Several species and numerous protocols have been tested to validate translational animal models which better mimic the physiological and behavioral states observed in human psychopathologies associated with chronic social stress including fish species (Øverli et al., 2004; Schjolden et al., 2005), birds (Roberts et al., 2007), rodents (Sgoifo et al., 1999; Veenema et al., 2003; Kompagne et al., 2008; Martinez et al., 2008; Hennessy et al., 2009), sheep (Stackpole et al., 2006), pigs (van der Staay et al., 2008), and non-human primates (Barros and Tomaz, 2002; Dettling et al., 2007).

These models show mammals present great genetic similarities and share corresponding neurophysiological mechanisms involved in socialization. However, their social organizations reveal a large range of differences in their size, composition, social bonding, parental care, and reproductive skew, creating a diversity of societies which is currently under investigation in terms of studying their complexity. This evidence demonstrates that the evolutionary pressures related to the natural environment demand adaptive responses which lead to a great diversity of strategies, thus making it difficult to apply the findings of some animal models to people. Therefore, these interspecific differences limit the suitability of a given species as an experimental model for comparative studies with humans (Kappeler, 2019), including non-human primates.

The common marmoset is a small New World primate and has gained attention mainly due to its complex social organization. This species has several social behaviors which are linked to auditory and visual cues like humans, including that they show gazing behavior, intentional pro-social behavior (Burkart and van Schaik, 2020; also known as altruism in humans), and observational social learning. In fact, their social cognition and communication seem more similar to that of humans than those of rhesus monkeys (Burkart and Finkenwirth, 2015). It is also suggested that humans and marmosets share main traits as cooperative breeders such as social tolerance and social monitoring resulting from cooperative breeding (Burkart and Finkenwirth, 2015).

Marmosets exhibit a range of changes at physiological and behavioral levels when facing stressful situations which depends on the individual, social and environmental characteristics resembling those observed in humans. They also have a well-defined ethogram (Stevenson and Poole, 1976), and there are procedures to measure cortisol in blood and urine, a non-invasive technique using feces (see de Sousa, 2017), and new methods have more recently been standardized for saliva (Cross and Rogers, 2004; Cross et al., 2004; Ash et al., 2018) in the laboratory and in hair in captive (Phillips et al., 2018) and wild marmosets at different ages (Garber et al., 2020).

These features make this species relevant for their use as a model in psychiatry studies related to chronic stress. It is largely understood that chronic social stress is the main etiology of Major Depressive Disorder (MDD; Tafet and Bernardini, 2003), General Anxiety Disorder (GAD; Juruena et al., 2020), and Post-Traumatic Stress Disorder (PTSD; Yehuda et al., 2015). In this sense, the cortisol profile is considered the marker of hypothalamus-pituitary-adrenal (HPA) axis disruption and has been used as a potential biomarker of some psychiatric syndromes (Dieleman et al., 2015; Herman et al., 2016). Thus, in this minireview, we aim to analyze recent studies to provide more evidence for the use of common marmosets as one of the strongest candidates today as an experimental model for research on psychiatric disorders related to stress.

Despite there being several protocols for inducing psychiatric disorders in animal models such as genetic (Sasaki, 2015), pharmacological (Costall et al., 2011; Pryce et al., 2011; Yasue et al., 2015), and behavioral (Cilia and Piper, 1997; Barros et al., 2000, 2008; Dettling et al., 2002b), the etiological models for mental disorders associated to chronic stress based on social challenging are closer to that which triggers human PTSD (Dettling et al., 2002a,b, 2007), GAD (Cilia and Piper, 1997; Barros et al., 2000, 2008) and MDD (Johnson et al., 1996; Galvão-Coelho et al., 2008, 2017). Therefore, animal models are promising to gain larger emphasis in scientific studies. In order to do so, it is essential to investigate and understand the neurobiological mechanisms underlying the associated physiological and psychological mechanisms that support the analysis of psychiatric disorders. The data obtained in studies using non-human models have significant limitations because the etiology of psychiatric disorders is characterized by a multiplicity of causal factors and symptoms (Salgado and Sandner, 2013). Furthermore, in the perspective that it is the combination of “nature” and “nurture” which contribute to different phenotypes of susceptibility and resilience to developing mood disorders (Hollander et al., 2020), the need for substantial information to attain the validation criteria of an animal model is strengthened.

The systematic study of the behavior and development of common marmosets (Callithrix jacchus) living in captivity in colonies worldwide started in the 1970s (Epple, 1970; Abbott and Hearn, 1978), and wild groups started to be monitored in Brazil in the 1980s (Stevenson and Rylands, 1988). In this context, the common marmoset is currently one of the most studied species among non-human primates in both wild and in captivity situations and consequently, the marmoset emerges as a distinct experimental model with respect to the amount of information available in both settings.

Despite recognition of increasing psychiatric disorder incidences being related to chronic stress in adolescents and the importance of chronic stress in this ontogenetic phase on long–term non-adaptive neuroplasticity changes (Thapar et al., 2012; Knowles et al., 2021), a large part of the literature about chronic stress related to neuropsychiatric disorders using marmoset models have only explored adult (Johnson et al., 1996; Cilia and Piper, 1997; Barros et al., 2000, 2008) and infant (Dettling et al., 2002a,b, 2007) ages. Therefore, being aware of this gap, our group recently validated the marmoset as a juvenile animal model for major depression (Galvão-Coelho et al., 2017).

In aiming at the complete validation of this juvenile marmoset animal model for major depression, we developed a protocol addressing: (a) ecological validity, which means that the symptoms in this model were triggered by similar occurrences for human diseases, and in this case we used the social isolation protocol; (b) construct validity: animals showed activation of physiological processes in a similar way to humans, such as cortisol levels; (c) face validity: the animals expressed symptoms/behavior changes similar to those of humans, such as changes in appetite and anhedonia; (d) predictive validity: animals and humans showed similar responses to treatments; (e) interrelational validity: we investigated the model in several domains such as behaviors, molecular biomarkers and cognition; (f) evolutionary criteria: reflects the ability of the proposed model to investigate specific domains in various species such as anhedonia, body weight and cortisol analysis, which can be done on marmosets, humans and other species such as rodents; and (g) population validity: the capacity of the proposed model to reflect the natural variance of phenotypes observed in the general population, as observed in some studies in the literature (Galvão-Coelho et al., 2008, 2017).

In this context, male and female juvenile marmosets (approximately 7 months) were subjected to a chronic social stressor protocol (13 weeks of social isolation) to induce a state of depression. Next, fecal cortisol, body weight, and some intra and interspecific behaviors were analyzed in the stressed group and compared with a control group where marmosets continued to live with the family throughout the study. In short, we observed a behavioral and neuroendocrine depressive state similar to patients with depression (Dean and Keshavan, 2017; Santiago et al., 2020) and other non-human primate models of depression (Li et al., 2013; Hennessy et al., 2014) for both sexes isolated from marmosets (male; female), but not for animals kept with the family. Symptoms included a significant reduction in cortisol levels, an increase in anxiety-like behavior (stereotypes, such as scratching and body piloerection), presence of anhedonia, sexual dimorphic changes in diet and body weight (Galvão-Coelho et al., 2017). Most of the altered behaviors, such as scratching, as well as the change in cortisol levels, were reversed by treatment with nortriptyline (7 days), but not by the vehicle (Galvão-Coelho et al., 2017).

The validation of this protocol gave way to developing depressive juvenile models with other non-human primate species (Teng et al., 2021) and enabled a step forward when a potential new alternative drug therapy (nortriptyline) for depression was tested (da Silva et al., 2019). Using that same validated protocol, some male and female juvenile marmosets (male; female) were treated with a single dose of ayahuasca (da Silva et al., 2019). Ayahuasca is a psychedelic decoction made from combining two plants from the Amazon rainforest: Psychotria viridis and Banisteriopsis caapi, which has shown promising fast antidepressant effects in humans (Palhano-Fontes et al., 2014, 2021; Perkins et al., 2021; Sarris et al., 2021). Thus, we observed a fast recovery in the decreased cortisol levels (hypocortisolemic state) and the bodyweight of depressive-like marmosets to the baseline values 24 h after an acute dose of Ayahuasca, and not after the vehicle, as well as reductions in anxiety-like stereotypic behaviors. Additionally, the single dose of ayahuasca also had long-lasting effects (14 days) and seemed to be more promising than nortriptyline treatment (da Silva et al., 2019).

These findings in the marmoset supported the development of clinical trials using ayahuasca treatment for resistant depression and showed positive results, including some similar to those seen in the marmoset (for example, regulating cortisol levels; de Almeida et al., 2019; Palhano-Fontes et al., 2019; Galvão-Coelho et al., 2020, 2021).

As mentioned earlier in this review, some scientists argue that current animal models are insufficient to express the full extent of mood disorders and therefore have no real value in understanding mental illness. However, new research initiatives to integrate the effort to study mental disorders, such as the Roadmap for Mental Health Research in Europe (ROAMER; Haro et al., 2014) and Research Domain Criteria (RDoC), funded by European and American public and private institutions (Insel et al., 2010; Elfeddali et al., 2014) intend to build a matrix of variables which constitute a unit of analysis involving studies from genetic, physiological, behavioral, and self-report evaluations. New information is added or contributions are made in these projects by revision of earlier knowledge on psychopathology analysis of symptoms, and both initiatives will facilitate progress in this field. They argue that these disorders are too complex to try to understand globally, so the knowledge gained step-by-step should provide more clarity and effectiveness. In addition, some specific symptoms are common to different psychopathologies, so that understanding one symptom for a certain disorder can be applied to another. Therefore, this new understanding makes studies on animal models even more important, since it is easier to focus on fewer symptoms and their pathophysiological correlates and their management. In turn, encouraging the development of new protocols and stimulating new studies on biomarkers, as well as on the development of new drugs. In addition, marmosets are the focus of a large–scale Japanese project called Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS; Okano and Mitra, 2015; Okano et al., 2015), and new colonies of marmosets show that the use of this small neotropical primate as experimental models continues to present a promising future for scientific research, including for investigations of neuropsychiatric diseases.

MS and NG-C wrote and edited the manuscript. MS, NG-C, and MM performed bibliographic research and main drafting. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.