An empirical estimate of the generation time of mouse lemurs.

The generation time of organisms drives the rate of change in populations and across evolutionary times. In long-lived species, generation time should also account for overlapping generations, and the average age of parents has been proposed as a best approximation under these conditions. This study uses this definition to estimate the generation time of a widely studied small primate, Microcebus murinus, based on parentage data generated for a free-living population over a 6-year period in northwestern Madagascar. The average age of parents was calculated separately for mothers and fathers of three different offspring cohorts that differed in the degree of demographic uncertainty. In addition, adult survival rates were calculated for males and females based on long-term capture data from the same population to estimate the possible upper limits of generation time. Adult survival was low with only 44% of adult females and 38% of adult males being recaptured at the beginning of their second breeding season. The average age of mothers was 1.56-1.91 years, pointing toward a 2-year female generation time due to the high proportion of 1-year old mothers in all three cohorts. Female generation time estimates were fairly stable across the three offspring cohorts. In contrast, the average age of fathers differed by more than 1 year from the first to the third offspring cohort (1.71-2.83 years) pointing toward a 3-year generation time, but also suggesting a higher degree of demographic uncertainty in the early years of the study. For future modeling purposes, we, therefore, propose to use the average, 2.5 years, of male and female values as new estimate for the generation time of mouse lemurs.

Agomelatine in the tree shrew model of depression: effects on stress-induced nocturnal hyperthermia and hormonal status.

The antidepressive drug agomelatine combines the properties of an agonist of melatonergic receptors 1 and 2 with an antagonist of the 5-HT2C receptor. We analyzed the effects of agomelatine in psychosocially stressed male tree shrews, an established preclinical model of depression. Tree shrews experienced daily social stress for a period of 5 weeks and were concomitantly treated with different drugs daily for 4 weeks. The effects of agomelatine (40 mg/kg/day) were compared with those of the agonist melatonin (40 mg/kg/day), the inverse 5-HT2C antagonist S32006 (10mg/kg/day), and the SSRI fluoxetine (15 mg/kg/day). Nocturnal core body temperature (CBT) was recorded by telemetry, and urinary norepinephrine and cortisol concentrations were measured. Chronic social stress induced nocturnal hyperthermia. Agomelatine normalized the CBT in the fourth week of the treatment (T4), whereas the other drugs did not significantly counteract the stress-induced hyperthermia. Agomelatine also reversed the stress-induced reduction in locomotor activity. Norepinephrine concentration was elevated by the stress indicating sympathetic hyperactivity, and was normalized in the stressed animals treated with agomelatine or fluoxetine but not in those treated with melatonin or S32006. Cortisol concentration was elevated by stress but returned to basal levels by T4 in all animals, irrespective of the treatment. These observations show that agomelatine has positive effects to counteract stress-induced physiological processes and to restore the normal rhythm of nocturnal CBT. The data underpin the antidepressant properties of agomelatine and are consistent with a distinctive profile compared to its constituent pharmacological components and other conventional agents.

Peripheral ossifying fibroma and juxtacortical chondrosarcoma in cynomolgus monkeys (Macaca fascicularis).

Literature on spontaneous primary bone tumors in nonhuman primates is sparse. This case report describes 2 different neoplastic bone lesions in 2 adult cynomolgus monkeys (Macaca fascicularis), including macroscopic, radiographic, histologic, and immunohistochemical findings. In one monkey, a firm mass located at the palatogingival junction of the left rostral maxilla was confirmed to be a peripheral ossifying fibroma in light of its histologic and immunohistochemical characteristics. In another monkey, a lobulated tumor at the right distal femur that radiographically showed moderate radiopacity with splotchy areas of mineralization was confirmed to be a juxtacortical chondrosarcoma on histologic examination. The 2 neoplastic bone lesions revealed rare histologic and immunohistochemical characteristics and contribute to the known tumor spectrum of cynomolgus monkeys.

Autoimmune optic neuritis in the common marmoset monkey: comparison of visual evoked potentials with MRI and histopathology.

PURPOSE: To assess the use of visual evoked potentials (VEPs) for the in vivo detection of impaired visual function in a marmoset model of multiple sclerosis. The sensitivity of the VEP recordings was determined by comparison with magnetic resonance imaging (MRI) and histopathology. METHODS: Baseline VEPs were recorded in six healthy marmoset monkeys in response to light-flash stimulation. Experimental autoimmune encephalomyelitis (EAE) was induced in four of the six monkeys. Clinical scores were assessed daily, and VEPs were recorded every second week. In vivo MRI and subsequent histopathology of the brains and optic nerves were performed at the end of the study. RESULTS: After induction of EAE, all four marmosets exhibited clinical signs between day 26 and 38 after immunization. VEPs were normal during the induction phase of the disease, but deteriorated in amplitude with the occurrence of clinical symptoms in all animals. MRI revealed bilateral optic neuritis and signal alterations in the optic tracts and occipital subcortical white matter in two of the animals. In the remaining two animals, MRI detected signal alterations in the occipital subcortical white matter. Histopathologic results were concordant with the MRI findings. CONCLUSIONS: VEPs are an easily accessible noninvasive tool for measuring visual function and diagnosing impairment of the visual pathway in a marmoset EAE model.

Experience-dependent recapture rates and reproductive success in male grey mouse lemurs (Microcebus murinus).

Male mating tactics can vary according to the potential for scramble or contest competition but also as a consequence of individual characteristics, such as body condition and previous experience. The influence of experience, i.e., residency, on male recapture rates and reproductive success was studied in a population of free-living grey mouse lemurs. Long-term capture data from 320 individuals revealed that both sexes had very low recapture probabilities within their first year in the study population, but recapture rates declined less sharply during the following years. Capture results and telemetric analyses on 12 focal males revealed that resident males had larger body mass and larger home ranges than new males. Home range size correlated with the number of accessible females, indicating that resident males had higher probabilities to meet mates than new males. The reproductive success of 132 candidate fathers, representing both resident and new males, was determined by means of molecular genotyping. Paternity determination was successful in 38 cases (success rate: 19%). Sixteen resident males and seventeen new males sired offspring. However, in relation to the number of candidate fathers being present in the mating season, resident males were twice as likely to reproduce successfully as new males. These findings suggest experience-dependent reproductive tactics that most likely correspond to a differential spatial knowledge of resources, mates and potential threats. The results generally agree with the predictions made for a scramble competition regime and demonstrate substantial behavioral plasticity in a nocturnal primate species with a dispersed multi-male/multi-female mating system.

The role of survival for the evolution of female philopatry in a solitary forager, the grey mouse lemur (Microcebus murinus).

It is widely accepted that natal philopatry is a prerequisite for the evolution of sociality. The life-history hypothesis maintains that longevity of adults results in extended territory tenure and thus limits breeding vacancies for offspring, which makes natal philopatry more likely. Here, we tested the importance of longevity for natal philopatry in females of a basal primate, the grey mouse lemur (Microcebus murinus). This species is regarded as being solitary due to its foraging habits but while males disperse, female offspring in this species forgo dispersal and form long-term sleeping groups with their mothers. We tested whether high adult survival could be a cause for natal philopatry of female offspring. In addition, we assessed costs and benefits associated with space sharing between mothers and daughters and whether mothers actively increase survival of daughters by beqeauthal of territories, information transfer about resources or thermoregulation. Contrary to our predictions, adult females had low-survival rates. Space sharing appeared to improve survival of both, mothers and daughters. This could be a result of information transfer about sleeping sites and thermoregulatory benefits. Our results cast doubt on the idea that longevity predisposes species for social traits and provide support for benefits of philopatry.

Differential macrophage/microglia activation in neocortical EAE lesions in the marmoset monkey.

Recent studies revealed an important involvement of the cerebral cortex in multiple sclerosis (MS) patients. Cortical lesions in MS were reported to be less inflammatory and to show less structural damage than white matter lesions. Animal models reflecting the histopathological hallmarks of cortical demyelinated lesions in MS are sparse. Induction of experimental autoimmune encephalomyelitis (EAE) in the common marmoset has turned out to be an attractive non-human-primate model for MS. In the present study we investigated the presence and detailed cellular composition of cortical inflammatory demyelinating pathology in the common marmoset upon immunization with myelin oligodendrocyte glycoprotein (MOG). Extensive cortical demyelination reflecting the topographically distinct cortical lesion types in MS patients was revealed by immunohistochemistry for myelin basic protein (MBP). We explored the density of T- and B-lymphocytes, MHC-II expressing macrophages/microglia cells and early activated macrophages (MRP14) at perivascular and parenchymal lesions sites in neocortex and subcortical white matter. Despite a similar density of perivascular inflammatory infiltrates in the demyelinated neocortex, a considerable lower fraction of macrophages was found to express MRP14 in the neocortex indicating a different activation pattern in cortical compared with white matter lesions. Furthermore, cortical EAE lesions in marmoset monkeys revealed immunoglobulin leakage and complement component C9 deposition in intracortical but not subpial demyelination. Our findings indicate that the inflammatory response, especially macrophage and microglia activation, may be regulated differently in gray matter areas in primate brain.

Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment.

Analysis of post-mortem tissue from patients with affective disorders has revealed a decreased number of glial cells in several brain areas. Here, we examined whether long-term psychosocial stress influences the number and morphology of hippocampal astrocytes in an animal model with high validity for research on the pathophysiology of major depression. Adult male tree shrews were submitted to 5 weeks of psychosocial stress, after which immunocytochemical and quantitative stereological techniques were used to estimate the total number and somal volume of glial fibrillary acidic protein-positive astrocytes in the hippocampal formation. Stress significantly decreased both the number (-25%) and somal volume (-25%) of astroglia, effects that correlated notably with the stress-induced hippocampal volume reduction. Additionally, we examined whether antidepressant treatment with fluoxetine, a selective serotonin reuptake inhibitor, offered protection from these stress-induced effects. Animals were subjected to 7 days of psychosocial stress before the onset of daily oral administration of fluoxetine (15 mg/kg per day), with stress continued throughout the 28-day treatment period. Fluoxetine treatment prevented the stress-induced numerical decrease of astrocytes, but had no counteracting effect on somal volume shrinkage. In nonstressed animals, fluoxetine treatment had no effect on the number of astrocytes, but stress exposure significantly reduced their somal volumes (-20%). These notable changes of astroglial structural plasticity in response to stress and antidepressant treatment support the notion that glial changes may contribute to the pathophysiology of affective disorders as well as to the cellular actions of antidepressants.

Monitoring of EAE onset and progression in the common marmoset monkey by sequential high-resolution 3D MRI.

Experimental autoimmune encephalomyelitis (EAE) induced by myelin-oligodendrocyte glycoprotein (MOG) in common marmosets (Callithrix jacchus) is a model for multiple sclerosis. Here, EAE was induced in four common marmosets by 250-300 microg recombinant rat MOG. In addition to a detailed disability scoring, T2- and T1-weighted high-resolution 3D MRI was performed to assess the onset and development of cerebral lesions. The findings were confirmed by histopathology in all animals. Although the animals exhibited a large heterogeneity with regard to onset and localization of lesions and also to disease duration and severity of disability signs, none of the animals revealed any evidence of recovery. A specification of the disability scoring system to account for different aspects of the disease led to a good concurrence of the first MRI-detectable lesion and the onset of central nervous system (CNS) symptoms. The results suggest that MRI monitoring of white matter lesions in conjunction with disability scores that focus on CNS symptoms may be a suitable method to evaluate novel therapeutic interventions even in the presence of pronounced interindividual heterogeneity.

Pharmacology of a new antidepressant: benefit of the implication of the melatonergic system.

The limitations of current antidepressant medications merit the exploration of alternative agents with novel antidepressant mechanisms of action. The established clinical finding that desynchronization of internal rhythms plays an important role in the pathophysiology of depressive disorders has stimulated the idea that resetting normal circadian rhythms may have antidepressant potential. Recent experiments using the novel melatonin receptor agonist and serotonin 2 (5-HT2c) receptor antagonist agomelatine (S20098; N[2-(7-methoxy-1-naphthyl)ethyl]- acetamide) revealed a notable chronobiotic activity and clear antidepressant-like effects in a variety of preclinical models. Binding studies performed in vitro proved that agomelatine is a high-affinity agonist at both the melatonin MT1 and MT2 receptor types. In addition, these studies revealed that agomelatine, in contrast to melatonin, blocks 5-HT2c receptors with significant affinity. Antagonism of 5-HT2c receptors is reported for various established antidepressant compounds. The antidepressant properties of agomelatine are thus based on its melatonergic actions and 5-HT2c receptor antagonism.

Chronic stress decreases the number of parvalbumin-immunoreactive interneurons in the hippocampus: prevention by treatment with a substance P receptor (NK1) antagonist.

Previous studies have demonstrated that stress may affect the hippocampal GABAergic system. Here, we examined whether long-term psychosocial stress influenced the number of parvalbumin-containing GABAergic cells, known to provide the most powerful inhibitory input to the perisomatic region of principal cells. Adult male tree shrews were submitted to 5 weeks of stress, after which immunocytochemical and quantitative stereological techniques were used to estimate the total number of hippocampal parvalbumin-immunoreactive (PV-IR) neurons. Stress significantly decreased the number of PV-IR cells in the dentate gyrus (DG) (-33%), CA2 (-28%), and CA3 (-29%), whereas the CA1 was not affected. Additionally, we examined whether antidepressant treatment offered protection from this stress-induced effect. We administered fluoxetine (15 mg/kg per day) and SLV-323 (20 mg/kg per day), a novel neurokinin 1 receptor (NK1R) antagonist, because the NK1R has been proposed as a possible target for novel antidepressant therapies. Animals were subjected to a 7-day period of psychosocial stress before the onset of daily oral administration of the drugs, with stress continued throughout the 28-day treatment period. NK1R antagonist administration completely prevented the stress-induced reduction of the number of PV-IR interneurons, whereas fluoxetine attenuated this decrement in the DG, without affecting the CA2 and CA3. The effect of stress on interneuron numbers may reflect real cell loss; alternatively, parvalbumin concentration is diminished in the neurons, which might indicate a compensatory attempt. In either case, antidepressant treatment offered protection from the effect of stress and appears to modulate the hippocampal GABAergic system. Furthermore, the NK1R antagonist SLV-323 showed neurobiological efficacy similar to that of fluoxetine.