Aged Mouse Lemurs Research Articles

Effect of ageing on the cardiac activity of the small primate Microcebus murinus

Age is an important factor of comorbidity in the development of cardiovascular diseases. Regardless of lifestyle, aged people suffer from maximal heart rate (HR) and HR variability (HRV) decrease that could impair blood circulation, tissue oxygenation and consequently self-sufficiency. Given the increase of old people in modern societies it is important to study the effect of ageing on the heart to treat the related consequence on the body physiology. To study the effect of aging on HR dynamics it is important to use appropriate animal models that could replicate the cardiac physiology, but also the neural environment that modulates HR in aged patients. The small primate Microcebus murinus, also known as gray mouse lemur (ML), responds to these criteria. Indeed, differently from mice it spontaneously develops neurodegenerative diseases. In addition, although ML lies in between the size of mice and rats, it can live up to 12 years in captivity, generating about 3 billion heartbeats in a lifetime. Thus, ML generates as many heartbeats as humans in a lifetime and about three times more than mice. To study HR and HRV in ML, we used a mini Holter and we developed a jacket to record surface electrocardiograms (ECGs) in young (1–5 years) and aged (6–10 years) animals of both genders. These experiments showed HR decrease in correlation with age in male MLs, but not in females. To get insights on the sympathetic tone of ML, we measured the coefficient of variability of the interval between two heartbeats (CVRR). Under handling stress, we found higher CVRR in aged versus young ML males, indicative of lower sympathetic tone. Conversely, the index of short-term HRV, related to parasympathetic modulation (RMSSD), showed no difference in response to stress in young and aged MLs of both genders. Next, we measured the concentration of adrenaline and noradrenaline in the urines of ML of different age and both genders. Accordingly, with our measurements of HRV we found a tendency of decrease in the urine concentration of noradrenaline in aged versus young ML males. Our preliminary results suggest that age impairs the autonomic regulation of HR, but this effect is evident in aged ML males and not in females.

Amyloid-β targeting immunisation in aged non-human primate (Microcebus murinus)

Non-human primates have an important translational value given their close phylogenetic relationship to humans. Studies in these animals remain essential for evaluating efficacy and safety of new therapeutic approaches, particularly in aging primates that display Alzheimer’s disease (AD) -like pathology. With the objective to improve amyloid-β (Aβ) targeting immunotherapy, we investigated the safety and efficacy of an active immunisation with an Aβ derivative, K6Aβ1-30-NH2, in old non-human primates. Thirty-two aged (4–10 year-old) mouse lemurs were enrolled in the study, and received up to four subcutaneous injections of the vaccine in alum adjuvant or adjuvant alone.Even though antibody titres to Aβ were not high, pathological examination of the mouse lemur brains showed a significant reduction in intraneuronal Aβ that was associated with reduced microgliosis, and the vaccination did not lead to microhemorrhages. Moreover, a subtle cognitive improvement was observed in the vaccinated primates, which was probably linked to Aβ clearance. This Aβ derivative vaccine appeared to be safe as a prophylactic measure based on the brain analyses and because it did not appear to have detrimental effects on the general health of these old animals.

Ageing decreases heart rate variability in the small primate Microcebus murinus

The World Health Organization estimates that 75% of the elderly develop cardiovascular deficiencies that can degenerate into fatal diseases. Regardless of lifestyle, aged people suffer from a decrease in maximal heart rate (HR) that could reduce their self-sufficiency. A decrease in physiological HR variability (HRV), resulting from the interaction between intrinsic cardiac activity, generated by the sinoatrial node (SAN), and its modulation by the autonomic nervous system, has been also suggested in aged humans and mice. Mechanisms underlying decreased HRV and the consequences on body physiology are still unclear. To investigate HRV in aging, we used the small primate Microcebus murinus, also known as mouse lemur (ML). MLs lay in between the size of mice and rats and it can live up to 12 years. MLs have a common genetic origin with our species and unlike mice, they spontaneously develop neurodegenerative diseases similar to those of humans. An increasing interest is thus raising for ML as a model to study the effect of ageing. To comply with the 3Rs rules of animal experimentation, we developed a jacket to record non-invasive surface electrocardiograms in MLs. We recorded HR in 4 young (1–5 years) and 4 old (6–10 years) MLs, under stress induced by animal manipulation and at rest ( Fig. 1 ). These preliminary tests showed lower HR and HRV in aged versus young MLs. In addition, we observed a reduced ability of aged MLs to recover resting HRV after manipulation. This was true for all indices of long-term RR variability, which are related to sympathetic activity, such as the coefficient of variability and Standard deviation 2 (SD2) of RR intervals. Conversely, short-term RR variability, measured as RMSSD and SD1, and related to parasympathetic modulation, showed an equivalent increase in young and aged MLs after manipulation. Yet, short-term RR variability was lower in aged versus young MLs at rest or under stress. Optical mapping recording of pacemaker activity in isolated SANs obtained from the hearts of aged MLs ( n = 14) showed impaired response to β-adrenergic activation after isoprenaline superfusion and normal response to acetylcholine. In conclusion our preliminary results suggest a stronger impairment of β-adrenergic versus muscarinic pathways in aged MLs, which may be related to an intrinsic inability of the SAN to receive sympathetic inputs sent by the autonomic nervous system.

Relationships between endogenous circadian period, physiological and cognitive parameters and sex in aged gray mouse lemurs (Microcebus murinus)

ABSTRACT The biological clock generates circadian rhythms, with an endogenous period tau close to 24 h. The circadian resonance theory proposes that lifespan is reduced when endogenous period goes far from 24 h. It has been suggested that daily resetting of the circadian clock to the 24 h external photoperiod might induce marginal costs that would accumulate over time and forward accelerate aging and affect fitness. In this study, we aimed to evaluate the link between the endogenous period and biomarkers of aging in order to investigate the mechanisms of the circadian resonance theory. We studied 39 middle-aged and aged Microcebus murinus, a nocturnal non-human primate whose endogenous period is about 23.1 h, measuring the endogenous period of locomotor activity, as well as several physiological and behavioral parameters (rhythm fragmentation and amplitude, energetic expenditure, oxidative stress, insulin-like growth factor-1 (IGF-1) concentrations and cognitive performances) in both males and females. We found that aged males with tau far from 24 h displayed increased oxidative stress. We also demonstrated a positive correlation between tau and IGF-1 concentrations, as well as learning performances, in males and females. Together these results suggest that a great deviation of tau from 24 h leads to increased biomarkers of age-related impairments.

Strengths and Weaknesses of the Gray Mouse Lemur (Microcebus murinus) as a Model for the Behavioral and Psychological Symptoms and Neuropsychiatric Symptoms of Dementia.

To face the load of the prevalence of Alzheimer’s disease in the aging population, there is an urgent need to develop more translatable animal models with similarities to humans in both the symptomatology and physiopathology of dementia. Due to their close evolutionary similarity to humans, non-human primates (NHPs) are of primary interest. Of the NHPs, to date, the gray mouse lemur (Microcebus murinus) has shown promising evidence of its translatability to humans. The present review reports the known advantages and limitations of using this species at all levels of investigation in the context of neuropsychiatric conditions. In this easily bred Malagasy primate with a relatively short life span (approximately 12 years), age-related cognitive decline, amyloid angiopathy, and risk factors (i.e., glucoregulatory imbalance) are congruent with those observed in humans. More specifically, analogous behavioral and psychological symptoms and neuropsychiatric symptoms of dementia (BPSD/NPS) to those in humans can be found in the aging mouse lemur. Aged mouse lemurs show typical age-related alterations of locomotor activity daily rhythms such as decreased rhythm amplitude, increased fragmentation, and increased activity during the resting-sleeping phase of the day and desynchronization with the light-dark cycle. In addition, sleep deprivation successfully induces cognitive deficits in adult mouse lemurs, and the effectiveness of approved cognitive enhancers such as acetylcholinesterase inhibitors or N-methyl-D-aspartate antagonists is demonstrated in sleep–deprived animals. This result supports the translational potential of this animal model, especially for unraveling the mechanisms underlying dementia and for developing novel therapeutics to prevent age-associated cognitive decline. In conclusion, actual knowledge of BPSD/NPS-like symptoms of age-related cognitive deficits in the gray mouse lemur and the recent demonstration of the similarity of these symptoms with those seen in humans offer promising new ways of investigating both the prevention and treatment of pathological aging.

How Aging Affects Grasping Behavior and Pull Strength in Captive Gray Mouse Lemurs (Microcebus murinus)

Prehension is essential for animal survival and fitness. It is involved in locomotion and feeding behavior and subject to physical and physiological constraints. Studies of prehension in primates have explored the importance of food properties and of the environment, but aging has rarely been studied although prehensile capacity may deteriorate with age in humans. To test the hypothesis that aging affects grasping abilities and to reveal possible behavioral adaptations to this, we quantified behavioral grasping strategies and pull strength in 10 young adult (2–3 yr old) and 10 aged (7–8 yr old) gray mouse lemurs (Microcebus murinus). We assessed grasping strategies in an experimental cage by quantifying grip types used to grasp static and mobile foods. We measured strength using a Kistler triaxial force platform. Our results show that 1) mobile and static foods affected individuals of different ages in similar ways; 2) older individuals used more mouth grasps than young ones; 3) aged individuals made twice as many attempts as young ones when grasping mobile food items but this difference was not significant; and 4) there were no differences in hand grip strength between age classes but young individuals showed a higher foot pull strength compared to old ones. These data suggest that the observed differences in behavior may be due to a decrease in foot grip strength, which in turn influences stability on narrow branches, forcing animals to use their hands to maintain stability and preventing them from using their hands for food-related tasks.

Effects of acute administration of donepezil or memantine on sleep-deprivation-induced spatial memory deficit in young and aged non-human primate grey mouse lemurs (Microcebus murinus).

The development of novel therapeutics to prevent cognitive decline of Alzheimer's disease (AD) is facing paramount difficulties since the translational efficacy of rodent models did not resulted in better clinical results. Currently approved treatments, including the acetylcholinesterase inhibitor donepezil (DON) and the N-methyl-D-aspartate antagonist memantine (MEM) provide marginal therapeutic benefits to AD patients. There is an urgent need to develop a predictive animal model that is phylogenetically proximal to humans to achieve better translation. The non-human primate grey mouse lemur (Microcebus murinus) is increasingly used in aging research, but there is no published results related to the impact of known pharmacological treatments on age-related cognitive impairment observed in this primate. In the present study we investigated the effects of DON and MEM on sleep-deprivation (SD)—induced memory impairment in young and aged male mouse lemurs. In particular, spatial memory impairment was evaluated using a circular platform task after 8 h of total SD. Acute single doses of DON or MEM (0.1 and 1mg/kg) or vehicle were administered intraperitoneally 3 h before the cognitive task during the SD procedure. Results indicated that both doses of DON were able to prevent the SD-induced deficits in retrieval of spatial memory as compared to vehicle-treated animals, both in young and aged animals Likewise, MEM show a similar profile at 1 mg/kg but not at 0.1mg/kg. Taken together, these results indicate that two widely used drugs for mitigating cognitive deficits in AD were partially effective in sleep deprived mouse lemurs, which further support the translational potential of this animal model. Our findings demonstrate the utility of this primate model for further testing cognitive enhancing drugs in development for AD or other neuropsychiatric conditions.

Touchscreen-based cognitive tasks reveal age-related impairment in a primate aging model, the grey mouse lemur (Microcebus murinus).

Mouse lemurs are suggested to represent promising novel non-human primate models for aging research. However, standardized and cross-taxa cognitive testing methods are still lacking. Touchscreen-based testing procedures have proven high stimulus control and reliability in humans and rodents. The aim of this study was to adapt these procedures to mouse lemurs, thereby exploring the effect of age. We measured appetitive learning and cognitive flexibility of two age groups by applying pairwise visual discrimination (PD) and reversal learning (PDR) tasks. On average, mouse lemurs needed 24 days of training before starting with the PD task. Individual performances in PD and PDR tasks correlate significantly, suggesting that individual learning performance is unrelated to the respective task. Compared to the young, aged mouse lemurs showed impairments in both PD and PDR tasks. They needed significantly more trials to reach the task criteria. A much higher inter-individual variation in old than in young adults was revealed. Furthermore, in the PDR task, we found a significantly higher perseverance in aged compared to young adults, indicating an age-related deficit in cognitive flexibility. This study presents the first touchscreen-based data on the cognitive skills and age-related dysfunction in mouse lemurs and provides a unique basis to study mechanisms of inter-individual variation. It furthermore opens exciting perspectives for comparative approaches in aging, personality, and evolutionary research.

Omega-3 PUFA supplementation differentially affects behavior and cognition in the young and aged non-human primate Grey mouse lemur (Microcebus murinus)

Data are divergent about the ability of dietary ω3 fatty acids to prevent age-associated cognitive decline. Most of the clinical trials failed to demonstrate a protective effect of ω3 fatty acids against cognitive decline and methodological issues are still under debate. Conversely to human studies, experiments performed in adult rodents clearly indicate that long chain ω3 fatty acids play a beneficial role in behavioral and cognitive functions. Inconsistent observations between human and rodent studies highlight the importance of the use of non-human primate models. We recently started a series of experiments on Grey mouse lemurs, an emerging non-human primate model of aging in order to assess the impact of ω3 fatty acids dietary supplementation on several brain functions. These experiments started with the determination of the fatty acids composition of target organs (brain, adipose tissue, liver, plasma) of animals fed under control diet. We then explored the impact of ω3 polyunsaturated fatty acids (PUFA) supplementation on cognition and behavior in young and aged grey mouse lemurs. The aim of the present review is to compare the observations made in young and aged grey mouse lemurs and to explore the possibilities of new experiments in order to bridge the gap between rodents and Humans.

Effects of Resveratrol on Daily Rhythms of Locomotor Activity and Body Temperature in Young and Aged Grey Mouse Lemurs

In several species, resveratrol, a polyphenolic compound, activates sirtuin proteins implicated in the regulation of energy balance and biological clock processes. To demonstrate the effect of resveratrol on clock function in an aged primate, young and aged mouse lemurs (Microcebus murinus) were studied over a 4-week dietary supplementation with resveratrol. Spontaneous locomotor activity and daily variations in body temperature were continuously recorded. Reduction in locomotor activity onset and changes in body temperature rhythm in resveratrol-supplemented aged animals suggest an improved synchronisation on the light-dark cycle. Resveratrol could be a good candidate to restore the circadian rhythms in the elderly.

Effect of dietary fish oil supplementation on the exploratory activity, emotional status and spatial memory of the aged mouse lemur, a non-human primate

The data are inconsistent about the ability of dietary omega-3 fatty acids to prevent age-associated cognitive decline. Indeed, most clinical trials have failed to demonstrate a protective effect of omega-3 fatty acids against cognitive decline, and methodological issues are still under debate. In contrast to human studies, experiments performed in adult rodents clearly indicate that omega-3 fatty acids supplement can improve behavioural and cognitive functions. The inconsistent observations between human and rodent studies highlight the importance of the use of non-human primate models. The aim of the present study was to address the impact of omega-3 fatty acids (given in the form of dietary fish oil) on exploratory activity, emotional status and spatial reference memory in the aged mouse lemur, a non-human primate.Aged animals fed fish oil exhibited decreased exploratory activity, as manifested by an increase in the latency to move and a reduced distance travelled in an open-field. The fish oil-supplemented animals exhibited no change in the anxiety level, but they were more reactive to go into the dark arms of a light/dark plus-maze. In addition, we found that fish oil supplementation did not significantly improve the spatial memory performance in the Barnes maze task.This study demonstrated for the first time that a fish oil diet initiated late in life specifically modifies the exploratory behaviour without improving the spatial memory of aged non-human primates. Omega-3 fatty acid supplementation may be effective when started early in life but less effective when started at later ages.

Physiological responses to chronic heat exposure in an aging non-human primate species, the gray mouse lemur ( Microcebus murinus)

Epidemiological evidence related to increased death from hyperthermia suggests higher frailty in the elderly when exposed to high ambient temperatures. Despite the recent awareness of such public health problems, integrative studies investigating the effects of age on the physiological responses to heat wave thermal conditions remain scarce. Daily rhythmicity of core temperature (T c) and locomotor activity (LA), as well as parameters representative of energy balance and IGF-1 levels which are involved in the aging process and stress resistance, were monitored in a non-human primate species, the gray mouse lemur ( Microcebus murinus). Adult and aged animals, acclimated to long days (LD) or short days (SD), were monitored during 8-day periods of exposure to 25 °C and 34 °C. Adult animals displayed efficient coping with heat exposure, regardless of the photoperiod. Hence, efficient responses resulted in decrease of energy intake, energy expenditure, IGF-1 levels and LA levels, promoting hyperthermia avoidance. Positive energy balance was maintained and water turnover did not change significantly after heat exposure. In contrast, while aged animals acclimated to LD responded similarly to adults, aged mouse lemurs acclimated to SD showed great difficulties coping with heat exposure. Indeed, in this group, normothermia impairment was associated with increased T c levels, alterations in daily rhythmicity, negative energy balance and increased IGF-1 levels. Impaired responses to heat exposure were seen in aged mouse lemurs acclimated to SD only. The main effects were observed during diurnal resting periods, suggesting decreased capacities with age to dissipate excess body heat. Taken together, these data highlight daily rhythmicity and IGF-1 pathway as main targets in the impaired response to heat exposure in the elderly.

The three-panel runway maze adapted to Microcebus murinus reveals age-related differences in memory and perseverance performances

Microcebus murinus, a mouse lemur primate appears to be a valuable model for cerebral aging study and for Alzheimer’s disease model since they can develop β-amyloid plaques with age. Although the biological and biochemical analyses of cerebral aging are well documented, the cognitive abilities of this primate have not been thoroughly characterized. In this study, we adapted a spatial working memory procedure described in rodents, the sequential choice task in the three-panel runway, to mouse lemurs. We analyzed the age-related differences in a procedural memory task in the absence or presence of visual cues. Sixty percent of young adult and 48% of aged lemurs completed the exploratory, choice habituation and testing phases at the beginning of the procedure. Young adult lemurs showed a higher level of perseverative errors compared with aged animals, particularly in the presence of visual stimuli. Over trials, old animals made more reference errors compared to young ones that improved quickly their performances under random level. No significant improvement was observed in young adults and old ones over sessions. This study showed that behavioural performances of M. murinus assessed on the sequential choice task in the three-panel runway markedly differ from the previously reported abilities of rodents. The behavioural response of young adult lemurs was influenced by novelty-related anxiety that contributed to their performance in terms of perseverative errors. Conversely, aged lemurs showed less perseverative errors, a rapid habituation to the three-panel runway maze, but made more memory errors. Overall, these findings demonstrate the feasibility to use the three-panel runway task in assessing memory performance, particularly in aged mouse lemurs.

Non-shivering thermogenesis activation and maintenance in the aging gray mouse lemur ( Microcebus murinus)

The cold-induced enhancement of non-shivering thermogenesis (NST), involving brown-adipose tissue (BAT) metabolism, could participate to impair energy balance in the aged gray mouse lemur ( Microcebus murinus). We first investigated the age-related modulations of cold-stimulated BAT cell morphology and contents. Then, NST was pharmacologically stimulated to assess whether aging impaired NST activation in the mouse lemur. In reference conditions, the ability to activate NST was preserved during aging in the mouse lemur as BAT morphology and UCP-1 presence did not differ between adult and aged mouse lemurs. Also, the pharmacological activation of NST revealed similar increased levels of O 2 consumption in adult and aged animals, confirming that no age effect could be evidenced on NST activation at 25 °C. However, preliminary histological data revealed a lack of lipid resources in one aged individual during cold exposure. Surprisingly, the pharmacological activation of NST revealed an impaired evacuation of the excess body heat in aged animals, associated with increased energy expenditure. Thus, aging seems to be related to decreased capacities in the maintenance of NST rather than in its activation. Energy mobilization could be impaired in the aging mouse lemur but remains to be demonstrated.

Impaired Control of Body Cooling during Heterothermia Represents the Major Energetic Constraint in an Aging Non-Human Primate Exposed to Cold

Daily heterothermia is used by small mammals for energy and water savings, and seems to be preferentially exhibited during winter rather than during summer. This feature induces a trade-off between the energy saved during daily heterothermia and the energy cost of arousal, which can impact energy balance and survival under harsh environmental conditions. Especially, aging may significantly affect such trade off during cold-induced energy stress, but direct evidences are still lacking. We hypothesized that aging could alter the energetics of daily heterothermia, and that the effects could differ according to season. In the gray mouse lemur (Microcebus murinus), a non-human primate species which exhibits daily heterothermia, we investigated the effects of exposures to 25 and 12°C on body composition, energy balance, patterns of heterothermia and water turnover in adult (N = 8) and aged animals (N = 7) acclimated to winter-like or summer-like photoperiods.Acclimation to summer prevented animals from deep heterothermia, even during aging. During winter, adult animals at 12°C and aged animals at 25°C exhibited low levels of energy expenditure with minor modulations of heterothermia. The major effects of cold were observed during winter, and were particularly pronounced in aged mouse lemurs which exhibited deep heterothermia phases. Body composition was not significantly affected by age and could not explain the age-related differences in heterothermia patterns. However, aging was associated with increased levels of energy expenditure during cold exposure, in concomitance with impaired energy balance. Interestingly, increased energy expenditure and depth of heterothermia phases were strongly correlated.In conclusion, it appeared that the exhibition of shallow heterothermia allowed energy savings during winter in adult animals only. Aged animals exhibited deep heterothermia and increased levels of energy expenditure, impairing energy balance. Thus, an impaired control of the heterothermic process induced high energy costs in the aging mouse lemur exposed to cold.

Daily Rhythms of Core Temperature and Locomotor Activity Indicate Different Adaptive Strategies to Cold Exposure in Adult and Aged Mouse Lemurs Acclimated to a Summer-Like Photoperiod

Daily variations in core temperature (Tc) within the normothermic range imply thermoregulatory processes that are essential for optimal function and survival. Higher susceptibility towards cold exposure in older animals suggests that these processes are disturbed with age. In the mouse lemur, a long-day breeder, we tested whether aging affected circadian rhythmicity of Tc, locomotor activity (LA), and energy balance under long-day conditions when exposed to cold. Adult (N = 7) and aged (N = 5) mouse lemurs acclimated to LD14/10 were exposed to 10–day periods at 25 and 12°C. Tc and LA rhythms were recorded by telemetry, and caloric intake (CI), body mass changes, and plasma IGF-1 were measured. During exposure to 25°C, both adult and aged mouse lemurs exhibited strong daily variations in Tc. Aged animals exhibited lower levels of nocturnal LA and nocturnal and diurnal Tc levels in comparison to adults. Body mass and IGF-1 levels remained unchanged with aging. Under cold exposure, torpor bout occurrence was never observed whatever the age category. Adult and aged mouse lemurs maintained their Tc in the normothermic range and a positive energy balance. All animals exhibited increase in CI and decrease in IGF-1 in response to cold. The decrease in IGF-1 was delayed in aged mouse lemurs compared to adults. Moreover, both adult and aged animals responded to cold exposure by increasing their diurnal LA compared to those under Ta = 25°C. However, aged animals exhibited a strong decrease in nocturnal LA and Tc, whereas cold effects were only slight in adults. The temporal organization and amplitude of the daily phase of low Tc were particularly well preserved under cold exposure in both age groups. Sexually active mouse lemurs exposed to cold thus seemed to prevent torpor exhibition and temporal disorganization of daily rhythms of Tc, even during aging. However, although energy balance was not impaired with age in mouse lemurs after cold exposure, aging was associated with lower LA and Tc during the night and delayed decrease in IGF-1. This might reflect that adaptive strategies to cold exposure differ with age in mouse lemurs acclimated to a summer-like photoperiod.

IC-P1-019: Patterns of cerebral atrophy and neuropathological alterations in mouse lemur primates suggest an evolutive disease

Background: Cerebral atrophy is a common pattern in Alzheimer’s disease and in many other neurodegenerative processes (1). It is also reported in aged mouse lemur primates (2). These small animals (12 cm, maximal life span of 12 years) can also display diffuse amyloid depositions and tau pathology while aging (3). Methods: The location of cerebral atrophy was assessed in 31 mouse lemurs aged from 1.9 to 11.3 years. 3D MR images (isotropic resolution 234 m) were recorded on a 4.7T Bruker system. An automatic segmentation technique was used to detect cerebro-spinal fluid (CSF) voxels in areas surrounding the cortex (2). Then, CSF voxels surrounding various functional regions (frontal and parietal (FPcort), parieto-temporal (PTcort), temporal (Tcort), occipital (Ocort) cortices) were manually labeled and counted. Histological evaluation (amyloid (anti-A 4G8 antibodies (Biovalley, France)) and GFAP stainings) was also performed in 7 lemurs (6.4 to 11.2 years) previously evaluated by MRI. Results: Significant CSF increase in pericortical regions was detected in only one young animal. The prevalence of cerebral atrophy increased with age (25% and 75% in middle aged and old animals), following a characteristic, sequential, pattern. First, some animals (n 3) displayed CSF accumulation in regions surrounding the FPcort (stage 1). In five animals, in addition to FPcort, the atrophy process involved one cortical region adjacent to FPcort. In 4 animals, this additional region was PTcort (stage 2a) while it was Tcort for one animal (stage 2b). In 2 additional animals, the atrophy process involved FPcort, PTcort and Tcort (stage 3). Finally, in 5 animals the atrophy involved FPcort, PTcort, Tcort, and Ocort. Only two of these lemurs had extracellular amyloid deposits. Most of these severely atrophied animals had intracellular amyloid deposits in cortical and hippocampal regions and activated glial accumulation. Conclusions: Our data suggest that cerebral atrophy in mouse lemurs follows a sequential pathway and that neuropathological alterations other than extracellular amyloid deposition should be investigated to explain the brain atrophy. Acknowledgements: Longevity-GIS, ‘NeuroscienceACI-programs’ (French Minister for Research), France-Alzheimer-Association.

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.

Calbindin D28K protein cells in a primate suprachiasmatic nucleus: localization, daily rhythm and age‐related changes

In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is the master circadian pacemaker. The SCN controls daily rhythms and synchronizes the organism to its environment and especially to photic signals. Photic signals via the retinohypothalamic tract reach the ventral part of the SCN, where the majority of calbindin-containing neurons are located. Calbindin cells seem important for the control of circadian rhythmicity. As ageing leads to marked changes in the expression of circadian rhythms, we investigated in the mouse lemur, a nocturnal primate, age-related changes in the oscillation of calbindin protein expression in SCN neurons. We used immunohistochemistry and quantitative analysis of calbindin expression in the SCN of adult and aged mouse lemurs. In this primate, a dense cluster of calbindin-positive neurons was found in the ventral part of the SCN. In adult animals, calbindin-positive SCN neurons did not exhibit daily rhythms in their number or intensity, but exhibited significant daily variations in the percentage of cells with a calbindin-positive nucleus, characterized by high values during the daytime and low values during the night. Immunoreactive intensity peaked in the middle of the daytime. Calbindin expression in the nuclei of calbindin cells in the SCN tends to be modified by ageing. The amplitude of daily variation in calbindin expression was damped, with a lower immunointensity during the daytime and a delayed decrease during the night. These changes may affect the ability of the SCN to transmit rhythmic information to other SCN cells and thereby modify the synchronization of the different cell populations in the SCN.

Aging affects executive functions and memory in mouse lemur primates

The decline of cognitive capacities with age in mouse lemur primates ( Microcebus murinus) was assessed. Eight young adults (2–4 years) and nine aged adults (7–11 years) were examined on tasks designed to measure executive functions, procedural and declarative memory. The mouse lemurs were tested on the go-no go successive discrimination task, set shifting tasks (including extra-dimensional shift and reversal discrimination) and a spatial rule-guided discrimination task. There were four major findings. First, the deficits observed were not global but only on specific tasks indicating that only specific cognitive abilities are impaired with aging. Second, there were variations among aged subjects suggesting different patterns of cognitive aging. Third, alterations in cognitive abilities with aging in mouse lemurs seemed to be comparable to those described in aged monkeys and humans. Indeed, executive functions and declarative memory were affected in subpopulations of aged subjects whereas procedural memory remained intact in all the tested aged subjects. Finally, two forms of executive dysfunctions were distinguished among the aged subjects. The ultimate goal is to correlate age-related cognitive deficit with brain alterations and this study has helped to select candidate regions to be thoroughly scrutinized in aged mouse lemurs.