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CHAPTER 26 The Marmoset as a Model in Behavioral Neuroscience and Psychiatric Research Jeffrey A. French Neuroscience Program and Callitrichid Research Center, University of Nebraska at Omaha, NE, United States INTRODUCTION top-down as well as bottom-up regulation of affect and emotion. Finally, the changes in NHP brain struc- In its mission statement, the US National Institutes of ture and function can facilitate the mediation of chal- Health provides a clear statement of its focus: “. to seek lenges associated with group living, including fundamental knowledge about the nature and behavior aggression, affiliation, and the establishment and main- of living systems and the application of that knowledge tenance of long-term complex social relationships that to enhance health, lengthen life, and reduce illness and distinguish these species from nonprimate animals [5]. disability” [emphasis added, www.nih.gov/about-nih/ what-we-do/mission-goals, 2015). Disorders associated with brain or behavioral dysfunction represent the lead- The Utility of Marmosets in Behavioral Models ing disease burden and highest source of lifetime years in Neuroscience and Psychiatric Research living with disability on a global basis (YLD: [1]) and together these disorders represent one of the leading From the perspective of a biomedically oriented contributors to disease-associated mortality worldwide focus, research on behavioral states (both normative [2]. Clearly, then, there is a premium on understanding and atypical) is of interest to the extent that it can pro- both normative behavioral states and their relationship vide useful information regarding the developmental to brain function and the nature of brain dysfunction factors that lead to normative neuropsychological func- as is relates to pathological behavioral states. tion, as well as the underlying neurobiological proper- As in all fields of biomedical science, animal models ties that contribute to atypical or pathological states. play an important role in characterizing the basic Animal models, primarily rodents, have been widely biology of brainebehavior relationships, in exploring used in exploring both developmental and neurobiolog- the potential etiology of disorders (genetics, develop- ical functions in the behavioral realm [6,7], but progress ment, environmental perturbations), and in developing has been limited with rodent models, relative to primate and refining treatments in a number of modalities that models, for multiple reasons. First, the complexity of the target dysfunction on brain processing. Nonhuman pri- central nervous system, primarily in cortical regions mates (NHPs) constitute an attractive animal model for important for complex thought, cognition, affect, social- behavioral and psychological states for a variety of ity, and decision-making, is not as elaborate in rodents as important reasons. Given the relatively recent common it is in primates, including humans [8]. The 80 million evolutionary origin of primates [3], NHPs share com- years since the last common ancestor between rodents monalities in complex brain structure and function (ho- and primates has led to divergence in the relative func- mologies), most importantly represented by an increase tional morphology and connectivity of the brain, in in brain size and elaboration of the neocortex, especially particular the expansion of the PFC in the primate line- the prefrontal cortex (PFC) [4]. As a consequence of age [9]. Second, the cognitive, social, and behavioral these morphological adaptations, NHPs are capable of phenotypes of primates are much richer and more com- complex cognitions that involve multisensory integra- plex than those of rodents [10], presumably a result of tion, complex and conditional decision-making, and the elaboration and patterns of connectivity among The Common Marmoset in Captivity and Biomedical Research https://doi.org/10.1016/B978-0-12-811829-0.00026-1 477 Copyright © 2019 Elsevier Inc. All rights reserved. 478 26. THE MARMOSET AS A MODEL IN BEHAVIORAL NEUROSCIENCE AND PSYCHIATRIC RESEARCH cortical regions of the primate brain. As a consequence, marmoset brain anatomy and function, including a there is a premium in developing suitable NHP models well-annotated brain atlas that is continuously updated from the perspective of face validity (behavioral pheno- [23], critical information regarding the structure and types in primates are more likely to be similar to connectivity of frontal cortices [24,25], a growing knowl- humans) and construct validity (the genetics, ontogeny, edge of sensory processing in a number of modalities and neural architecture are likely to be homologous in [26e29], and details on motor control circuitry [30].In primates and humans). addition, in the past 5 years a remarkable suite of tools The common marmoset (Callithrix jacchus) represents in the neurosciences have been developed with and/or an NHP species of growing interest in biomedical and applied to the marmoset central nervous system. Silva behavioral research. Among the reasons for the [31] recently reviewed advances in imaging of the increased use of this species are both practical and man- marmoset brain, and the methodologies include high- agement issues. These include their small size resolution structural MRI, functional connectivity (350e500 g), thereby reducing the need for large enclo- among multiple brain regions during processing in a sures and animal facilities. Marmosets are also highly host of sensory modalities, and two-photon laser cap- fecund, capable of producing two twin (or larger) litters ture microscopy for monitoring neural activity at the per year. Relative to cercopithecine models (e.g., rhesus level of individual neuronal cells. A host of techniques macaques) or hominoid primates (e.g., chimpanzees), have been utilized to alter gene function in the the zoonotic risk posed by marmosets is low. marmoset brain (see review in Ref. [32]), including the A more compelling case for the marmoset as a model production of transgenic marmosets relevant for a num- in biobehavioral and neuroscience research derives from ber of pathologies associated with the brain, lentiviral the scientific relevance of a host of features associated retrograde vectors for tract tracing in the brain, and with the natural history and associated phenotypes of shRNA silencing of gene expression in targeted regions the species. Marmosets (and most other callitrichinae of the brain. Finally, the “proof of concept” for an opto- primates) are obligate twinning species, producing dizy- genetic preparation in the marmoset, via the induction gotic twins. Twins are dizygotic or fraternal, and of channelrhodopsin into multiple cortical regions of because of unique features of the development of the brain [33], anticipates the potential to manipulate placental and shared embryonic vasculature, twin fe- neuronal function in the marmoset brain within tight tuses exchange embryonic stem cells and multiple spatial and temporal boundaries. Thus, within the neu- signaling molecules across these vascular anastomoses. rosciences the marmoset may well deserve its recent As a consequence, marmoset twins are chimeric in hem- designation as a “supermodel” in the biomedical sense atopoietically derived tissues [11] and perhaps in other of the word [34]. tissues as well [12]. Twinning is thus potentially impor- tant from the perspective of experimental design (e.g., Organization of this Review differential twin phenotypes that develop in spite of a shared intrauterine environment [13] and in the explora- This review of marmosets as behavioral models in tion of immuneebrain interactions [14e16]). From a biomedical and behavioral research is organized in developmental perspective, marmoset life span trajec- line with the Research Domain Criteria (RDoC) taxon- tories are considerably accelerated relative to other omy. The RDoC movement at the NIH began in light NHP models and humans, passing through the infant of decreasing rates of morbidity and mortality from a stage in several months, reaching sexual and social host of disease states (e.g., cardiovascular disease, can- maturity by 18 months of age, and displaying morpho- cer) as a consequence of investments in and knowledge logical and behavioral signs of senescence within gained in basic and clinical science, but mortality rates 6e8 years [17,18]. From the perspective of social neuro- have remained unchanged for mental illness, and science, the marmoset represents an exceptional model depending on the disorder, prevalence rates across for human sociality [19]. The marmoset shares many fea- recent decades have remained stable or have increased tures in the realm of social phenotypes with humans, [35]. The RDoC as a research tool represents a move including the fundamental social unit (small nuclear or away from the standard clinical diagnostic protocols extended family social groups [20]), offspring rearing for psychological disorders [the American Psychiatric dynamics (cooperative breeding, which entails shared Association’s DSM-V (www.dsm5.org) and the World infant care by mothers, fathers, and older offspring Health Organization’s ICD-10, www.who.int/whosis/ within the family group [21]), and the nature of adult icd10]. These protocols dictate the diagnosis of mental heterosexual social relationships (consisting of many disorders based on clusters of behavioral symptoms, a features associated with social monogamy [22]). procedure that likely poses a potential problem for From

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