Squirrel monkeys (Saimiri sp.) in Biomedical Research

Larry Williams and Charlotte E. Hotchkiss

Introduction

Figure 1. Saimiri boliviensis can be distinguished from S. sciureus by the rounded arch over the eyes.

It has long been recognized that the squirrel monkey (Saimiri sp.) is an important nonhuman primate model in biomedical research. Squirrel monkeys are one of the most commonly used neotropical primates in biomedical research. 1-3 In the late 1970’s, the NIH recognized that supply and availability of squirrel monkeys from source countries had become very vulnerable and that a self-sustaining breeding resource in the United States was the only way to assure continued availability of squirrel monkeys. For this reason, the Squirrel Monkey Breeding and Research Resourcea was established through ORIP (then NCRR) to ensure a constant population of pedigreed monkeys with known medical histories. The breeding colonies of the SMBRR include three species/subspecies of squirrel monkeys: Bolivian squirrel monkeys (Saimiri boliviensis boliviensis) comprising about 68%; Guyanese or common squirrel monkeys (Saimiri sciureus sciureus) comprising about 28%; and Peruvian squirrel monkeys (Saimiri boliviensis peruviensis) comprising about 4%.

a https://www.mdanderson.org/research/departments-labs-institutes/programs-centers/michale-e-keeling-center-for-comparative-medicine-and-research/national-research-resources-program.html 

Natural Biology

Squirrel monkeys are distributed widely in the Amazon basin, with disjunct populations occurring in Central America. Eight species are currently recognized: S. oerstedii in Central America, and seven South American forms: S. boliviensis, S. sciureus, S. collinsi, S. ustus, S. vanzolinii, S. cassiquiarensis, and S. macrodon.4,5 S. boliviensis and S. sciureus are the two most commonly used species in biomedical investigations. The species are defined by physiological and behavioral characteristics. For example, adult S. sciureus are more susceptible to gallstone formation than S. boliviensis, and infant S. sciureus are less active and less irritable than S. boliviensis.6

Squirrel monkeys live in various habitats, including primary or secondary rain forests, and habitats affected by human disturbances.7-13 They do well in areas of secondary growth due to their high consumption of insects.14 Squirrel monkey home ranges are large, varying from 150 to 250 hectares,8,14,15 but these are not defended, and there can be overlap in the ranges of neighboring troops.

Figure 2. Mealworms provide for nutritional enrichment, and puzzle feeders can be used to promote foraging activity. Note that offspring are carried on the back rather than being held ventrally.Squirrel monkey groups are generally large, ranging from 25-75 individuals.16 However, unlike patterns of basic ecology, such as diet and habitat use, the social organization in the genus Saimiri is extremely diverse. In some species, males are dominant over females (e.g., S. sciureus), while others are female-dominant (e.g., S. boliviensis), and yet in others, there are negligible dominance interactions between females and males (S. oerstedi). These inter-species differences in social structure have been documented both in wild and captive settings. However, it should be noted that, due to the difficulty of recognizing individual monkeys in the wild, much is unknown about social structure and interactions in the genus.

The genus Saimiri is characterized by extremely high pre- and post-natal maternal investment. Even though dams usually have single infants, squirrel monkeys rank highest among neotropical primates in infant care costs, including the cost of transporting heavy infants over long day ranges.17 The gestation period is long in squirrel monkeys (5 months18), and is similar to that of the larger capuchins.19 Neonates are large, usually weighing 16-20% of the mother’s body weight20,21 and have 60% of adult brain mass at birth.22 Because of this large size, dystocia is common.23 In the resource setting, squirrel monkeys produce twins at a rate of approximately 1 in 150 pregnancies (Williams, personal observation).

Biomedical Models 

 Genomics
186 Gbp of sequence data (BioSample: SAMN16846876) has been generated using the PacBio Sequel platform. This represents 69X coverage of the expected 2.7 Gbp squirrel monkey genome. In addition, genetic variation of the different species and subspecies has been studied using sequencing of mitochondria,4,24 satellite DNA25,26 and specific genes.27-29 Cytogenetics (including karyotyping and chromosome painting) is a useful tool in studying the evolution of squirrel monkeys, as different species have different positioning of centromeres within chromosomes.30-32

 Virology
Squirrel monkeys have been used to study several viral diseases, historically focusing on measles and herpesviruses.33-40 Squirrel monkeys have been used as a model for polyomavirus viruses.3,41 In recent years there has been a greater focus on Zika virus, because Saimiri is an endemic host for the virus in South America,42-44 and Zika virus causes prenatal disorders and congenital Zika syndrome in squirrel monkeys.45,46

 Malaria Vaccine Development
The squirrel monkey is an important animal model for malaria vaccine development studies.47 Because Plasmodium sp. are host specific, animal models used to study human malaria must be susceptible to the same strains that cause disease in humans. The Bolivian squirrel monkey has been shown to be a superior model for studies of the pathogenesis of P. vivax,48 developing lesions and clinical signs similar to those reported in the human disease. Squirrel monkeys are also used to screen P. falciparum vaccine candidates for humans.49

Figure 3. The match-to-sample test is used to assess cognitive ability. Neuroscience and Vision
Squirrel monkeys are used extensively in neuroscience. Saimiri are a good model for Alzheimer’s Disease (AD),50,51 and recent work has investigated using CpG oligodeoxynucleotides to ameliorate some AD symptoms in squirrel monkeys.52 Studies using squirrel monkeys have also contributed to the understanding of injury-induced reorganization of the sensory cortex and somatotopic reorganization of the brain stem and thalamus.53-55 Saimiri and other neotropical non-human primates have contributed to vision research with regard to adaptation of the vestibule-ocular reflex,56 the topography of cones and rods,57 and color vision.58,59 In squirrel monkeys, as in many New World primates, there is a single opsin gene with allelic diversity on the X chromosome, with the result that all males and some females have dichromatic vision.60 This is in contrast to Old World primates, which are usually trichromatic. Gene therapy has been used to insert a third type of cone pigment into dichromatic retinas, allowing color blind squirrel monkeys to develop color vision, as assessed by a modified Cambridge Colour Test.61

References

1. Tardif S, Bales K, Williams L, et al. Preparing New World monkeys for laboratory research.ILAR J 2006;47:307-315.
2. Nudo RJ, Larson D, Plautz EJ, et al. A squirrel monkey model of poststroke motor recovery.ILAR journal 2003;44:161-174.
3. Rogers DL, McClure GB, Ruiz JC, et al. Endemic viruses of squirrel monkeys (Saimiri spp.).Comparative medicine 2015;65:232-240.
4. Chiou KL, Pozzi L, Lynch Alfaro JW, et al. Pleistocene diversification of living squirrelmonkeys (Saimiri spp.) inferred from complete mitochondrial genome sequences. Mol Phylogenet Evol 2011;59:736-745.
5. Lynch Alfaro JW, Cortes-Ortiz L, Di Fiore A, et al. Special issue: Comparative biogeographyof Neotropical primates. Mol Phylogenet Evol 2015;82 Pt B:518-529.
6. Mulholland MM, Williams LE, Abee CR. Neonatal activity and state control differences amongthree squirrel monkey subspecies (Saimiri sciureus sciureus, S. boliviensis boliviensis, and S. boliviensis peruviensis). Am J Primatol 2020;82:e23048.
7. Boinski S. The Effects of Body Size, Morphological Specializations, and Food Distribution onForaging Behavior in the Cebinae. American journal of physical anthropology 1989;78:195-195.
8. Carretero-Pinzon X, Defler TR, McAlpine CA, et al. The influence of landscape relative to siteand patch variables on primate distributions in the Colombian Llanos. Landscape Ecol 2017;32:883-896.
9. Lima EM, Ferrari SF. Diet of a free-ranging group of squirrel monkeys (Saimiri sciureus) ineastern Brazilian Amazonia. Folia Primatol (Basel) 2003;74:150-158.
10. Pontes ARM. Habitat partitioning among primates in Maraca island, Roraima, northern Brazilian Amazonia. Int J Primatol 1997;18:131-157.
11. Paim FP, Silva JDE, Valsecchi J, et al. Diversity, Geographic Distribution and Conservation of Squirrel Monkeys, Saimiri (Primates, Cebidae), in the Floodplain Forests of Central Amazon. Int J Primatol 2013;34:1055-1076.
12. Peres CA. Primate Responses to Phenological Changes in an Amazonian Terra-Firme Forest. Biotropica 1994;26:98-112.
13. Terborgh J. Five New World primates. Princenton: NJ: Princeton University Press, 1983.
14. Stone AI. Responses of squirrel monkeys to seasonal changes in food availability in an eastern Amazonian forest. Am J Primatol 2007;69:142-157.
15. Mitchell CL. The ecological basis for female social dominance: A behavioral study of the squirrel monkey (Saimiri sciureus) in the wild. DISSERTATION ABSTRACTS INTERNATIONAL 1990;B51(4):1614.
16. Boinski S. The social organizations of squirrel monkeys: Implications for ecological models of social evolution. Evol Anthropol 1999;8:101-112.
17. Tardif SD, Garber PA. Social and reproductive patterns in neotropical primates: Relation to ecology, body size, and infant care. Am J Primatol 1994;34:111-114.
18. Stone AI. Juvenile feeding ecology and life history in a neotropical primate, the squirrel monkey (Saimiri sciureus). Department of Anthropology: University of Illinois at Urbana-Champaign, 2004.
19. Hartwig WC. Perinatal life history traits in New World monkeys. American Journal of Primatology 1996;40:99-130.
20. Milligan LA, Gibson SV, Williams LE, et al. The composition of milk from Bolivian squirrel monkeys (Saimiri boliviensis boliviensis). Am J Primatol 2008;70:35-43.
21. Williams L, Gibson S, McDaniel M, et al. Allomaternal interactions in the Bolivian squirrel monkey (Saimiri boliviensis boliviensis). Am J Primatol 1994;34:145-156.
22. Elias MF. Relative maturity of cebus and squirrel monkeys at birth and during infancy. Developmental psychobiology 1977;10:519-528.
23. Meireles BC, Goldschmidt B, Resende FC, et al. Neotropical primate nursery in a squirrel monkey breeding unit in Brazil. Lab Anim 2016;50:67-72.
24. Mercês MP, Lynch Alfaro JW, Ferreira WA, et al. Morphology and mitochondrial phylogenetics reveal that the Amazon River separates two eastern squirrel monkey species: Saimiri sciureus and S. collinsi. Mol Phylogenet Evol 2015;82 Pt B:426-435.
25. Valeri MP, Dias GB, Moreira CN, et al. Characterization of Satellite DNAs in Squirrel Monkeys genus Saimiri (Cebidae, Platyrrhini). Scientific reports 2020;10:7783.
26. Baker JN, Walker JA, Denham MW, et al. Recently integrated Alu insertions in the squirrel monkey (Saimiri) lineage and application for population analyses. Mob DNA 2018;9:9.
27. Sweeney CG, Rando JM, Panas HN, et al. Convergent Balancing Selection on the Mu-Opioid Receptor in Primates. Molecular biology and evolution 2017;34:1629-1643.
28. Lugo JS, Cadavid LF. Patterns of MHC-G-Like and MHC-B Diversification in New World Monkeys. PloS one 2015;10:e0131343.
29. Wallis M. Coevolution of insulin-like growth factors, insulin and their receptors and binding proteins in New World Monkeys. Growth Horm IGF Res 2015;25:158-167.
30. Chiatante G, Capozzi O, Svartman M, et al. Centromere repositioning explains fundamental number variability in the New World monkey genus Saimiri. Chromosoma 2017;126:519-529.
31. Capozzi O, Archidiacono N, Lorusso N, et al. The 14/15 association as a paradigmatic example of tracing karyotype evolution in New World monkeys. Chromosoma 2016;125:747-756.
32. Fan X, Supiwong W, Weise A, et al. Comprehensive characterization of evolutionary conserved breakpoints in four New World Monkey karyotypes compared to Chlorocebus aethiops and Homo sapiens. Heliyon 2015;1:e00042.
33. Brandler S, Marianneau P, Loth P, et al. Measles vaccine expressing the secreted form of West Nile virus envelope glycoprotein induces protective immunity in squirrel monkeys, a new model of West Nile virus infection. J Infect Dis 2012;206:212-219.
34. Delpeut S, Sawatsky B, Wong XX, et al. Nectin-4 Interactions Govern Measles Virus Virulence in a New Model of Pathogenesis, the Squirrel Monkey (Saimiri sciureus). J Virol 2017;91.
35. Eberle R, Black D. Sequence analysis of herpes simplex virus gB gene homologs of two platyrrhine monkey alpha-herpesviruses. Arch Virol 1993;129:167-182.
36. Eberle R, Jones-Engel L. Understanding Primate Herpesviruses. J Emerg Dis Virol 2017;3.
37. Houff SA, London WT, DiChiro G, et al. Neuroradiological studies of JCV-induced astrocytomas in nonhuman primates. Progress in clinical and biological research 1983;105:253-259.
38. Hsu EC, Sarangi F, Iorio C, et al. A single amino acid change in the hemagglutinin protein of measles virus determines its ability to bind CD46 and reveals another receptor on marmoset B cells. J Virol 1998;72:2905-2916.
39. Kobune F, Takahashi H, Terao K, et al. Nonhuman primate models of measles. Lab Anim Sci 1996;46:315-320.
40. Zaragoza C, Li RM, Fahle GA, et al. Squirrel monkeys support replication of BK virus more efficiently than simian virus 40: an animal model for human BK virus infection. J Virol 2005;79:1320-1326.
41. Nehete P, Ruiz J, Nehete B, et al. Intensive immune suppression of Bolivian squirrel monkeys activates latent polyomavirus (HUM8P. 337): Am Assoc Immnol, 2014.
42. Milich KM, Koestler BJ, Simmons JH, et al. Methods for detecting Zika virus in feces: A case study in captive squirrel monkeys (Saimiri boliviensis boliviensis). PloS one 2018;13:e0209391.
43. Rogers DL, McClure GB, Ruiz JC, et al. Endemic Viruses of Squirrel Monkeys (Saimiri spp.). Comp Med 2015;65:232-240.
44. Vanchiere JA, Ruiz JC, Brady AG, et al. Experimental Zika Virus Infection of Neotropical Primates. The American journal of tropical medicine and hygiene 2018;98:173-177.
45. de Alcantara BN, Imbeloni AA, de Brito Simith Durans D, et al. Histopathological lesions of congenital Zika syndrome in newborn squirrel monkeys. Scientific reports 2021;11:6099.
46. Imbeloni AA, de Alcantara BN, Coutinho LN, et al. Prenatal disorders and congenital Zika syndrome in squirrel monkeys. Scientific reports 2021;11:2698.
47. Collins WE. Nonhuman primate models. II. Infection of Saimiri and Aotus monkeys with Plasmodium vivax. Methods Mol Med 2002;72:85-92.
48. Fernandez-Becerra C, Aparici-Herraiz I, Del Portillo HA. Cryptic erythrocytic infections in Plasmodium vivax, another challenge to its elimination. Parasitology International 2021:102527.
49. Collins WE, Sullivan JS, Fryauff DJ, et al. Adaptation of a chloroquine-resistant strain of Plasmodium vivax from Indonesia to New World monkeys. The American journal of tropical medicine and hygiene 2000;62:491-495.
50. Heuer E, Jacobs J, Du R, et al. Amyloid-Related Imaging Abnormalities in an Aged Squirrel Monkey with Cerebral Amyloid Angiopathy. J Alzheimers Dis 2017;57:519-530.
51. Walker LC, Masters C, Beyreuther K, et al. Amyloid in the brains of aged squirrel monkeys. Acta Neuropathol 1990;80:381-387.
52. Patel AG, Nehete PN, Krivoshik SR, et al. Innate immunity stimulation via CpG oligodeoxynucleotides ameliorates Alzheimer's disease pathology in aged squirrel monkeys. Brain 2021.
53. Yang PF, Qi HX, Kaas JH, et al. Parallel functional reorganizations of somatosensory areas 3b and 1, and S2 following spinal cord injury in squirrel monkeys. The Journal of neuroscience : the official journal of the Society for Neuroscience 2014;34:9351-9363.
54. Shi Z, Wilkes DM, Yang PF, et al. On the Relationship between MRI and Local Field Potential Measurements of Spatial and Temporal Variations in Functional Connectivity. Scientific reports 2019;9:8871.
55. Plautz EJ, Barbay S, Frost SB, et al. Effects of Subdural Monopolar Cortical Stimulation Paired With Rehabilitative Training on Behavioral and Neurophysiological Recovery After Cortical Ischemic Stroke in Adult Squirrel Monkeys. Neurorehabil Neural Repair 2016;30:159-172.
56. Migliaccio AA, Minor LB, Della Santina CC. Adaptation of the vestibulo-ocular reflex for forward-eyed foveate vision. The Journal of physiology 2010;588:3855-3867.
57. Finlay BL, Franco EC, Yamada ES, et al. Number and topography of cones, rods and optic nerve axons in New and Old World primates. Visual neuroscience 2008;25:289-299.
58. Jacobs GH. Genetics and Evolution of Color Vision in Primates. Oxford Research Encyclopedia of Neuroscience, 2019.
59. Jacobs GH. Photopigments and the dimensionality of animal color vision. Neuroscience & Biobehavioral Reviews 2018;86:108-130.
60. Neitz M, Neitz J. Curing color blindness--mice and nonhuman primates. Cold Spring Harbor perspectives in medicine 2014;4:a017418-a017418.
61. Mancuso K, Hauswirth WW, Li Q, et al. Gene therapy for red-green colour blindness in adult primates. Nature 2009;461:784-787.