A key characteristic of human language efficiency is that more frequently used words tend to be shorter in length—the ‘law of brevity’. To date, no test of this relationship between frequency of use and length has been carried out on non-human animal vocal communication. We show here that the vocal repertoire of the Formosan macaque (Macaca cyclopis) conforms to the pattern predicted by the law of brevity, with an inverse relationship found between call duration and rate of utterance. This finding provides evidence for coding efficiency in the vocal communication system of this species, and indicates commonality in the basic structure of the coding system between human language and vocal communication in this non-human primate.
Formosan macaque; communication; language; coding; primate
All non-human primates communicate with conspecifics using vocalizations, a system involving both the production and perception of species-specific vocal signals. Much of the work on the neural basis of primate vocal communication in cortex has focused on the sensory processing of vocalizations, while relatively little data are available for vocal production. Earlier physiological studies in squirrel monkeys had shed doubts on the involvement of primate cortex in vocal behaviors. The aim of the present study was to identify areas of common marmoset (Callithrix jacchus) cortex that are potentially involved in vocal communication. In this study, we quantified cFos expression in three areas of marmoset cortex – frontal, temporal (auditory), and medial temporal – under various vocal conditions. Specifically, we examined cFos expression in these cortical areas during the sensory, motor (vocal production), and sensory–motor components of vocal communication. Our results showed an increase in cFos expression in ventrolateral prefrontal cortex as well as the medial and lateral belt areas of auditory cortex in the vocal perception condition. In contrast, subjects in the vocal production condition resulted in increased cFos expression only in dorsal premotor cortex. During the sensory–motor condition (antiphonal calling), subjects exhibited cFos expression in each of the above areas, as well as increased expression in perirhinal cortex. Overall, these results suggest that various cortical areas outside primary auditory cortex are involved in primate vocal communication. These findings pave the way for further physiological studies of the neural basis of primate vocal communication.
immediate early gene expression; common marmoset; vocal communication; frontal cortex; auditory cortex; medial temporal cortex
Pitch, our perception of how high or low a sound is on a musical scale, is a fundamental perceptual attribute of sounds and is important for both music and speech. After more than a century of research, the exact mechanisms used by the auditory system to extract pitch are still being debated. Theoretically, pitch can be computed using either spectral or temporal acoustic features of a sound. We have investigated how cues derived from the temporal envelope and spectrum of an acoustic signal are used for pitch extraction in the common marmoset (Callithrix jacchus), a vocal primate species, by measuring pitch discrimination behaviorally and examining pitch-selective neuronal responses in auditory cortex. We find that pitch is extracted by marmosets using temporal envelope cues for lower pitch sounds composed of higher-order harmonics, whereas spectral cues are used for higher pitch sounds with lower-order harmonics. Our data support dual-pitch processing mechanisms, originally proposed by psychophysicists based on human studies, whereby pitch is extracted using a combination of temporal envelope and spectral cues.
The ability to record well-isolated action potentials from individual neurons in naturally behaving animals is crucial for understanding neural mechanisms underlying natural behaviors. Traditional neurophysiology techniques, however, require the animal to be restrained which often restricts natural behavior. An example is the common marmoset (Callithrix jacchus), a highly vocal New World primate species, used in our laboratory to study the neural correlates of vocal production and sensory feedback. When restrained by traditional neurophysiological techniques marmoset vocal behavior is severely inhibited. Tethered recording systems, while proven effective in rodents pose limitations in arboreal animals such as the marmoset that typically roam in a three-dimensional environment. To overcome these obstacles, we have developed a wireless neural recording technique that is capable of collecting single-unit data from chronically implanted multi-electrodes in freely moving marmosets. A lightweight, low power and low noise wireless transmitter (headstage) is attached to a multi-electrode array placed in the premotor cortex of the marmoset. The wireless headstage is capable of transmitting 15 channels of neural data with signal-to-noise ratio (SNR) comparable to a tethered system. To minimize radio-frequency (RF) and electro-magnetic interference (EMI), the experiments were conducted within a custom designed RF/EMI and acoustically shielded chamber. The individual electrodes of the multi-electrode array were periodically advanced to densely sample the cortical layers. We recorded single-unit data over a period of several months from the frontal cortex of two marmosets. These recordings demonstrate the feasibility of using our wireless recording method to study single neuron activity in freely roaming primates.
Action potential; free-roaming; marmoset; multi-channel; multi-electrode array; natural behavior; neurophysiology; neural telemetry; primate; single-unit; vocalization; wireless
The marmoset (Callithrix jacchus) is a valuable non-human primate model for studying behavioral and neural mechanisms related to vocal communication. It is also well suited for investigating neural mechanisms related to cochlear implants. The purpose of this study was to characterize marmoset temporal bone anatomy and investigate the feasibility of implanting a multi-channel intracochlear electrode into the marmoset scala tympani. Micro computed tomography (microCT) was used to create high-resolution images of marmoset temporal bones. Cochlear fluid spaces, middle ear ossicles, semicircular canals and the surrounding temporal bone were reconstructed in three-dimensional space. Our results show that the marmoset cochlea is ~16.5 mm in length and has ~2.8 turns. The cross-sectional area of the scala tympani is greatest (~0.8 mm2) at ~1.75 mm from the base of the scala, reduces to ~0.4 mm2 at 5 mm from the base, and decreases at a constant rate for the remaining length. Interestingly, this length-area profile, when scaled 2.5 times, is similar to the scala tympani of the human cochlea. Given these dimensions, a compatible multi-channel implant electrode was identified. In a cadaveric specimen, this electrode was inserted ¾ turn into the scala tympani through a cochleostomy at ~1 mm apical to the round window. The depth of the most apical electrode band was ~8 mm. Our study provides detailed structural anatomy data for the middle and inner ear of the marmoset, and suggests the potential of the marmoset as a new non-human primate model for cochlear implant research.
cochlear implant; marmoset; cochlear scalae; temporal bone anatomy
Many vocalizations are encoded with a diversity of acoustic information about the signal producer. Amongst this information content are social categories related to the identity of the caller that are important for determining if and how a signal receiver may interact with that individual. Here we employed a novel playback method in common marmosets (Callithrix jacchus) to test individual recognition during bouts of antiphonal calling. These experiments utilized custom, interactive playback software that effectively engaged subjects in antiphonal calling using vocalizations produced by a single individual and presented ‘probe’ vocalization stimuli representing a different individual at specific points within bouts of calling. The aim here was to test whether marmosets would recognize that the probe stimulus was a phee call produced by a different individual. Data indicated that marmosets were able to detect the change in caller identity; subjects produced significantly fewer antiphonal call responses to probe than control stimuli and, in some conditions, exhibited a shorter latency to produce the vocal response. These data suggest that marmosets recognize the identity of the individual during bouts of antiphonal calling. Furthermore, these results provide a methodological foundation for implementing the probe playback procedure to examine a broader range of social categorization during vocal interactions.
The common marmoset (Callithrix jacchus) is poised to become a standard nonhuman primate aging model. With an average lifespan of 5 to 7 years and a maximum lifespan of 16.5 years, marmosets are the shortest-lived anthropoid primates. They display age-related changes in pathologies that mirror those seen in humans, such as cancer, amyloidosis, diabetes, and chronic renal disease. They also display predictable age-related differences in lean mass, calf circumference, circulating albumin, hemoglobin, and hematocrit. Features of spontaneous sensory and neurodegenerative change—for example, reduced neurogenesis, β-amyloid deposition in the cerebral cortex, loss of calbindin D28k binding, and evidence of presbycusis—appear between the ages of 7 and 10 years. Variation among colonies in the age at which neurodegenerative change occurs suggests the interesting possibility that marmosets could be specifically managed to produce earlier versus later occurrence of degenerative conditions associated with differing rates of damage accumulation. In addition to the established value of the marmoset as a model of age-related neurodegenerative change, this primate can serve as a model of the integrated effects of aging and obesity on metabolic dysfunction, as it displays evidence of such dysfunction associated with high body weight as early as 6 to 8 years of age.
aging research; hearing loss; marmoset (Callithrix jacchus); neurodegeneration; nonhuman primate (NHP); obesity
Using measurements based on particle image velocimetry in combination with a novel compact theoretical framework to describe hair mechanics, we found that spider and cricket air motion sensing hairs work close to the physical limit of sensitivity and energy transmission in a broad range of relatively high frequencies. In this range, the hairs closely follow the motion of the incoming flow because a minimum of energy is dissipated by forces acting in their basal articulation. This frequency band is located beyond the frequency at which the angular displacement of the hair is maximum which is between about 40 and 600 Hz, depending on hair length (Barth et al.  Phil. Trans. R. Soc. Lond. B
340, 445–461 (doi:10.1098/rstb.1993.0084)). Given that the magnitude of natural airborne signals is known to decrease with frequency, our results point towards the possible existence of spectral signatures in the higher frequency range that may be weak but of biological significance.
filiform hairs; airborne signals; sensory physiology; trichobothria; mechanoreceptors
The remarkable clinical efficacy of anti-CD20 monoclonal antibodies (mAb) in relapsing-remitting multiple sclerosis points at the critical involvement of B cells in the disease. However, the exact pathogenic contribution of B cells is poorly understood. In this publication we review new data on the role of CD20+ B cells in a unique experimental autoimmune encephalomyelitis (EAE) model in common marmosets (Callithrix jacchus), a small-bodied neotropical primate. We will also discuss the relevance of these data for MS. Different from rodent EAE models, but similar to MS, disease progression in marmosets can develop independent of autoantibodies. Progressive disease is mediated by MHC class Ib (Caja-E) restricted cytotoxic T cells, which are activated by γ-herpesvirus-infected B cells and cause widespread demyelination of cortical gray matter. B-cell directed monoclonal antibody therapies (anti-CD20 versus anti-BLyS and anti-APRIL) have a variable effect on EAE progression, which we found associated with variable depletion of the Epstein Barr virus (EBV)-like γ-herpesvirus CalHV3 from lymphoid organs. These findings support an important pathogenic role of CD20+ B cell in MS, especially of the subset infected with EBV.
MS; EAE; EBV; non-human primate; B cell; T cell; immunotherapy
Researchers have described multilevel societies with one-male, multifemale units (OMUs) forming within a larger group in several catarrhine species, but not in platyrhines. OMUs in multilevel societies are associated with extremely large group sizes, often with >100 individuals, and the only platyrhine genus that forms groups of this size is Cacajao. We review available evidence for multilevel organization and the formation of OMUs in groups of Cacajao, and test predictions for the frequency distribution patterns of male–male and male–female interindividual distances within groups of red-faced uakaris (Cacajao calvus ucayalii), comparing year-round data with those collected at the peak of the breeding season, when group cohesion may be more pronounced. Groups of Cacajao fission and fuse, forming subgroup sizes at frequencies consistent with an OMU organization. In Cacajao calvus ucayalii and Cacajao calvus calvus, bachelor groups are also observed, a characteristic of several catarrhine species that form OMUs. However, researchers have observed both multimale–multifemale groups and groups with a single male and multiple females in Cacajao calvus. The frequency distributions of interindividual distances for male–male and male–female dyads are consistent with an OMU-based organization, but alternative interpretations of these data are possible. The distribution of interindividual distances collected during the peak breeding season differed from those collected year-round, indicating seasonal changes in the spatial organization of Cacajao calvus ucayalii. We suggest a high degree of flexibility may characterize the social organization of Cacajao calvus ucayalii, which may form OMUs under certain conditions. Further studies with identifiable individuals, thus far not possible in Cacajao, are required to confirm the social organization.
Breeding system; Mating system; One-male unit; Pitheciine; Social structure
Several recent studies suggested a role for neuronal major histocompatibility complex class I (MHCI) molecules in certain forms of synaptic plasticity in the hippocampus of rodents. Here, we report for the first time on the expression pattern and functional properties of MHCI molecules in the hippocampus of a nonhuman primate, the common marmoset monkey (Callithrix jacchus). We detected a presynaptic, mossy fiber-specific localization of MHCI proteins within the marmoset hippocampus. MHCI molecules were present in the large, VGlut1-positive, mossy fiber terminals, which provide input to CA3 pyramidal neurons. Furthermore, whole-cell recordings of CA3 pyramidal neurons in acute hippocampal slices of the common marmoset demonstrated that application of antibodies which specifically block MHCI proteins caused a significant decrease in the frequency, and a transient increase in the amplitude, of spontaneous excitatory postsynaptic currents (sEPSCs) in CA3 pyramidal neurons. These findings add to previous studies on neuronal MHCI molecules by describing their expression and localization in the primate hippocampus and by implicating them in plasticity-related processes at the mossy fiber–CA3 synapses. In addition, our results suggest significant interspecies differences in the localization of neuronal MHCI molecules in the hippocampus of mice and marmosets, as well as in their potential function in these species.
Electronic supplementary material
The online version of this article (doi:10.1007/s10571-010-9510-3) contains supplementary material, which is available to authorized users.
Calbindin; CA3; GFAP; Piccolo; Neuronal plasticity; PSD95; sEPSC; VGAT; VGlut1; VGlut 2
The recent finding of a novel Epstein-Barr virus-related lymphocryptovirus (CalHV-3) in a captive colony of common marmoset (Callithrix jacchus) in the United States modifies the view that the host range of lymphocryptovirus is restricted to humans and Old World primates. We investigated the presence of Epstein-Barr virus-related viruses in 79 samples of New World monkeys caught in the wild, including six species of the Cebidae family and one of the Callitrichidae, living in the rain forest of French Guiana. Using a degenerate consensus PCR method for the herpesvirus DNA polymerase gene, we identified three novel lymphocryptoviruses from golden-handed tamarin (Saguinus midas) of the Callitrichidae family and squirrel monkey (Saimiri sciureus) and white-faced saki (Pithecia pithecia) of the Cebidae family. With the CalHV-3 strain, these three novel viruses constitute a well-supported phylogenetic clade in the Lymphocryptovirus genus, which is clearly distinct from the lineage of Old World lymphocryptovirus, hosted by catarrhine monkeys and humans. In tamarins, the prevalence of the novel lymphocryptovirus was more than 50%, indicating that it circulates well in the wild population, perhaps due to specific ecoethological patterns such as confrontations and intergroup migration. The detection and partial molecular characterization of the polymerase gene of three novel Gamma-1-Herpesvirinae from New World monkeys caught in the wild clearly indicate that free-ranging populations of platyrrhine are natural hosts of lymphocryptoviruses. Further characterization of these novel viruses will provide new insight not only into the origin and evolution of Gammaherpesvirinae but also into their pathogenicity.
Distortion-product otoacoustic emissions (DPOAEs) were measured in a New World primate, the common marmoset (Callithrix jacchus). We determined the optimal primary-tone frequency ratio (f2/f1) to generate DPOAEs of maximal amplitude between 3 – 24 kHz. The optimal f2/f1, determined by varying f2/f1 from 1.02 – 1.40 using equilevel primary tones, decreased with increasing f2 frequency between 3 – 17 kHz, and increased at 24 kHz. The optimal f2/f1 ratio increased with increasing primary-tone levels from 50 – 74 dB SPL. When all stimulus parameters were considered, the mean optimal f2/f1 was 1.224 – 1.226. Additionally, we determined the effect of reducing L2 below L1. Decreasing L2 below L1 by 0, 5, and 10 dB (f2/f1 = 1.21) minimally affected DPOAE strength. DPOAE levels were stronger in females than males and stronger in the right ear than the left, just as in humans. This study is the first to measure OAEs in the marmoset, and the results indicate that the effect of varying the frequency ratio and primary-tone level difference on marmoset DPOAEs is similar to the reported effects in humans and Old World primates.
OAE; DPOAE; parameter optimization; primary-tone frequency ratio; primary-tone level difference; animal model; primate; marmoset
Young primates in the family Callitrichidae (the marmosets and tamarins) receive extensive and relatively prolonged care from adults. Of particular note, callitrichid young are routinely provisioned until well after weaning by parents and helpers, which is in stark contrast to typical juvenile primates, who must acquire most of their food independently once they are weaned. Adults of some callitrichid species produce a specialized vocalization that encourages immature group members to take proffered food from the caller. Here, I report that wild adult golden lion tamarins (Leontopithecus rosalia) not only used this food-offering call to encourage young, mobile offspring to approach and take captured prey from them, but as the young began to spend significant time foraging for themselves and to acquire prey by independent means, the frequency of these vocalizations in the context of food transfer declined. Adults then began to use food-offering calls in a novel context: to direct juveniles to foraging sites that contained hidden prey that the adults had found but not captured. During the period of these most frequent adult-directed prey captures, the independent prey-capture success rates of juveniles improved. Thus, adults modified their provisioning behavior in a progressive developmentally sensitive manner that may have facilitated learning how to find food. I hypothesize that as a result of these demonstrations by adults, juveniles either may be encouraged to continue foraging despite low return rates or to learn the properties of productive prey-foraging substrates in a complex environment.
golden lion tamarin; infant development; parenting behavior; prey foraging; provisioning; teaching
Pitch is one of the most fundamental percepts in the auditory system and can be extracted using either spectral or temporal information in an acoustic signal. While pitch perception has been extensively studied in human subjects, it is far less clear how non-human primates perceive pitch. We have addressed this question in a series of behavioral studies in which marmosets, a vocal non-human primate species, were trained to discriminate complex harmonic tones differing in either spectral (fundamental frequency [f0]) or temporal envelope (repetition rate) cues. We found that marmosets used temporal envelope information to discriminate pitch for acoustic stimuli with higher order harmonics and lower f0's and spectral information for acoustic stimuli with lower order harmonics and higher f0's. We further measured frequency resolution in marmosets using a psychophysical task in which pure tone thresholds were measured as a function of notched noise masker bandwidth. Results show that only the first four harmonics are resolved at low f0's and up to sixteen harmonics are resolved at higher f0's. Resolvability in marmosets is different from that in humans, where the first five to nine harmonics are consistently resolved across most f0's, and is likely the result of a smaller marmoset cochlea. In sum, these results show that marmosets employ two mechanisms to extract pitch (harmonic templates [spectral] for resolved harmonics, and envelope extraction [temporal] for unresolved harmonics) and that species differences in stimulus resolvability need to be taken into account when investigating and comparing mechanisms of pitch perception across animals.
auditory; behavior; psychophysics; primate; pitch; harmonic; missing fundamental; resolvability; frequency selectivity; notched-noise; equivalent; rectangular bandwidth
Burkholderia pseudomallei is a dangerous human pathogen. Phosphoantigens specifically the target primate specific γ9+δ2+ T cells subset and some have been developed as potential immunotherapeutics. Previously, we demonstrated that, when stimulated with the phosphoantigen CHDMAPP, γ9+δ2+ T cells aid in the killing of intracellular B. pseudomallei bacteria. Moreover, we found that common marmoset (Callithrix Jacchus) γ9+ T cells increase in frequency and respond to the phosphoantigen CHDMAPP and/or B. pseudomallei, in combination with IL-2, in a similar manner to human γ9+δ2+ T cells. Here we evaluate the efficacy of the phosphoantigen CHDMAPP, in combination with IL-2, as a therapy against B. pseudomallei infection, in vivo. We found that the previous studies predicted the in vivo responsiveness of γ9+ T cells to the CHDMAPP+IL-2 treatment and significant expansion of the numbers of peripheral and splenic γ9+ T cells were observed. This effect was similar to those reported in other primate species treated with phosphoantigen. Furthermore, splenocytes were retrieved 7 days post onset of treatment, restimulated with CHDMAPP or heat-killed B. pseudomallei and the cultured γ9+ T cells demonstrated no reduction in IFN-γ response when CHDMAPP+IL-2 animals were compared to IL-2 only treated animals. Using an established model of B. pseudomallei infection in the marmoset, we assessed the potential for using phosphoantigen as a novel immunotherapy. The CHDMAPP treatment regime had no effect on the progression of respiratory melioidosis and this was despite the presence of elevated numbers of γ9+ T cells in the spleen, liver and lung and an increased proportion of IFN-γ+ cells in response to infection. We therefore report that the common marmoset has proven a good model for studying the effect in vivo of γ9+ T cell stimulation; however, γ9+ T cells have little or no effect on the progression of lethal, respiratory B. pseudomallei infection.
The common marmoset monkey (Callithrix jacchus), a small non-endangered New World primate native to eastern Brazil, is becoming increasingly used as a non-human primate model in biomedical research, drug development and safety assessment. In contrast to the growing interest for the marmoset as an animal model, the molecular tools for genetic analysis are extremely limited.
Here we report the development of the first marmoset-specific oligonucleotide microarray (EUMAMA) containing probe sets targeting 1541 different marmoset transcripts expressed in hippocampus. These 1541 transcripts represent a wide variety of different functional gene classes. Hybridisation of the marmoset microarray with labelled RNA from hippocampus, cortex and a panel of 7 different peripheral tissues resulted in high detection rates of 85% in the neuronal tissues and on average 70% in the non-neuronal tissues. The expression profiles of the 2 neuronal tissues, hippocampus and cortex, were highly similar, as indicated by a correlation coefficient of 0.96. Several transcripts with a tissue-specific pattern of expression were identified. Besides the marmoset microarray we have generated 3215 ESTs derived from marmoset hippocampus, which have been annotated and submitted to GenBank [GenBank: EF214838 – EF215447, EH380242 – EH382846].
We have generated the first marmoset-specific DNA microarray and demonstrated its use to characterise large-scale gene expression profiles of hippocampus but also of other neuronal and non-neuronal tissues. In addition, we have generated a large collection of ESTs of marmoset origin, which are now available in the public domain. These new tools will facilitate molecular genetic research into this non-human primate animal model.
The purpose of this study was to examine the possibility that all-trans-retinoic acid (RA) in the eye is a signal related to changes in scleral extracellular matrix in a primate model of postnatal eye growth.
Juvenile marmosets (Callithrix jacchus) were divided into two experimental groups based on their response to monocular deprivation with diffusers: group 1, treated eyes becoming longer than fellow control eyes (n = 8), and group 2, treated eyes becoming shorter than control eyes (n = 7). Eyes were enucleated, dissected, and assayed for changes in the rates of scleral glycosaminoglycan (GAG) synthesis and ocular RA synthesis. The rate of incorporation of 35SO4 into CPC-precipitable GAG in scleras was taken as a measure of the rate of synthesis of proteoglycans. In the same eyes the rate of RA synthesis in vivo was measured separately in the retina and the choroid/RPE (choroid with RPE attached) by HPLC. The effect of RA on the rate of scleral GAG synthesis was also examined in tissue-cultured pieces of sclera from additional marmosets.
Induced changes in vitreous chamber length in diffuser-treated eyes correlated inversely with the rate of scleral GAG synthesis (P < 0.05) and directly correlated with the rate of RA synthesis measured separately in the retina (P < 0.05) and the choroid/RPE (P < 0.05). In group 1, the rate of scleral GAG synthesis was significantly lower (P < 0.01) in the treated eyes relative to control eyes, and the rate of RA synthesis in both the retina and the choroid/RPE was significantly higher (P < 0.01). In group 2, the rates of scleral GAG synthesis and RA synthesis in either the retina or choroid/RPE were not found to change significantly in the treated eyes compared with the control eyes. RA partially reduces the rate of scleral GAG synthesis in tissue-cultured primate sclera in a dose-dependent manner after several days.
RA may play a role in the visual control of postnatal eye growth in primates, possibly by inducing changes in scleral extracellular matrix associated with increasing eye size. Decreasing growth rate below control levels may involve other mechanisms.
The common marmoset (Callithrix jacchus) is a small New World primate that has been used as a non-human primate model for various biomedical studies. We previously demonstrated that transplantation of neural stem/progenitor cells (NS/PCs) derived from mouse and human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) promote functional locomotor recovery of mouse spinal cord injury models. However, for the clinical application of such a therapeutic approach, we need to evaluate the efficacy and safety of pluripotent stem cell-derived NS/PCs not only by xenotransplantation, but also allotransplantation using non-human primate models to assess immunological rejection and tumorigenicity. In the present study, we established a culture method to efficiently derive NS/PCs as neurospheres from common marmoset ESCs. Marmoset ESC-derived neurospheres could be passaged repeatedly and showed sequential generation of neurons and astrocytes, similar to that of mouse ESC-derived NS/PCs, and gave rise to functional neurons as indicated by calcium imaging. Although marmoset ESC-derived NS/PCs could not differentiate into oligodendrocytes under default culture conditions, these cells could abundantly generate oligodendrocytes by incorporating additional signals that recapitulate in vivo neural development. Moreover, principal component analysis of microarray data demonstrated that marmoset ESC-derived NS/PCs acquired similar gene expression profiles to those of fetal brain-derived NS/PCs by repeated passaging. Therefore, marmoset ESC-derived NS/PCs may be useful not only for accurate evaluation by allotransplantation of NS/PCs into non-human primate models, but are also applicable to analysis of iPSCs established from transgenic disease model marmosets.
While much is known about adult obesity in nonhuman primates, very little is known regarding development of childhood adiposity. As small monkeys that are easy to handle and have a relatively fast life history, common marmoset monkeys (Callithrix jacchus) offer interesting opportunities to examine the question of fat versus lean mass growth in a nonhuman primate. This paper provides an overview of our understanding of early life growth in mass in marmoset monkeys, based primarily upon our past 20 years of research, culminating in our recent findings on early life obesity in this species. Common marmosets display variance in early life growth patterns that is related to both pre- and post-natal factors and the marmoset uterine environment is exquisitely designed to reflect resources available for the gestation of multiple offspring, making them an interesting model of developmental programming. We have demonstrated that obesity can be generated in very early life in captive marmosets, with excess adiposity evident by one month of age, making this species a potentially valuable model in which to study pediatric obesity and its sequelae. Birth weight is associated with adiposity in animals vulnerable to obesity. Early life exposure to higher fat diets enhances the chances of post-weaning obesity development. However, overall higher food consumption is also associated with obesity development at later ages. One unexpected finding in our studies has been the relatively high body fat percentage of neonatal (12–18%) marmosets suggesting that hypotheses regarding the uniqueness of high human neonatal adiposity merit further examination.
pediatric obesity; adiposity; growth; nonhuman primate; marmoset
A T cell response against myelin basic protein (MBP) is thought to contribute to the central nervous system (CNS) inflammation that occurs in the human demyelinating disease multiple sclerosis. To test whether MBP-reactive T cells that are normally retrieved from the circulation are capable of inducing CNS disease, MBP-reactive T cell clones were isolated from the peripheral blood of healthy, unimmunized Callithrix jacchus (C. jacchus) marmosets. This primate species is characterized by a natural chimerism of bone marrow elements between siblings that should make possible adoptive transfer of MBP-reactive T cells. We report that MBP-reactive T cell clones efficiently and reproducibly transfer CNS inflammatory disease between members of C. jacchus chimeric sets. The demyelination that is characteristic of experimental allergic encephalomyelitis induced in C. jacchus by immunization against human white matter did not occur after adoptive transfer of the MBP-reactive clones. It was noteworthy that encephalitogenic T cell clones were diverse in terms of their recognition of different epitopes of MBP, distinguishing the response in C. jacchus from that in some inbred rodents in which restricted recognition of MBP occurs. These findings are the first direct evidence that natural populations of circulating T cells directed against a CNS antigen can mediate an inflammatory autoimmune disease.
There has been a recent resurgence of interest in New World monkeys within the biomedical research community, driven both by the sequencing of the common marmoset (Callithrix jacchus) genome as well as a growing demand for alternatives to Old World primates. New World monkeys offer attractive advantages over Old World species including cheaper and simpler husbandry while still maintaining a greater evolutionary proximity to humans than other animal models. Although numerous commonalities across primate species exist, there are also important genetic and reproductive differences that can and should play a critical role in selecting appropriate animal models. Common marmosets in particular have significantly reduced diversity at the major histocompatibility complex loci and are born as hematopoietic chimeras. New World primates can make ideal translational models for research, but scientists must necessarily incorporate complete understandings of their genetic and phenotypic differences from humans and other model organisms.
Platyrrhines; Callitrichidae; Callithrix jacchus; Saimiri sp; Saguinus oedipus; Animal Models
Handling of common marmoset (Callithrix jacchus) usually requires chemical restraint. Ketamine has been associated with muscle damage in primates, while common marmosets, compared to other primates, additionally display an exceptional high sensitivity to ketamine-associated side-effects. Notably, muscle twitching movements of limbs and hands, and a marked increase in salivation are observed. We investigated two alternative intramuscular (i.m.) immobilisation protocols against ketamine (50 mg/kg; protocol 1) in a double-blind randomised crossover study in ten healthy adult common marmosets for use as a safe reliable, short-term immobilisation and sedation. These protocols comprised: alphaxalone (12 mg/kg; protocol 2) and 25 mg/kg ketamine combined with 0.50 mg/kg medetomidine (reversal with 2.5 mg/kg atipamezole; protocol 3A). Following completion and unblinding, the project was extended with an additional protocol (3B), comprising 25 mg/kg ketamine combined with 0.05 mg/kg medetomidine (reversal with 0.25 mg/kg atipamezole, twice with 35 min interval).
All protocols in this study provided rapid onset (induction times <5 min) of immobilisation and sedation. Duration of immobilisation was 31.23 ± 22.39 min, 53.72 ± 13.08 min, 19.73 ± 5.74 min, and 22.78 ± 22.37 min for protocol 1, 2, 3A, and 3B, respectively. Recovery times were 135.84 ± 39.19 min, 55.79 ± 11.02 min, 405.46 ± 29.81 min, and 291.91 ± 80.34 min, respectively. Regarding the quality, and reliability (judged by pedal withdrawal reflex, palpebral reflex and muscle tension) of all protocols, protocol 2 was the most optimal. Monitored vital parameters were within clinically acceptable limits during all protocols and there were no fatalities. Indication of muscle damage as assessed by AST, LDH and CK values was most prominent elevated in protocol 1, 3A, and 3B.
We conclude that intramuscular administration of 12 mg/kg alphaxalone to common marmosets is preferred over other protocols studied. Protocol 2 resulted in at least comparable immobilisation quality with acceptable and less frequent side effects and superior recovery quality. In all protocols, supportive therapy, such as external heat support, remains mandatory. Notably, an unacceptable long recovery period in both ketamine/medetomidine protocols (subsequently reversed with atipamezole) was observed, showing that α-2 adrenoreceptor agonists in the used dose and dosing regime is not the first choice for sedation in common marmosets in a standard research setting.
Alphaxalone; Atipamezole; Common marmoset; Immobilisation; Induction; Ketamine; Medetomidine; Recovery; Sedation
Due to its short lifespan, ease of use and age-related pathologies that mirror those observed in humans, the common marmoset (Callithrix jacchus) is poised to become a standard nonhuman primate model of aging. Blood and extracellular fluid possess two major thiol-dependent redox nodes involving cysteine (Cys), cystine (CySS), glutathione (GSH) and glutathione disulfide (GSSG). Alteration in these plasma redox nodes significantly affects cellular physiology, and oxidation of the plasma Cys/CySS redox potential (EhCySS) is associated with aging and disease risk in humans. The purpose of this study was to determine age-related changes in plasma redox metabolites and corresponding redox potentials (Eh) to further validate the marmoset as a nonhuman primate model of aging. We measured plasma thiol redox states in marmosets and used existing human data with multivariate adaptive regression splines (MARS) to model the relationships between age and redox metabolites. A classification accuracy of 70.2% and an AUC of 0.703 were achieved using the MARS model built from the marmoset redox data to classify the human samples as young or old. These results show that common marmosets provide a useful model for thiol redox biology of aging.
•Characterization of the Common Marmoset as a model for aging research.•Plasma thiol redox measurements in marmosets ranging in age from 2–16 years.•Similar to humans, marmosets exhibit age-related alterations in plasma thiol redox metabolites.•Marmoset redox data can be used to classify humans as young or old.
Cysteine; Cystine; Glutathione; Marmoset; Plasma
Several studies have reported the generation of spermatogonia-derived pluripotent stem cells from human testes. The initial aim of the present study was the derivation of equivalent stem cells from an established and experimentally accessible non-human primate model, the common marmoset monkey (Callithrix jacchus). However, an essential prerequisite in the absence of transgenic reporters in primates and man is the availability of validated endogenous markers for the identification of specific cell types in vitro.
METHODS AND RESULTS
We cultured marmoset testicular cells in a similar way to that described for human testis-derived pluripotent cells and set out to characterize these cultures under different conditions and in differentiation assays applying established marker panels. Importantly, the cells emerged as testicular multipotent stromal cells (TMSCs) instead of (pluripotent) germ cell-derived cells. TMSCs expressed many markers such as GFR-α, GPR125, THY-1 (CD90), ITGA6, SSEA4 and TRA-1-81, which were considered as spermatogonia specific and were previously used for the enrichment or characterization of spermatogonia. Proliferation of TMSCs was highly dependent on basic fibroblast growth factor, a growth factor routinely present in germ cell culture media. As reliable markers for the distinction between spermatogonia and TMSCs, we established VASA, in combination with the spermatogonia-expressed factors, MAGEA4, PLZF and SALL4.
Marmoset monkey TMSCs and spermatogonia exhibit an overlap of markers, which may cause erroneous interpretations of experiments with testis-derived stem cells in vitro. We provide a marker panel for the unequivocal identification of spermatogonia providing a better basis for future studies on primate, including human, testis-derived stem cells.
testis; germ line stem cell; spermatogonia; multipotent stromal cell; non-human primate