Sex-specific heterothermy patterns in wintering captive Microcebus murinus do not translate into differences in energy balance.

The physiological mechanisms of responses to stressors are at the core of ecophysiological studies that examine the limits of an organism's flexibility. Interindividual variability in these physiological responses can be particularly important and lead to differences in the stress response among population groups, which can affect population dynamics. Some observations of intersexual differences in heterothermy raise the question of whether there is a difference in energy management between the sexes. In this study, we assessed male and female differences in mouse lemurs (Microcebus murinus), a highly seasonal malagasy primate, by measuring their physiological flexibility in response to caloric restriction and examining the subsequent impact on reproductive success. Using complementary methods aiming to describe large-scale and daily variations in body temperature throughout a 6-month winter-like short-day (SD) period, we monitored 12 males and 12 females, applying chronic 40% caloric restriction (CR) to 6 individuals in each group. We found variations in Tb modulation throughout the SD period and in response to caloric treatment that depended on sex, as females, regardless of food restriction, and CR males, only, entered deep torpor. The use of deeper torpor, however, did not translate into a lower loss of body mass in females and did not affect reproductive success. Captive conditions may have buffered the depth of torpor and minimised the positive effects of torpor on energy savings. However, the significant sex differences in heterothermy we observed may point to physiological benefits other than preservation of energy reserves.

EthoLoop: automated closed-loop neuroethology in naturalistic environments.

Accurate tracking and analysis of animal behavior is crucial for modern systems neuroscience. However, following freely moving animals in naturalistic, three-dimensional (3D) or nocturnal environments remains a major challenge. Here, we present EthoLoop, a framework for studying the neuroethology of freely roaming animals. Combining real-time optical tracking and behavioral analysis with remote-controlled stimulus-reward boxes, this system allows direct interactions with animals in their habitat. EthoLoop continuously provides close-up views of the tracked individuals and thus allows high-resolution behavioral analysis using deep-learning methods. The behaviors detected on the fly can be automatically reinforced either by classical conditioning or by optogenetic stimulation via wirelessly controlled portable devices. Finally, by combining 3D tracking with wireless neurophysiology we demonstrate the existence of place-cell-like activity in the hippocampus of freely moving primates. Taken together, we show that the EthoLoop framework enables interactive, well-controlled and reproducible neuroethological studies in large-field naturalistic settings.

Overview of age-related changes in psychomotor and cognitive functions in a prosimian primate, the gray mouse lemur (Microcebus murinus): Recent advances in risk factors and antiaging interventions.

Aging is not homogeneous in humans and the determinants leading to differences between subjects are not fully understood. Impaired glucose homeostasis is a major risk factor for cognitive decline in middle-aged humans, pointing at the existence of early markers of unhealthy aging. The gray mouse lemur (Microcebus murinus), a small lemuriform Malagasy primate, shows relatively slow aging with decreased psychomotor capacities at middle-age (around 5-year old). In some cases (∼10%), it spontaneously leads to pathological aging. In this case, some age-related deficits, such as severe cognitive decline, brain atrophy, amyloidosis, and glucoregulatory imbalance are congruent with what is observed in humans. In the present review, we inventory the changes occurring in psychomotor and cognitive functions during healthy and pathological aging in mouse lemur. It includes a summary of the cerebral, metabolic, and cellular alterations that occur during aging and their relation to cognitive decline. As nutrition is one of the major nonpharmacological antiaging strategies with major potential effects on cognitive performances, we also discuss its role in brain functions and cognitive decline in this species. We show that the overall approach of aging studies in the gray mouse lemur offers promising ways of investigation for understanding, prevention, and treatments of pathological aging in humans.

Scleral and corneal xanthomatous inflammation in a gray mouse lemur (Microcebus murinus).

Bilateral multifocal corneal opacity was detected in a 4.5-year-old male captive gray mouse lemur (Microcebus murinus) without other clinical ocular changes. Histopathological examination revealed a severe diffuse granulomatous scleritis and focal keratitis with intralesional cholesterol, consistent with xanthomatous inflammation. This is the first report of xanthomatous inflammation in a gray mouse lemur. This condition may be the result of systemic factors (lipid metabolism disorders) and/or local predisposing factors such as hemorrhage or inflammation. The pathogenesis in this case could not be fully determined. Further studies on lemurs are required for a better understanding of their lipid metabolism, as well as for diagnosing and evaluating the incidence of xanthomatous inflammation in these species.

Long-chain n-3 PUFAs from fish oil enhance resting state brain glucose utilization and reduce anxiety in an adult nonhuman primate, the grey mouse lemur.

Decreased brain content of DHA, the most abundant long-chain n-3 polyunsaturated fatty acid (n-3 LCPUFA) in the brain, is accompanied by severe neurosensorial impairments linked to impaired neurotransmission and impaired brain glucose utilization. In the present study, we hypothesized that increasing n-3 LCPUFA intake at an early age may help to prevent or correct the glucose hypometabolism observed during aging and age-related cognitive decline. The effects of 12 months' supplementation with n-3 LCPUFA on brain glucose utilization assessed by positron emission tomography was tested in young adult mouse lemurs (Microcebus murinus). Cognitive function was tested in parallel in the same animals. Lemurs supplemented with n-3 LCPUFA had higher brain glucose uptake and cerebral metabolic rate of glucose compared with controls in all brain regions. The n-3 LCPUFA-supplemented animals also had higher exploratory activity in an open-field task and lower evidence of anxiety in the Barnes maze. Our results demonstrate for the first time in a nonhuman primate that n-3 LCPUFA supplementation increases brain glucose uptake and metabolism and concomitantly reduces anxiety.

Senescence or selective disappearance? Age trajectories of body mass in wild and captive populations of a small-bodied primate.

Classic theories of ageing consider extrinsic mortality (EM) a major factor in shaping longevity and ageing, yet most studies of functional ageing focus on species with low EM. This bias may cause overestimation of the influence of senescent declines in performance over condition-dependent mortality on demographic processes across taxa. To simultaneously investigate the roles of functional senescence (FS) and intrinsic, extrinsic and condition-dependent mortality in a species with a high predation risk in nature, we compared age trajectories of body mass (BM) in wild and captive grey mouse lemurs (Microcebus murinus) using longitudinal data (853 individuals followed through adulthood). We found evidence of non-random mortality in both settings. In captivity, the oldest animals showed senescence in their ability to regain lost BM, whereas no evidence of FS was found in the wild. Overall, captive animals lived longer, but a reversed sex bias in lifespan was observed between wild and captive populations. We suggest that even moderately condition-dependent EM may lead to negligible FS in the wild. While high EM may act to reduce the average lifespan, this evolutionary process may be counteracted by the increased fitness of the long-lived, high-quality individuals.

Shallow hypothermia depends on the level of fatty acid unsaturation in adipose and liver tissues in a tropical heterothermic primate.

Optimal levels of unsaturated fatty acids have positive impacts on the use of prolonged bouts of hypothermia in mammalian hibernators, which generally have to face low winter ambient temperatures. Unsaturated fatty acids can maintain the fluidity of fat and membrane phospholipids at low body temperatures. However, less attention has been paid to their role in the regulation of shallow hypothermia, and in tropical species, which may be challenged more by seasonal energetic and/or water shortages than by low temperatures. The present study assessed the relationship between the fatty acids content of white adipose and liver tissues and the expression of shallow hypothermia in a tropical heterothermic primate, the gray mouse lemur (Microcebus murinus). The adipose tissue is the main tissue for fat storage and the liver is involved in lipid metabolism, so both tissues were expected to influence hypothermia dependence on fatty acids. As mouse lemurs largely avoid deep hypothermia (i.e. torpor) use under standard captive conditions, the expression of hypothermia was triggered by food-restricting experimental animals. Hypothermia depth increased with time, with a stronger increase for individuals that exhibited higher contents of unsaturated fatty acids suggesting that they were more flexible in their use of hypothermia. However these same animals delayed the use of long hypothermia bouts relative to individuals with a higher level of saturated fatty acids. This study evidences for the first time that body fatty acids unsaturation levels influence the regulation of body temperature not only in cold-exposed hibernators but also in tropical, facultative heterotherms.

Animal models of Alzheimer's disease and drug development.

Animal disease models are considered important in the development of drugs for Alzheimer's disease. This brief review will discuss possible reasons why their success in identifying efficacious treatments has been limited, and will provide some thoughts on the role of animal experimentation in drug development. Specifically, none of the current models of Alzheimer's disease have either construct or predictive validity, and no model probably ever will. Clearly, specific animal experiments contribute to our understanding of the disease and generate hypotheses. Ultimately, however, the hypothesis can only be tested in human patients and only with the proper tools. These tools are a pharmacologically active intervention (in humans) and a clinical trial suited to evaluate the mechanism of action. Integration of knowledge in quantitative (sub) models is considered important if not essential in this process.

Characterization of blood biochemical markers during aging in the Grey Mouse Lemur (Microcebus murinus): impact of gender and season.

BACKGROUND: Hematologic and biochemical data are needed to characterize the health status of animal populations over time to determine the habitat quality and captivity conditions. Blood components and the chemical entities that they transport change predominantly with sex and age. The aim of this study was to utilize blood chemistry monitoring to establish the reference levels in a small prosimian primate, the Grey Mouse Lemur (Microcebus murinus). METHOD: In the captive colony, mouse lemurs may live 10-12 years, and three age groups for both males and females were studied: young (1-3 years), middle-aged (4-5 years) and old (6-10 years). Blood biochemical markers were measured using the VetScan Comprehensive Diagnostic Profile. Because many life history traits of this primate are highly dependent on the photoperiod (body mass and reproduction), the effect of season was also assessed. RESULTS: The main effect of age was observed in blood markers of renal functions such as creatinine, which was higher among females. Additionally, blood urea nitrogen significantly increased with age and is potentially linked to chronic renal insufficiency, which has been described in captive mouse lemurs. The results demonstrated significant effects related to season, especially in blood protein levels and glucose rates; these effects were observed regardless of gender or age and were likely due to seasonal variations in food intake, which is very marked in this species. CONCLUSION: These results were highly similar with those obtained in other primate species and can serve as references for future research of the Grey Mouse Lemur.

Secretagogin is a Ca2+-binding protein specifying subpopulations of telencephalic neurons.

The Ca(2+)-binding proteins (CBPs) parvalbumin, calbindin, and calretinin are phenotypic markers of terminally differentiated neurons in the adult brain. Although subtle phylogenetic variations in the neuronal distribution of these CBPs may occur, morphologically and functionally diverse subclasses of interneurons harbor these proteins in olfactory and corticolimbic areas. Secretagogin (scgn) is a recently cloned CBP from pancreatic beta and neuroendocrine cells. We hypothesized that scgn is expressed in the mammalian brain. We find that scgn is a marker of neuroblasts commuting in the rostral migratory stream. Terminally differentiated neurons in the olfactory bulb retain scgn expression, with scgn being present in periglomerular cells and granular layer interneurons. In the corticolimbic system, scgn identifies granule cells distributed along the dentate gyrus, indusium griseum, and anterior hippocampal continuation emphasizing the shared developmental origins, and cytoarchitectural and functional similarities of these neurons. We also uncover unexpected phylogenetic differences in scgn expression, since this CBP is restricted to primate cholinergic basal forebrain neurons. Overall, we characterize scgn as a neuron-specific CBP whose distribution identifies neuronal subtypes and hierarchical organizing principles in the mammalian brain.

A novel system of polymorphic and diverse NK cell receptors in primates.

There are two main classes of natural killer (NK) cell receptors in mammals, the killer cell immunoglobulin-like receptors (KIR) and the structurally unrelated killer cell lectin-like receptors (KLR). While KIR represent the most diverse group of NK receptors in all primates studied to date, including humans, apes, and Old and New World monkeys, KLR represent the functional equivalent in rodents. Here, we report a first digression from this rule in lemurs, where the KLR (CD94/NKG2) rather than KIR constitute the most diverse group of NK cell receptors. We demonstrate that natural selection contributed to such diversification in lemurs and particularly targeted KLR residues interacting with the peptide presented by MHC class I ligands. We further show that lemurs lack a strict ortholog or functional equivalent of MHC-E, the ligands of non-polymorphic KLR in "higher" primates. Our data support the existence of a hitherto unknown system of polymorphic and diverse NK cell receptors in primates and of combinatorial diversity as a novel mechanism to increase NK cell receptor repertoire.

[Caloric restriction in primates: how efficient as an anti-aging approach?]. / La restriction calorique chez les primates.

Caloric restriction (CR) is the only non-genetic intervention known to date to slow the onset of age-related diseases and increase average and maximum lifespan in several species. Its interest is continually growing, particularly for the identification of mechanisms involved in increasing longevity. Unlike studies in invertebrate and rodent models have provided some indication about the mechanisms of the CR, the efficacy of CR as an anti-aging protocol in primates has not yet been fully established. In this review we present the advantages of using non human primates as relevant models to the study of human aging in general and specifically in the context of therapeutic interventions applicable to humans, such as CR. Through the longitudinal findings in the Grey Mouse Lemur (Microcebus murinus), we stress the importance of primate studies in the context of research on aging and their potential to advance the development of molecules which can mimic the beneficial effects of CR, already observed in some species, without imposing a reduced calorie diet.

Has Biomimicry in Architecture Arrived in France? Diversity of Challenges and Opportunities for a Paradigm Shift.

Biomimicry is a growing field of developing environmental innovations for materials, facade systems, buildings, and urban planning. In France, we observe an extensive diversity of initiatives in biomimicry for the development of regenerative cities. These initiatives blossom in a large range of areas, from education to urban policies, to achieve a major environmental, social and economic paradigm shift. To provide a comprehensive understanding of this development at the national scale, this paper presents and discusses the diversity of the developed initiatives over the last 10 years in six main fields-education, urban policies, fundamental and applied research, design demonstrators, arts, and communication. This research is an opportunistic study based on the analysis of these initiatives enriched by the feedback of the stakeholders collected by the authors working in the field of biomimicry over the last seven years. We identify that biomimicry in France has mainly extended through individual initiatives of teachers, territorial authorities, architectural studios, or researchers rather than through the support of public policies. Putting into perspective developments in biomimicry by other countries, this cross-discipline analysis provides recommendations for the extensive development of regenerative architecture and urbanism at the national scale.

Animal model considerations to evaluate prosthetic tricuspid valve implants.

AIMS: Determining tricuspid valve comparative anatomy and appropriate animal models for preclinical evaluation of prosthetic tricuspid valve implants. METHODS AND RESULTS: We described and measured 81 heart specimens: 12 humans, 22 dogs, 21 sheep and 26 pigs. Tricuspid annulus circumference varied in humans from 109 to 149 mm, in pigs from 85 to 140 mm, and were ≤125 mm in dogs and sheep. Tricuspid leaflet demarcation in dogs is similar to humans, while in pigs and sheep we observed three distinct leaflets. In humans, sheep and pigs, papillary muscle positions are similar. In dogs they are all based on the septum. A moderator band was observed in all species, but was of consistent thickness only in sheep. CONCLUSIONS: Sheep and pigs are relevant animal models for evaluating prosthetic tricuspid valve implants. Seventy to 90 kg pigs have a tricuspid annulus size comparable to that in a dilated human heart, but due to possible fast growth leading to sizing incompatibilities, this represents a model for short-term study. Sheep are more stable in size for long term study, however, their tricuspid annulus size is the most similar to that in a healthy, non-dilated human heart. Dogs are not a suitable model due to their significantly different sub-valvular anatomy and smaller size.

Exploring the behavioral reactions to a mirror in the nocturnal grey mouse lemur: sex differences in avoidance.

Most mirror-image stimulation studies (MIS) have been conducted on social and diurnal animals in order to explore self-recognition, social responses, and personality traits. Small, nocturnal mammals are difficult to study in the wild and are under-represented in experimental behavioral studies. In this pilot study, we explored the behavioral reaction of a small nocturnal solitary forager-the grey mouse lemur (Microcebus murinus)-an emergent animal model in captivity. We assessed whether MIS can be used to detect a repeatable behavioral reaction, whether individuals will present a similar reaction toward a conspecific and the mirror, and whether males and females respond similarly. We tested 12 individuals (six males and six females) twice in three different contexts: with a mirror, with a live conspecific, and with a white board as a neutral control. We detected significant repeatability for the activity component of the behavioral reaction. There was a significant effect of the context and the interaction between presentation context and sex for avoidance during the first session for males but not for females. Males avoided the mirror more than they avoided a live conspecific. This pilot study opens a discussion on the behavioral differences between males and females regarding social interactions and reproduction in the nocturnal solitary species, and suggests that males are more sensitive to context of stimulation than females.

Orientation Preference Maps in Microcebus murinus Reveal Size-Invariant Design Principles in Primate Visual Cortex.

Orientation preference maps (OPMs) are a prominent feature of primary visual cortex (V1) organization in many primates and carnivores. In rodents, neurons are not organized in OPMs but are instead interspersed in a "salt and pepper" fashion, although clusters of orientation-selective neurons have been reported. Does this fundamental difference reflect the existence of a lower size limit for orientation columns (OCs) below which they cannot be scaled down with decreasing V1 size? To address this question, we examined V1 of one of the smallest living primates, the 60-g prosimian mouse lemur (Microcebus murinus). Using chronic intrinsic signal imaging, we found that mouse lemur V1 contains robust OCs, which are arranged in a pinwheel-like fashion. OC size in mouse lemurs was found to be only marginally smaller compared to the macaque, suggesting that these circuit elements are nearly incompressible. The spatial arrangement of pinwheels is well described by a common mathematical design of primate V1 circuit organization. In order to accommodate OPMs, we found that the mouse lemur V1 covers one-fifth of the cortical surface, which is one of the largest V1-to-cortex ratios found in primates. These results indicate that the primate-type visual cortical circuit organization is constrained by a size limitation and raises the possibility that its emergence might have evolved by disruptive innovation rather than gradual change.

Secretagogin is a Ca2+-binding protein identifying prospective extended amygdala neurons in the developing mammalian telencephalon.

The Ca(2+)-binding proteins (CBPs) calbindin D28k, calretinin and parvalbumin are phenotypic markers of functionally diverse subclasses of neurons in the adult brain. The developmental dynamics of CBP expression are precisely timed: calbindin and calretinin are present in prospective cortical interneurons from mid-gestation, while parvalbumin only becomes expressed during the early postnatal period in rodents. Secretagogin (scgn) is a CBP cloned from pancreatic beta and neuroendocrine cells. We hypothesized that scgn may be expressed by particular neuronal contingents during prenatal development of the mammalian telencephalon. We find that scgn is expressed in neurons transiting in the subpallial differentiation zone by embryonic day (E)11 in mouse. From E12, scgn(+) cells commute towards the extended amygdala and colonize the bed nucleus of stria terminalis, the interstitial nucleus of the posterior limb of the anterior commissure, the dorsal substantia innominata (SI) and the central and medial amygdaloid nuclei. Scgn(+) neurons can acquire a cholinergic phenotype in the SI or differentiate into GABA cells in the central amygdala. We also uncover phylogenetic differences in scgn expression as this CBP defines not only neurons destined to the extended amygdala but also cholinergic projection cells and cortical pyramidal cells in the fetal nonhuman primate and human brains, respectively. Overall, our findings emphasize the developmentally shared origins of neurons populating the extended amygdala, and suggest that secretagogin can be relevant to the generation of functional modalities in specific neuronal circuitries.

Resveratrol suppresses body mass gain in a seasonal non-human primate model of obesity.

BACKGROUND: Resveratrol, a natural polyphenolic compound, was shown to protect rodents against high-fat-diet induced diabesity by boosting energy metabolism. To the best of our knowledge, no data is yet available on the effects of resveratrol in non-human primates. Six non-human heterotherm primates (grey mouse lemurs, Microcebus murinus) were studied during four weeks of dietary supplementation with resveratrol (200 mg/kg/day) during their winter body-mass gain period. Body mass, spontaneous energy intake, resting metabolic rate, spontaneous locomotor activity and daily variations in body temperature were measured. In addition, the plasma levels of several gut hormones involved in satiety control were evaluated. RESULTS: Resveratrol reduced the seasonal body-mass gain by concomitantly decreasing energy intake by 13% and increasing resting metabolic rate by 29%. Resveratrol supplementation inhibited the depth of daily torpor, an important energy-saving process in this primate. The daily amount of locomotor activity remained unchanged. Except for an increase in the glucose-dependent insulinotropic polypeptide, a gut hormone known to promote mobilization of fat stores, no major change in satiety hormone plasma levels was observed under resveratrol supplementation. CONCLUSIONS: These results suggest that in a non-human primate, resveratrol reduces body-mass gain by increasing satiety and resting metabolic rate, and by inhibiting torpor expression. The measured anorectic gut hormones did not seem to play a major role in these observations.

Sex-Specific Response to Caloric Restriction After Reproductive Investment in Microcebus murinus: An Integrative Approach.

In seasonal environments, males and females usually maintain high metabolic activity during the whole summer season, exhausting their energy reserves. In the global warming context, unpredictability of food availability during summer could dramatically challenge the energy budget of individuals. Therefore, one can predict that resilience to environmental stress would be dramatically endangered during summer. Here, we hypothesized that females could have greater capacity to survive harsh conditions than males, considering the temporal shift in their respective reproductive energy investment, which can challenge them differently, as well as enhanced flexibility in females' physiological regulation. We tackled this question on the gray mouse lemur (Microcebus murinus), focusing on the late summer period, after the reproductive effort. We monitored six males and six females before and after a 2-weeks 60% caloric restriction (CR), measuring different physiological and cellular parameters in an integrative and comparative multiscale approach. Before CR, females were heavier than males and mostly characterized by high levels of energy expenditure, a more energetic mitochondrial profile and a downregulation of blood antioxidants. We observed a similar energy balance between sexes due to CR, with a decrease in metabolic activity over time only in males. Oxidative damage to DNA was also reduced by different pathways between sexes, which may reflect variability in their physiological status and life-history traits at the end of summer. Finally, females' mitochondria seemed to exhibit greater flexibility and greater metabolic potential than males in response to CR. Our results showed strong differences between males and females in response to food shortage during late summer, underlining the necessity to consider sex as a factor for population dynamics in climate change models.

The Forearm Musculature of the Gray Mouse Lemur (Microcebus murinus): An Ontogenetic Study.

Although studies have sought to characterize variation in forearm muscular anatomy across the primate order, none have attempted to quantify ontogenetic changes in forearm myology within a single taxon. Herein, we present muscle architecture data for the forearm musculature (flexors and extensors of the wrist and digits) of Microcebus murinus, a small Lemuroid that has been the focus of several developmental studies. A quadratic curvilinear model described ontogenetic changes in muscle mass and fascicle length; however, fascicle lengths reached peak levels at an earlier age and showed a stronger decline during senescence. Conversely, physiological cross-sectional area followed a more linear trend, increasing steadily throughout life. As previous studies into the functional role of the primate forelimb emphasize the importance of long muscle fascicles within arboreal taxa in order to maximize mobility and flexibility, the early attainment of peak fascicle lengths may consequently reflect the importance of agility within this mobile and highly arboreal species. Similarly, observed myological trends in forearm strength are supported by previous in vivo data on grip strength within M. murinus in which senescent individuals showed no decline in forearm force relative to prime age individuals. This trend is interpreted to reflect compensation for the previously reported decline in hind limb grip strength in the hind limb with age, such that older individuals are able to maintain arboreal stability. Interestingly, the ontogenetic trajectory of each architectural variable mirrored previous observations of the masticatory musculature in M. murinus, suggesting that ontogenetic trends are relatively conserved between anatomical regions. Anat Rec, 303:1354-1363, 2020. © 2019 American Association for Anatomy.