a primate

Effects of an 18-month treatment with a moderate, chronic caloric restriction (CR) or an oral supplementation with resveratrol (RSV), a potential CR mimetic, on cognitive and motor performances were studied in non-human primates, grey mouse lemurs (Microcebus murinus).Thirty-three adult male mouse lemurs were assigned to three different groups: a control (CTL) group fed ad libitum, a CR group fed 70% of the CTL caloric intake, and an RSV group (RSV supplementation of 200 mg.kg(-1).day(-1)) fed ad libitum. Three different cognitive tests, two motor tests, one emotional test and an analysis of cortisol level were performed in each group.Compared to CTL animals, CR or RSV animals did not show any change in motor performances evaluated by rotarod and jump tests, but an increase in spontaneous locomotor activity was observed in both groups. Working memory was improved by both treatments in the spontaneous alternation task. Despite a trend for CR group, only RSV supplementation increased spatial memory performances in the circular platform task. Finally, none of these treatments induced additional stress to the animals as reflected by similar results in the open field test and cortisol analyses compared to CTL animals.The present data provided the earliest evidence for a beneficial effect of CR or RSV supplementation on specific cognitive functions in a primate. Taken together, these results suggest that RSV could be a good candidate to mimic long-term CR effects and support the growing evidences that nutritional interventions can have beneficial effects on brain functions even in adults.     

The inbreeding strategy of a solitary primate,Microcebus murinus

Inbreeding depression may be common in nature, reflecting either the failure of inbreeding avoidance strategies or inbreeding tolerance when avoidance is costly. The combined assessment of inbreeding risk, avoidance and depression is therefore fundamental to evaluate the inbreeding strategy of a population, that is how individuals respond to the risk of inbreeding. Here, we use the demographic and genetic monitoring of 10 generations of wild grey mouse lemurs (Microcebus murinus), small primates from Madagascar with overlapping generations, to examine their inbreeding strategy. Grey mouse lemurs have retained ancestral mammalian traits, including solitary lifestyle, polygynandry and male‐biased dispersal, and may therefore offer a representative example of the inbreeding strategy of solitary mammals. The occurrence of close kin among candidate mates was frequent in young females (~37%, most often the father) and uncommon in young males (~6%) due to male‐biased dispersal. However, close kin consistently represented a tiny fraction of candidate mates (< 1%) across age and sex categories. Mating biases favouring partners with intermediate relatedness were detectable in yearling females and adult males, possibly partly caused by avoidance of daughter–father matings. Finally, inbreeding depression, assessed as the effect of heterozygosity on survival, was undetectable using a capture–mark–recapture study. Overall, these results indicate that sex‐biased dispersal is a primary inbreeding avoidance mechanism at the population level, and mating biases represent an additional strategy that may mitigate residual inbreeding costs at the individual level. Combined, these mechanisms explain the rarity of inbreeding and the lack of detectable inbreeding depression in this large, genetically diverse population.     

Effects of age on thermoregulatory responses during cold exposure in a nonhuman primate, Microcebus murinus

Cold resistance appears altered with aging. Among existing hypotheses, the impaired capacity in response to cold could be related to an altered regulation of plasma IGF-1 concentration. The combined effects of age and cold exposure were studied in a short-living primate, the gray mouse lemur (Microcebus murinus), which adjusts its energy balance using a daily torpor phase, to avoid high energy cost of normothermia maintenance. Changes in body mass, core temperature, locomotor activity, and caloric intake were monitored under 9-day exposures to 25 degrees C and 12 degrees C in captive animals in winter conditions. Short-term (after 2 days) and long-term (after 9 days) cold-induced changes in IGF-1 levels were also evaluated. In thermoneutral conditions (25 degrees C), general characteristics of the daily rhythm of core temperature were preserved with age. At 12 degrees C, age-related changes were mainly characterized by a deeper hypothermia and an increased frequency of torpor phases, associated with a loss of body mass. A short-term cold-induced decrease in plasma IGF-1 levels was observed. IGF-1 levels returned to basal values after 9 days of cold exposure. No significant effect of age could be evidenced on IGF-1 response. However, IGF-1 levels of cold-exposed aged animals were negatively correlated with the frequency of daily torpor. Responses exhibited by aged mouse lemurs exposed to cold revealed difficulties in the maintenance of normothermia and energy balance and might involve modulations of IGF-1 levels.     

First evidence for relocation of stationary food resources during foraging in a strepsirhine primate (Microcebus murinus)

Field observations suggest that the diet of the Malagasy gray mouse lemur consists not only of non-stationary animal prey (invertebrates or small vertebrates), but also of stationary food resources such as gum or homopteran larvae secretions (HLS). We studied the foraging behavior of five mouse lemurs radiotelemetrically, each during six consecutive nights in the dry season, to explore to which extent they use these food resources and whether there is evidence for their relocation. We found that animals used all three different food categories. Mouse lemurs fed on gums and spent 68.5% (range 20.1-99.7%) of their feeding time eating this item. They were observed eating HLS in 8.4% (range 0-71.5%) of the feeding time and consuming small animals in 8.4% (range 0.3-26%) of their feeding time. The animals relocated stationary feeding sites significantly more frequently than non-stationary ones. They revisited the relocated stationary food sites about five times over the six nights. Furthermore, departure directions when leaving the sleeping site at dusk were not randomly distributed but showed a preferred orientation. Altogether, we provided first evidence for the relocation of stationary food resources in nature and thereby for the potential significance of spatial memory during foraging in a strepsirhine primate.     

Retinal afferents of hypothalamic origin in a prosimian primate: Microcebus murinus. Study using retrograde fluorescent tracers

The central efferent connections to the retina in Microcebus were identified using the retrograde axonal transport of fluorescent dyes. After unilateral intraocular injection of the tracer, two populations of labeled neurons were observed. Fluorescent neurons were located immediately posterior to the optic chiasma, in the anterior part of the arcuate nuclei. In addition, fluorescent neurons were observed in the suprachiasmatic nuclei; the latter pathway appears to close up an anatomical retino-hypothalamo-retinal loop between the suprachiasmatic nucleus and the retina.     

On the relationship between sweet taste and seasonal body weight changes in a primate (Microcebus murinus)

The relationship between obesity and taste, especially sweettaste, has been and is of interest. From this point of viewof a small primate, the lesser mouse lemur (Microcebus murinus),is of particular interest. It goes through a yearly cycle ofphysiological changes, one of which is an extreme variationin body weight of up to 100%. This occurs concomitantly withsignificant changes of the animal's liking for sucrose; measuredby two-bottle preference tests, the threshold for sucrose changesfrom 28–45 in lean to 77–105 mM in obese animals.It is possible that a change in peripheral taste sensitivitymight be the cause for these preference changes. To test thispossibility we studied the ability of M.murinus to taste sucrosewith electrophysiological and conditioned taste aversion techniques.The electrophysiological recordings were obtained from the chordatympani proper nerve in two heavy and three lean animals. Wedid not record any difference between the two groups in theirneural response to a series of sucrose concentrations. Conditionedtaste aversion experiments with 200 mM sucrose as conditioningstimulus and 50 and 200 mM sucrose as test stimuli gave similarresults. No difference was found between three heavy and fourlean animals; both groups rejected the sucrose concentrations.The results support the notion that the seasonal variationsin preference threshold to sucrose were unrelated to the abilityof M.murinus to taste sucrose.     

Effects of dietary calorie restriction or exercise on the PI3K and Ras signaling pathways in the skin of mice

Weight control by exercise and dietary calorie restriction (DCR) has been associated with reduced cancer risk, but the underlying mechanisms are not well understood. This study was designed to compare the effects of weight loss by increasing physical activity or decreasing calorie intake on tumor promoter-induced Ras-MAPK and PI3K-Akt pathways. SENCAR mice were randomly assigned to one of the following five groups: ad libitum-fed sedentary control, ad libitum-fed exercise (AL+Exe), exercise but pair-fed at the amount as controls (PF+Exe), 20% DCR, and 20% DCR plus exercise (DCR+Exe). After 10 weeks, body weight and body fat significantly decreased in the groups of DCR, DCR+Exe, and PF+Exe when compared with the controls. AL+Exe did not induce weight loss due to, at least in part, increased food intake. Plasma IGF-1 levels reduced significantly in DCR and DCR+Exe but not PF+Exe. The protein H-Ras and activated Ras-GTP significantly decreased in TPA-induced skin tissues of DCR-fed mice but not exercised mice. PI3K protein, phosphoserine Akt, and p42/p44-MAPK were reduced, however, in both DCR and PF+Exe groups. Immunohistochemistry demonstrated that the significantly reduced H-Ras occurred in subcutaneous fat cells, while the reduced PI3K and PCNA took place only in the epidermis. Plasma leptin decreased in PF+Exe, DCR, and DCR+Exe, while the caspase-3 activity increased in DCR+Exe only. Genomic microarray analysis further indicated that the expression of 34 genes relevant to PI3K and 31 genes to the MAPK pathway were significantly regulated by either DCR or PF+Exe treatments. The reduced PI3K in PF+Exe mice was partially reversed by IGF-1 treatment. The overall results of this study demonstrated that DCR abrogated both Ras and PI3K signaling, which might inhibit TPA-induced proliferation and anti-apoptosis. Selective inhibition of PI3K by PF+Exe but not AL+Exe seems more attributable to the magnitude of the caloric deficit and/or body fat loss than diet versus exercise comparison.     

Effects of long-term grouping on serum cortisol levels in Microcebus murinus (Prosimii)

The influence of social interactions on plasma cortisol was studied in captive Microcebus murinus, a prosimian primate. Regardless the group composition, there is an annual variation in cortisol levels characterized by an autumn peak that coincides with the fattening and sexual resting period. The beginning of activity, early in January, is accompanied by a fall in cortisol levels. Cortisol levels are higher in females than in males both in pairs and in heterosexual groups. In paired animals, mean cortisol levels vary around 140 ng/ml in males and 230 ng/ml in females. In all grouped animals, a persistent adrenocortical activation was found and represents a 75 to 120% increase compared to paired animals. Due to the fact that M. murinus, the mouse lemur, is a solitary species with a primitive social structure, the high concentrations of cortisol found in grouped mouse lemurs could be a reaction to persistent social stress. Such high concentrations of cortisol may be related to poor reproductive success of grouped females and could play a major part in the pathological lesions found in males that die while maintained in social groups.     

Daily energy expenditure of the grey mouse lemur (Microcebus murinus): a small primate that uses torpor

We aimed to investigate the pattern of utilisation of torpor and its impact on energy budgets in free-living grey mouse lemurs (Microcebus murinus), a small nocturnal primate endemic to Madagascar. We measured daily energy expenditure (DEE) and water turnover using doubly labelled water, and we used temperature-sensitive radio collars to measure skin temperature (T _sk) and home range. Our results showed that male and female mouse lemurs in the wild enter torpor spontaneously over a wide range of ambient temperatures (T _a) during the dry season, but not during the rainy season. Mouse lemurs remained torpid between 1.7–8.9 h with a daily mean of 3.4 h, and their T _sk s fell to a minimum of 18.8 °C. Mean home ranges of mouse lemurs which remained normothermic were similar in the rainy and dry season. During the dry season, the mean home range of mouse lemurs showing daily torpor was significantly smaller than that of animals remaining normothermic. The DEE of M. murinus remaining normothermic in the rainy season (122 ± 65.4 kJ day⁻¹) was about the same of that of normothermic mouse lemurs in the dry season (115.5 ± 27.3 kJ day⁻¹). During the dry season, the mean DEE of M. murinus that utilised daily torpor was 103.4 ± 32.7 kJ day⁻¹ which is not significantly different from the mean DEE of animals remaining normothermic. We found that the DEE of mouse lemurs using daily torpor was significantly correlated with the mean temperature difference between T _sk and T _a (r ²=0.37) and with torpor bout length (r ² =0.46), while none of these factors explained significant amounts of variation in the DEE of the mouse lemurs remaining normothermic. The mean water flux rate of mouse lemurs using daily torpor (13.0 ± 4.1 ml day⁻¹) was significantly lower than that of mouse lemurs remaining normothermic (19.4 ± 3.8 ml day⁻¹), suggesting the lemurs conserve water by entering torpor. Thus, this first study on the energy budget of free-ranging M. murinus demonstrates that torpor may not only reflect its impact on the daily energy demands, but involve wider adaptive implications such as water requirements. Accepted: 29 August 2000     

Effects of Caller Characteristics on Auditory Laterality in an Early Primate (Microcebus murinus)

Background

Auditory laterality is suggested to be characterized by a left hemisphere dominance for the processing of conspecific communication. Nevertheless, there are indications that auditory laterality can also be affected by communicative significance, emotional valence and social recognition.

Methodology/Principal Findings

In order to gain insight into the effects of caller characteristics on auditory laterality in the early primate brain, 17 gray mouse lemurs were tested in a head turn paradigm. The head turn paradigm was established to examine potential functional hemispheric asymmetries on the behavioral level. Subjects were presented with playbacks of two conspecific call types (tsak calls and trill calls) from senders differing in familiarity (unfamiliar vs. familiar) and sex (same sex vs. other sex). Based on the head turn direction towards these calls, evidence was found for a right ear/left hemisphere dominance for the processing of calls of the other sex (Binomial test: p = 0.021, N = 10). Familiarity had no effect on the orientation biases.

Conclusions/Significance

The findings in this study support the growing consensus that auditory laterality is not only determined by the acoustic processing of conspecific communication, but also by other factors like the sex of the sender.     

Effects of calorie restriction on life span of microorganisms

Calorie restriction (CR) in microorganisms such as budding and fission yeasts has a robust and well-documented impact on longevity. In order to efficiently utilize the limited energy during CR, these organisms shift from primarily fermentative metabolism to mitochondrial respiration. Respiration activates certain conserved longevity factors such as sirtuins and is associated with widespread physiological changes that contribute to increased survival. However, the importance of respiration during CR-mediated longevity has remained controversial. The emergence of several novel metabolically distinct microbial models for longevity has enabled CR to be studied from new perspectives. The majority of CR and life span studies have been conducted in the primarily fermentative Crabtree-positive yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, but studies in primarily respiratory Crabtree-negative yeast and obligate aerobes can offer complementary insight into the more complex mammalian response to CR. Not only are microorganisms helping characterize a conserved cellular mechanism for CR-mediated longevity, but they can also directly impact mammalian metabolism as part of the natural gut flora. Here, we discuss the contributions of microorganisms to our knowledge of CR and longevity at the level of both the cell and the organism.     

A case of adult cannibalism in the gray mouse lemur, Microcebus murinus

Cannibalism, defined as the eating of conspecific flesh, has been observed in a number of primate species, although it is still a relatively rare phenomenon. In cases where primates were seen feeding on an individual of the same species, the victims have exclusively been infants or juveniles. Here, I report an event of a free-living, adult male gray mouse lemur, Microcebus murinus, cannibalizing an adult conspecific female that died of an unknown cause. This observation has implications for the basic ecology of the species and highlights the potential for great flexibility in diet and behavior by a primate. This is, to my knowledge, the first communication of cannibalistic behavior in this species, as well as the first reported case of a nonhuman primate cannibalizing an adult conspecific.     

Exercise with calorie restriction improves insulin sensitivity and glycogen synthase activity in obese postmenopausal women with impaired glucose tolerance

Our objective was to compare the effects of in vivo insulin on skeletal muscle glycogen synthase (GS) activity in normal (NGT) vs. impaired glucose-tolerant (IGT) obese postmenopausal women and to determine whether an increase in insulin activation of GS is associated with an improvement in insulin sensitivity (M) following calorie restriction (CR) and/or aerobic exercise plus calorie restriction (AEX + CR) in women with NGT and IGT. We did a longitudinal, clinical intervention study of CR compared with AEX + CR. Overweight and obese women, 49-76 yr old, completed 6 mo of CR (n = 46) or AEX + CR (n = 50) with Vo(2?max), body composition, and glucose tolerance testing. Hyperinsulinemic euglycemic (80 mU·m(-2)·min(-1)) clamps (n = 73) and skeletal muscle biopsies (before and during clamp) (n = 58) were performed before and after the interventions (n = 50). After 120 min of hyperinsulinemia during the clamp, GS fractional activity and insulin's effect to increase GS fractional activity (insulin - basal) were significantly lower in IGT vs. NGT (P < 0.01) at baseline. GS total activity increased during the clamp in NGT (P < 0.05), but not IGT, at baseline. CR and AEX + CR resulted in a significant 8% weight loss with reductions in total fat mass, visceral fat, subcutaneous fat, and intramuscular fat. Overall, M increased (P < 0.01), and the change in M (postintervention - preintervention) was associated with the change in insulin-stimulated GS fractional activity (partial r = 0.44, P < 0.005). In IGT, the change (postintervention - preintervention) in insulin-stimulated GS total activity was greater following AEX + CR than CR alone (P < 0.05). In IGT, insulin-stimulated GS-independent (P < 0.005) and fractional activity (P = 0.06) increased following AEX + CR. We conclude that the greatest benefits at the whole body and cellular level (insulin activation of GS) in older women at highest risk for diabetes are derived from a lifestyle intervention that includes exercise and diet.     

Combined effects of short-term calorie restriction and exercise on insulin action in normal rats

The present study examined the effect of combination of short-term calorie restriction (CR) and moderate exercise on insulin action in normal rats. Rats were divided randomly into 4 groups: ad libitum, sedentary (A-Sed); calorie restriction, sedentary (CR-Sed); ad libitum, exercise (A-Ex); and calorie restriction, exercise (CR-Ex). Rats in the exercise groups were run on a rodent treadmill. Rats in the CR groups were fed every alternate day. Oral glucose tolerance test (OGTT) showed improvements in both CR-Sed and A-Ex groups compared with the A-Sed group; no further improvement in glucose tolerance was observed in the CR-Ex group. In contrast, glucose infusion rates (GIRs) determined by the hyperinsulinemic-euglycemic clamp method indicated that the GIR of the CR and exercise combination was significantly better than that of the sole intervention of CR or exercise. There was no difference in the levels of fasting glucose, insulin, or high-molecular weight forms of adiponectin among the 4 groups. Protein expression of GLUT-4 in the skeletal muscle increased by exercise, but not by CR. Our findings indicate that the combination of exercise and CR may be effective in enhancing insulin sensitivity at the skeletal muscle in normal subjects.     

Effect of calorie restriction on skeletal muscle and liver insulin binding in growing rat

The effect of specific calorie deprivation was studied in meal-fed growing rats. It resulted in a 50% decrease in growth rate. Blood glucose and most non-essential blood free amino acid levels were depressed. Postprandial plasma insulin was decreased. With insulin ranging from 0.01 to 100 nM, insulin binding to crude Triton X-100 solubilized membranes from liver was higher in calorie restricted rats when compared with control rats. Wheat germ agglutinin (WGA) purified receptor preparations also exhibited higher insulin binding in liver from experimental group but the significance (P less than 0.05) was only visible with low insulin levels; both basal and insulin-stimulated tyrosine-kinase activity were left unchanged. In contrast, whatever the skeletal muscle insulin receptor preparation (enriched plasma membranes, crude Triton X-100 solubilized or wheat-germ agglutinin purified extracts) insulin binding was similar in control and calorie-restricted rats.