Marmoset Models Commonly Used in Biomedical Research

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Overview Marmoset Models Commonly Used in Biomedical Research

Keith Mansfield, DVM

The common marmoset (Callithrix jacchus ) is a small, nonendangered New World primate that is native to Brazil and has been used extensively in biomedical research. Historically the common marmoset has been used in neuroscience, reproductive biology, infectious disease, and behavioral research. Recently, the species has been used increasingly in drug development and safety assessment. Advantages relate to size, cost, husbandry, and biosafety issues as well as unique physiologic differences that may be used in model development. Availability and ease of breeding in captivity suggest that they may represent an alternative species to more traditional nonhuman primates. The marmoset models commonly used in biomedical research are presented, with emphasis on those that may provide an alternative to traditional nonhuman primate species.

In contrast to many other laboratory animal species, use of nonhuman primate species. nonhuman primates has increased in recent years and there Common marmosets represent an attractive alternative non- currently exists a substantial shortage of such animals for use human primate species for a variety of reasons. These small in biomedical research. The national supply of macaque mon- hardy animals breed well in captivity, with reproductive effi- keys has been unable to meet the current or projected demands ciency that may exceed 150% (number of live born per year/ of the research community. Although efforts are underway to number of breeding females). Furthermore, sexual maturity is increase domestic production and to identify alternative foreign reached by 18 months of age, allowing rapid expansion of exist- sources, this will unlikely alter short-term availability. Despite ing colonies. The small relative size of the common marmoset, these ongoing efforts, the shortage of well defined research ani- compared with that of macaque species, may represent another mals likely will negatively impact national biomedical and de- potential advantage. This smaller size translates into lower cag- fense research initiatives for the foreseeable future. In addition ing and feeding costs and reduced floor space requirements. to increasing production of rhesus macaques, one solution to Smaller size facilitates social housing of common marmosets this shortage is to provide alternative primate species that may and implementation of environmental enrichment programs. be used by investigators in their research programs. The com- The marmoset is less destructive to its environment than are mon marmoset (Callithrix jacchus) is one such species, and has larger nonhuman primates, which makes possible provision of a a number of distinct advantages, compared with those of other more complex and enriching environment. In drug development, larger Old World primates. reduced body mass may substantially decrease compound syn- The common marmoset is a small New World primate that is thesis costs and time requirements. This coupled with lower pur- native to eastern Brazil and has been used extensively in biomedi- chase price of common marmosets, compared with macaques, cal research models in North America and Europe. New World pri- may translate into substantial cost savings when performing mates (platyrrhines) represent a diverse group of animals equivalent studies. encompassing two families (the Cebidae and Callitrichidae), and Enhanced biosafety represents an additional benefit. Marmo- at least 76 distinct species. Separation from Old World primates sets may carry infective agents, such as Giardia, Cryptosporidium, occurred approximately 26 to 27 million years ago, and this and Strongyloides spp., as well as other zoonotic disease organ- early separation coupled with adaptations to the neotropical isms; however, they do not spontaneously harbor herpes B virus environment has resulted in a number of distinct differences (Cercopithecine herpesvirus 1). Although universal precautions from Old World primates (catarrhines). The laboratory animal should be followed when handling any nonhuman primates, scientist must appreciate these substantial differences in physi- this may alleviate some biosafety concerns at facilities that no ology, behavior, dietary requirements, and disease susceptibili- longer accept animals that are seropositive for this agent. ties when using marmosets in pursuit of their research goals. A number of unique physiologic differences between Old Such differences may also present unique opportunities in World and New World primates have been used in the develop- model development that are not available in more traditional ment of novel models. Examples include anatomic differences in placentation, which leads to bone marrow chimerism of twins.

Received: 4/21/03. Revision requested: 6/02/03. Accepted: 7/07/03. Twins may be used in adoptive transfer experiments to examine New England Primate Research Center, Harvard Medical School, One Pine Hill components of the cellular immune responses to a variety of Drive, Southborough, Massachusetts, 01772. antigens and in disease pathogenesis (48). Similar experiments 383 Vol 53, No 4 Comparative Medicine August 2003

are currently difficult or impossible to perform in Old World pri- Table 1. Examples of infectious disease models involving the common mates. Limited diversity at both major histocompatibility com- marmoset (Callithrix jacchus) plex (MHC) class-I and -II loci has been identified in tamarins Agent Animal model Reference and marmosets, and may be responsible for differences in dis- Viral ease susceptibilities that are exploited in infectious disease Herpesvirus ateles Acute oncogenesis (3) studies (5). Finally, unique features of marmoset biology have Herpes simplex virus Vector safety assessment (64) Herpesvirus saimiri Acute oncogenesis (123) facilitated examination of the behavioral regulation of repro- Epstein Barr virus Viral persistence (32) ductive performance. Hepatitis A virus Acute hepatitis (94) Although there are appreciable advantages to the use of mar- GB virus B Acute hepatitis (25) Measles virus Pathogenesis (77) mosets in the vivarium, there are also potential disadvantages Junin virus Hemorrhagic fever (6) that must be overcome. Size and cost are relative, and though Parasitic the purchase price and cost of housing a common marmoset are Brugia malayi Filariasis (36) less than those of a rhesus macaque, they are substantially Plasmodium sp. Malaria (92) more than those for most rodent or other non-rodent species. Bacterial Similarly, although their size may be of benefit in some studies, Mycoplasma genitalium Urogenital infection (117) this smaller size may make it difficult or impossible to perform Legionella pneumophila Legionnaire’s disease (14, 15) certain procedures or techniques. For example, size may limit Chlamydia trachomatis (68, 69) the type and volume of blood samples that may be obtained. In Chronic periodontal disease (4, 82) general, maximal blood draw is one percent of body weight or Other three to four milliliters once every two to three weeks. Marmo- BSE/scrapie Prion disease (7) sets may also require specialized husbandry and veterinary BSE = Bovine spongiform encephalopathy. care, which may not be available at all facilities. Finally, one of the reasons that rhesus macaques are attractive as a model is complementary strands of DNA. Recently, the Affymetrix the critical mass of investigators using this species. Thus, tools GeneChip (Affymetrix, Santa Clara, Calif.) has been validated in initially developed in one model may be applied to others, and several species of nonhuman primates, including common mar- synergies are established when divergent groups use similar mosets, and has been used to investigate gene expression in species. Since there are currently fewer investigators using brain tissue (85). marmosets, this synergy is not as well advanced. Research Areas Research Tools Historically the common marmoset has been used in neuro- The laboratory animal scientist and veterinary staff often science, reproductive biology, infectious disease, and behavioral play a key role in assisting investigators in the selection of ap- research. Recently the species has increasingly been used in propriate animal models. The availability of research tools is a drug development and safety assessment. critical issue when evaluating species choice in model development. Although there are clearly not as many research tools Infectious Diseases available for marmosets as there are for macaque species, re- Historically, common marmosets have been used extensively in sources have now been developed in a number of key areas. Ex- infectious disease research due in large part to their unique sus- amples include demographic databases (115, 116, 127) as well ceptibility to a number of important human infective agents. Re- as specialized techniques, such as remote telemetry, stereotactic search programs have been established to examine viral, bacterial, neuroanatomic localization, and multi-electrode implantation and parasitic agents. In particular, marmosets are susceptible to a (19, 35, 52, 81). variety of herpesvirus agents, including gammaherpesviruses, Immunohistochemical analysis is a critical tool that can be such as Epstein Barr virus (EBV) and Herpesvirus saimiri (HVS), used to interpret morphologic changes in tissue sections. A few both of which may cause lymphoproliferative disorders in this antibodies have been developed specifically for marmoset anti- species. Common marmosets are also highly susceptible to gens. However, because of the phylogenetic relationship between alphaherpesviruses, such as herpes simplex virus (HSV), and humans and marmosets, there are many shared epitopes and they develop acute disseminated disease with neurologic involve- some polyclonal and monoclonal antibodies developed principally ment. The species has been used in models of hepatitis A virus for human antigens will effectively stain marmoset tissue. A infection, Junin virus infection, malaria, measles, and infection number of published surveys document these cross-reactive anti- with GB virus B, a surrogate model of human hepatitis C virus bodies and techniques (120, 125). Similarly, flow cytometry is a (Table 1). The reason marmosets are highly susceptible to infec- common research tool that is used in the characterization of in- tion with many of these agents is not understood, but limited flammatory cells in blood and tissue. Although there are no com- diversity at MHC class-I and -II loci is hypothesized to play a mercially available antibodies developed against marmoset role (5, 124). antigens for flow cytometry, monoclonal antibodies developed Gammaherpesvirus models of acute oncogenesis. A dis- against human epitopes may often be used. Published surveys tinct characteristic of gammaherpesviruses is their ability to have documented techniques and cross-reactive antibodies and a establish latent infections in lymphoid cells and their associa- website provides an extensive listing of cross-reactive clones tion with abnormal lymphoid proliferation and cancer in hu- (http://research.bidmc.harvard.edu/v_path/) (20, 91, 97). mans and nonhuman primates (71). The first open reading Microarray technology is a technique used to probe differ- frame of the primate gammaherpesviruses has been reported to ences in gene expression, and is based on specific affinity of directly contribute to viral associated pathogenesis, and these 384 Marmoset models in biomedical research

gene products are capable of eliciting cellular signal transduc- The GB virus B model of hepatitis. The GB virus B is a tion events, resulting in cell growth transformation. The mar- newly recognized infective agent and is a member of the moset model has been used to evaluate the in vivo importance flaviviridae family related to hepatitis C (17). Hepatitis C virus of oncogene deletion or substitution (40, 57, 80). (HCV) is the most common blood-borne pathogen recognized in Inoculation of common marmosets with HSV is a well-estab- the United States, and the incidence and health impact of this lished model of acute viral oncogenesis, and has been used to in- agent is expected to increase markedly in the next decade. The vestigate the molecular pathogenesis of viral induced lymphoma. HCV causes persistent viral infection, leading to chronic hepa- Sequence divergence among HVS isolates is most extensive at titis and hepatocellular carcinoma. The only current animal the left end of the viral genomic DNA, and is the basis for the model of HCV involves the chimpanzee. However, this model is classification of HVS into subgroups A, B, and C (37). Sequence faced with a number of drawbacks, including ethical issues, variation in the saimiri transforming protein (STP) gene in this availability, and cost of housing such animals (79). region correlates with differences in viral capacity to induce in The GB agents are a group of closely related viruses initially vitro immortalization of T lymphocytes and for the induction of that were recognized by investigators attempting to identify lymphoma in nonhuman primates (114, 122). Subgroup A and other infectious causes of non A–E hepatitis in humans. GB vi- subgroup C viruses can immortalize common marmoset T lym- rus A, another member of the flaviviridae family, may be found phocytes to interleukin 2-independent proliferation, and highly as a common asymptomatic infection of many species of New oncogenic subgroup C strains are able to immortalize human, World primates. GB virus B is a hepatotropic virus, which causes rabbit, and rhesus monkey lymphocytes. Inoculation of marmo- acute hepatitis when inoculated into New World primates (23). sets with HVS type C results in malignant lymphoma within Unlike GB virus A, the natural host of GB virus B is unknown. three to four weeks. The malignant cells infiltrate a number of GB virus B shares overall genomic organization with HCV and organs, including the liver, spleen, kidneys, and gastrointestinal 25 to 30% homology with the HCV polyprotein (106). The puta- tract, and leukemia can be visualized in peripheral blood smears. tive envelope proteins E1 and E2 share structural motifs with Techniques have been developed to construct mutant HVS HCV, and similar function and specificity have been docu- strains and examine the subsequent effect of these deletions mented for the NS3 serine protease in cleaving the viral and viral gene substitutions on in vitro viral replication and in polyprotein (105, 107). Inoculation of several species of New vivo disease course. In such experiments a number of outcomes, World primates with GB virus B results in development of acute including viral load, tumor induction and survival, may be mea- hepatitis, showing promise as a novel surrogate animal model of sured (37). Since recombinant HVS lacking STP can be repeat- HCV infection of humans. edly isolated from the blood of common marmosets for months Marmosets inoculated with GB virus B develop multifocal or years, STP is not required for viral replication or persistence nonsuppurative hepatitis, with portal inflammatory cell infil- in vivo, but is essential for transformation in cell culture and for trates and piecemeal necrosis. Sequential hepatic biopsy speci- lymphoma induction in common marmosets. mens may be obtained under ultrasonic guidance to examine Gammaherpesvirus models of persistent viral infec- morphologic and immunophenotypic changes in individual ani- tion. Although most gammaherpesvirus research in common mals, a technique that should prove useful in elucidating cellu- marmosets has focused on the use of HVS, the pathogenesis of lar immune responses to viral infection. Immunophenotypically H. ateles and EBV also has been studied (3). Inoculation of com- large numbers of CD3CD8-positive lymphocytes can be found to mon marmosets with EBV may induce a more indolent disease infiltrate the hepatic parenchyma. course, with similarities to infectious mononucleosis and has Recently, an in vitro primary hepatocyte culture system has been used to investigate the effect of immunization on viral been developed that supports the growth of GB virus B (16). shedding (2, 32). Disease outcome may be dependant on viral This, coupled with the availability of infective molecular clones strain used. Co-inoculation of animals with Plasmodium of the virus and the ability to infect several species of New brasilanum and EBV also has been studied as an experimental World primates, promises to foster development of a useful ani- model of Burkitt’s lymphoma (121). mal model with which to study the pathogenesis of chronic he- More recently, an indigenous gammaherpesvirus related to patic infections caused by this group of agents (24, 106). The EBV has been recognized in common marmosets and may serve potential to create chimeric GB virus B-HCV molecular clones as an additional model of viral oncogenesis and persistence (28). may allow examination of viral determinants of virulence and This virus, termed marmoset lymphocryptovirus (LCV) or persistence in a small nonhuman primate model. Callitrichine herpesvirus 3, was first identified in animals with spontaneous B-cell lymphomas at the Wisconsin National Pri- Neuroscience mate Research Center. Subsequent work has indicated that 40 Marmosets have been used widely in neuroscience research to 60% of captive marmosets are seropositive for this virus, with programs in models of cerebral vascular disease, tardive dyski- most animals not manifesting overt signs of clinical disease. nesia, multiple sclerosis (MS), and neurodegenerative diseases, Recently, sequencing of the virus has been completed (98). Defi- such as Parkinson’s and Huntington’s disease (Table 2; 1, 74, nition of the viral gene repertoire revealed collinear genomic or- 84). In addition to use in models of human disease, marmosets ganization and 60 open reading frames with homology to those have figured prominently in studies of normal neurophysiology seen in EBV and other primate LCVs. In addition to these con- (22, 55, 63). served regions, a number of unique putative genes were recog- Experimental allergic encephalitis of multiple sclerosis. nized that are hypothesized to play a role in viral persistence. The induction of experimental allergic encephalitis (EAE) in Future work to compare and contrast these closely related vi- common marmosets has been used extensively as a model of ruses may provide insight into gammaherpesvirus pathogenesis. human MS (1). Multiple sclerosis is an important chronic dis- 385 Vol 53, No 4 Comparative Medicine August 2003

Table 2. Examples of neuroscience models involving the common marmoset Marmoset models of Parkinson’s disease. Parkinson’s Disease Reference disease is a common neurodegenerative disorder affecting 1.5 million Americans. Progressive dysfunction of the nigrostriatal Degenerative dopaminergic pathway results in striatal dopamine deficiency Parkinson’s disease MPTP administration (54) 6-OHDA administration (99) and development of clinical signs of disease, including tremors, Huntington’s disease Striatal transplantation (72, 73) rigidity, and bradykinesia. Although the cause of Parkinson’s Alzheimer’s disease Spontaneous amyloid deposition (83) Experimental induction (8) disease is unknown, environmental and genetic factors may play a role, with oxidative stress and mitochondrial dysfunction Behavior as common pathways. Fear and anxiety Conditioned and unconditioned response models (13) Two methods of disease induction have been studied in com- Reproductive behavior Social and endocrine influence mon marmosets. In the first, stereotactic injections of 6- on reproduction (41, 102) hydroxydopamine (6-OHDA) into the nigrostriatal bundle is Child behavior and development Early deprivation (27, 39) performed. The 6-OHDA is taken up directly by dopaminergic neurons, resulting in their destruction in an anatomically local- Other ized manner. In the second,1-methyl-4-phenyl-1,2,3,6- Stroke Cerebral vascular occlusion (84) Multiple sclerosis Experimental allergic encephalitis (1, 49) tetrahydropyridine (MPTP) is administered as a single dose or repeated doses and is metabolized to its toxic constituents be- MTPT = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 6-OHDP = 6- hydroxydopamine. fore acting on target neurons in the central nervous system. Rodent models, including 6-OHDA- and MPTP-treated rats, and abling neurologic disorder of young adults, with prevalence of 1 in more recently, transgenic mice expressing human a -synuclein 1,000. The cause is unknown, but genetic and environmental fac- have been used extensively as animal models of Parkinson’s dis- tors have been indicated in its pathogenesis. Although an infective ease and should be considered as alternative species. Primate agent may have an initiating role, a number of autoantigens also models may be particularly useful for investigation of trans- are involved. plantation, gene therapy, and biopharmaceutical therapeutic In common marmosets, EAE may be induced through injection interventions. Scoring systems for motor activity and dyskine- of whole myelin, myelin extracts in complete Freund’s adjuvant sia have been developed for the common marmoset (75). (CFA), and human recombinant myelin oligodendrocyte glyco- Of the two systems, administration of MPTP has been used protein (MOG) in CFA (1). Clinical signs of disease in marmosets most extensively in common marmosets and results in bilateral more closely resemble MS than do those in rodent or other pri- lesions and a clinical syndrome that closely approximates mate models, and may be classified in such animals as having a Parkinson’s disease in humans. The MPTP is converted to its relapsing-remitting and primary progressive course. The lesions active metabolite 1-methyl-4-phenyl pyridine (MPP+) in astro- are initially characterized by a multifocal nonsuppurative in- cytes by monoamine oxidase B. The MPP+ is taken up by flammatory cell infiltrate, with differing degrees of demyelin- dopaminergic neurons through the dopamine transporter and is ization and axonal degeneration (58). A number of measured concentrated in the mitochondria where it inhibits the electron outcomes have been developed and used in the EAE model and transport chain and induces oxidative stress, which destroys include neurologic impairment scores, magnetic resonance im- dopaminergic neurons in the nigrostriatal pathway (18). aging scores, and results of histologic examination (47, 50). A variety of MPTP dosing schedules have been used to induce Magnetic resonance imaging can confirm the multifocal and acute onset and chronic Parkinson’s disease, most requiring re- progressive nature of the lesion, a characteristic feature of MS peated subcutaneous injections over a period of one to four in humans (87). weeks. Appreciable biosafety and occupational health and Marmosets routinely give birth to genetically non-identical safety issues are associated with use of MPTP in laboratory ani- twins or triplets, and placental anastomosis results in full bone mals (66, 96). Standard operating procedures should be devel- marrow chimerism of littermates. Thus, an alloimmune re- oped for administration of MPTP and disposal of animal waste. sponse is absent from fraternal twins after transplantation of Needleless devices should be used whenever possible for deliv- tissue or marrow elements. This unique biologic feature of mar- ery of the compound, and appropriate training should be pro- mosets has been exploited to examine the role of antigen-spe- vided for all laboratory and animal care staff. cific T-cell subsets in disease pathogenesis. Results of adoptive After administration of MPTP, clinical signs of disease in non- and passive transfer experiments have indicated that T cells human primates may include akinesia, hunched posture, rigid- and pathogenic antibody are required for disease recapitulation ity, loss of vocalization, and postural action or body tremors. and the importance of myelin basic protein-specific CD4 T cells Intra-animal variation is substantial, and fluids and hand feed- in disease pathogenesis (86). ing may be required before some compensation is achieved. Epitope mapping experiments have been undertaken, using Body weight in marmosets should be monitored closely, and recombinant MOG peptides, and antigenic determinants re- levadopa or other dopaminergic drugs should be administered sponsible for disease induction have been identified. Residues in to alleviate severe clinical signs of disease. Criteria for treat- the extracellular domain of MOG elicit disease-producing T- and ment and euthanasia should be established during protocol de- B-cell responses in the context of the major histocompatibility velopment. allele Caja-DRB*W1201 (21). More recently, the EAE model has -Amyloid deposition in the brain of marmosets. Sev- been used in the preclinical evaluation of novel immunothera- eral reports have documented amyloid plaques in aged marmo- pies, such as testing new anti-inflammatory agents, tolerance- sets, suggesting that the species may represent a novel animal based therapies, and costimulated target therapy (46, 51). model of Alzheimer’s disease (53, 83). Analysis of aged common 386 Marmoset models in biomedical research

marmosets older than seven years revealed high incidence of b- mental compounds has become an increasingly important con- amyloid deposits in brain tissue. The b-amyloid immunoreactive cern. The young age of sexual maturity, high reproduction effi- plaques were detected principally in cortical zones and less fre- ciency, and similarities in placentation between humans and quently in paralimbic areas. Deposits also were found in cortical marmosets suggests that the marmoset may make an attractive and meningeal vessels in the form of an amyloid angiopathy. model to investigate the teratologic potential of xenogenous Staining for thioflavin S revealed presence of b-pleated sheet compounds. Similar to that in other primates, marmosets have conformation in compact fibrillar plaques, but immunohis- a discoid hemochorial placenta. In some instances, the terato- tochemical analysis for phosphorylated tau protein failed to de- logic effects of compounds may differ substantially between ro- tect dystrophic neurites in association with these plaques. dent and primate species. Thalidomide administration during Functional deficits have yet to be correlated with these morpho- early gestation results in specific and dramatic limb defects in logic changes in aged animals. primates, an outcome not observed in laboratory rodents, such In most instances, the cause of Alzheimer’s disease remains as the rat and mouse. Indeed, the marmoset has been used to unknown. An experimental system has been developed to inves- comprehensively investigate the mechanism of thalidomide ter- tigate the effect of reductions in cholinergic activity on amyloid atogenesis (59, 60, 76, 88). Experimental work conducted in the precursor protein in the neocortex and hippocampus. In this marmoset has suggested that metabolites of thalidomide may model, an immunoglobulin saporin conjugate was injected by cause down-regulation of surface adhesion receptors, thereby use of stereotactic guidance to induce selective loss of cholin- altering cell-to-cell and cell-to-extracellular matrix interactions ergic neurons and their axonal projections to the temporal and in the developing limb bud (92). frontal cortices (44). This immunotoxin treatment resulted in increased expression of amyloid precursor protein, as measured Reproductive Biology by immunohistochemical and image analyses, and supports a The marmoset has found widespread use in studies of repro- role for cholinergic dysfunction in the pathogenesis of ductive biology and embryology, and focus has been placed on Alzheimer’s disease. areas of normal reproductive physiology, such as the mechanism of luteal regression and regulation of reproductive behav- Toxicology and Drug Development ior. Marmosets have also been used to investigate novel Particularly in Europe, the marmoset has been used as a non- methods of immunocontraception, and the first primate em- rodent second species in drug safety assessment and pharma- bryonal stem cells were derived from C. jacchus at the Wiscon- ceutical toxicology (109). Because of the closer phylogenetic sin National Primate Research Center (118, 119). The common relationship of marmosets to humans than to other second spe- marmoset ovarian cycle lasts approximately 28 days, with ovu- cies, such as the dog, common marmosets may be more suitable lation occurring around day 10, and shows similarities to hu- for certain types of pharmacokinetic and toxicologic screening. man and other nonhuman primate cycles in terms of steroid Biotechnology-derived pharmaceuticals or biopharmaceuticals hormone profiles. Luteolysis may be induced and cycles con- should be evaluated in a relevant animal species in which the trolled through intramuscular injection of cloprostenol (113). test material is pharmacologically active. In instances in which Similarities in reproductive biology between humans and mar- the mechanism of action is dependent on specific receptors or mosets, their small size, and breeding capacity in captivity has epitopes, relevant species may be restricted to nonhuman pri- facilitated use of C. jacchus to investigate aspects of normal re- mates, and use of such in biopharamaceutical development can productive physiology. Luteal formation and regression is a com- be anticipated to increase (45). Although pharmacodynamic plex differentiation process that involves extrinsic and ovarian variables are dependent on metabolic rate and excretion path- factors. The common marmoset has been used to examine the ef- ways, the small size of common marmosets may represent an fect of luteinizing hormone and follicle-stimulating hormone on additional advantage, as it often reduces the quantity of com- granulosa cell development and steroidogenesis (61, 62). The pound to be synthesized and may translate into shorter develop marmoset has been used to define the mechanisms of estradiol times (110). inactivation in the primate endometrium through the differen- The success of any such program is dependent on a compre- tial expression of hydroxysteroid dehydrogenase isotypes (65). hensive understanding of the background pathology in the spe- Immunocontraception. Immunocontraception has been cies to be studied and an appreciation of species-specific proposed as a potential birth control method for humans and xenometabolic pathways. Recently, the molecular and compara- other animal species. Investigations have focused on antigens in tive characterization of the cytochrome p450 pathway has been the zona pellucida as a potential vaccine target, as this glyco- undertaken in marmosets and several other species, and such protein surrounds the oocyte and plays a key role in fertilization work should facilitate species selection for toxicologic testing and early embryo development. A problematic consequence of (108). Common marmosets have also been used for evaluation of zona pellucida vaccines is the induction of immune-mediated gene therapy vectors, particularly HSV vectors, for which the ovarian dysfunction, resulting in depletion of primordial fol- species is highly susceptible. Specialized techniques, such as te- licles. Such an outcome is unacceptable for any vaccine slated lemetry and use of the brainstem auditory evoked response, for human use. The common marmoset has been used to inves- have been adapted to marmosets to evaluate ototoxicity (78). In tigate the effect of immunization, using zona pellucida antigens, addition to their use in toxicology programs, marmosets have on ovarian function and fertility (90, 93). Results of mapping been used in the study of hepatic metabolism, including the ex- studies conducted in this species indicated immunodominant perimental induction of lipodystrophy and hepatic hemosidero- epitopes and suggested that multivalent vaccines may be devel- sis (25, 33, 34, 56, 89). oped that consistently induce infertility without concurrent ova- Reproductive toxicology. The teratologic effect of experi- rian pathology (93). 387 Vol 53, No 4 Comparative Medicine August 2003

Behavioral Research conflict paradigm, conditioned response tests consist of a non- The common marmoset has several unique advantages over suppressed component in which a trained response is positively Old World primate species with regard to behavioral research. reinforced with food rewards. Rewards and aversive stimuli are Because of the small size of marmosets, it is possible to keep then administered concurrently in the suppressed “conflict” animals in a social setting that is similar in size and composi- component. Anxiolytic or anxiogenic stimuli and treatments tion to that found in their natural environment. Coupled with may then be measured as an alteration in the response rate the greater environmental complexity that can be maintained during this conflict phase. in the New World primate laboratory, this is likely to promote Unconditioned response models are more commonly used in more natural behavior in animals kept in captivity. The short marmosets, and are based on non-painful aversive stimuli mim- generation time and short birth interval facilitate examination icking stressors that may be present in animals in their natural of reproductive behavior and parental care of offspring. It is also habitat. A variety of unconditioned response models have been possible to study individual animals from infancy to adulthood developed in marmosets and include involuntary social isola- over a short period. In the discipline of behavioral biology, mar- tion, conspecific confrontation, human threat, and predator con- mosets have been used to investigate the regulation of repro- frontation procedures (13, 11, 26, 29). Using these models, ductive behavior and in models of fear and anxiety. In addition observers blinded to the treatment groups score relevant behav- to traditional tools of behavioral research, techniques to investi- iors. Ethograms have been developed to assess behaviors and gate functional brain imaging, using positron emission tomogra- standardize scoring systems, and are based on normal and char- phy, have been developed, and use of such imaging modalities acteristic behavioral patterns of common marmosets (111, 112). can be expected to increase in the future (43). Signs of anxiety-related behavior include scent marking, head Regulation of reproductive behavior. Common marmo- weaving, the “wet-dog” shake, and huddling. Aggressive behav- sets and other callitrichidae have a cooperative breeding strat- ior includes piloerection, slit-stare, and anogenital presentation egy comprising extended family units in which siblings remain (29). Allogrooming, self-grooming, and scratching are considered in their natal groups and assist in rearing of subsequent off- displacement activities, which may increase during stressful spring. Only the dominant female in these units is reproduc- situations. In many instances, these unconditioned response tively active, and regulation of reproductive performance in models have been validated with use of diazepam, a well-known subordinate animals has been a subject of intense investigation. benzodiazepine anxiolytic, and subsequently have been used to Reproductive failure in subordinate females results from sup- investigate the properties of a number of novel and experimen- pression of ovulation and behavioral alterations. Social control tal compounds (10, 12, 30, 31, 70). of reproductive performance in these extended family units has Recently, an early deprivation model has been developed to been investigated as a model of regulation of reproductive be- examine the effect of environmental influences and stress on havior (9, 100, 104). Although physiologic mechanisms resulting neurobehavioral development (38, 39). This model is a paradigm in anovulation play an important role in the regulation of repro- initially developed for rats in which one littermate is separated ductive performance, a substantial number of subordinate fe- from the parents for a limited period each day during the first males cycle but fail to conceive (104). Ovarian activity of four weeks of life. Nonhuman primates more closely approxi- subordinate marmosets was influenced by sexual status of the mate human infants with respect to their precocial develop- mother and older female siblings, as well as the genetic rela- ment and hypothalamic-pituitary axis at birth than do rodent tionship of the dominant male in the family group. Cycling sub- species (95). Early deprivation of marmoset neonates resulted ordinate females had evidence of luteal phase deficiency in alterations in stress-related endocrine responses, including characterized by longer interluteal periods and lower peak and increases in cortisol, epinephrine, and norepinephrine concen- mean plasma progesterone concentrations (101). This effect was trations and behavioral differences to subsequent social separa- found to be largely mediated through suppression of pituitary tion and novelty challenge (38, 39). The model should prove luteinizing hormone and was rapidly reversed when females useful in investigating early environmental influences on neu- were removed from social groups. robiological and behavioral development. The interactions of the hypothalamic pituitary axis in subordinate female marmosets also have been examined (101, 103). Conclusions Subordinate and anovulatory females have lower plasma corti- The common marmoset is a widely used nonhuman primate sol concentration, and the effect of ovariectomy on cortisol val- in biomedical research and an attractive alternative to more ues has been evaluated. Those investigations indicated that traditional species. Advantages relate to size, cost, husbandry, alterations in the hypothalamic-pituitary axis are mediated and biosafety issues as well as unique physiologic differences through reproductive hormones rather than as a direct result of that may be exploited in model development. Marmosets have social subordination (103). been used extensively in neuroscience, reproductive biology, in- Marmoset models of anxiety and stress. In addition to fectious disease, and behavioral research programs, and their the close phylogenetic relationship between nonhuman pri- use is anticipated to increase in the future. mates and humans, similar physiologic and behavioral responses to stress provide justification for use of primates in fear and anxiety research (11). Conditioned and unconditioned re- Acknowledgments sponse models have been used in a variety of nonhuman pri- This work was supported by a grant from the National Institutes mate species to examine fear and anxiety. On the basis of a of Health, National Council of Research Resources P51 RR000168.

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