Nonhuman Primate Models to Study Anxiety, Emotion Regulation, and Psychopathology

Abstract

This paper demonstrates that the rhesus monkey provides an excellent model to study mechanisms underlying human anxiety and fear and emotion regulation. In previous studies with rhesus monkeys, stable, brain, endocrine, and behavioral characteristics related to individual differences in anxiety were found. It was suggested that, when extreme, these features characterize an anxious endophenotype and that these findings in the monkey are particularly relevant to understanding adaptive and maladaptive anxiety responses in humans. The monkey model is also relevant to understanding the development of human psychopathology. For example, children with extremely inhibited temperament are at increased risk to develop anxiety disorders, and these children have behavioral and biological alterations that are similar to those described in the monkey anxious endophenotype. It is likely that different aspects of the anxious endophenotype are mediated by the interactions of limbic, brain stem, and cortical regions. To understand the brain mechanisms underlying adaptive anxiety responses and their physiological concomitants, a series of studies in monkeys lesioning components of the neural circuitry (amygdala, central nucleus of the amygdala and orbitofrontal cortex) hypothesized to play a role are currently being performed. Initial findings suggest that the central nucleus of the amygdala modulates the expression of behavioral inhibition, a key feature of the endophenotype. In preliminary FDG positron emission tomography (PET) studies, functional linkages were established between the amygdala and prefrontal cortical regions that are associated with the activation of anxiety.

Temperament and hypothalamic–pituitary–adrenal axis function in healthy adults

“…As mentioned above, behavioral inhibition is characterized by a tendency to withdraw and inhibit behavior in response to novel stimuli (Fox et al, 2005). Rhesus monkeys with behavioral inhibition have elevated concentrations of CRH in cerebrospinal fluid and increases in plasma cortisol (Kalin and Shelton, 2003). Similarly, social wariness and internalizing behaviors in children are positively associated with basal salivary cortisol concentrations (de Haan et al, 1998;Gunnar et al, 1997;Kagan et al, 1987;Scerbo and Kolko, 1994;Schmidt et al, 1997;Smider et al, 2002), and two studies have found an association between behavioral inhibition and genetic markers at the CRH locus (Smoller et al, 2003(Smoller et al, , 2005.…”

“…Behavioral inhibition is another temperament factor that has been found predictive of anxiety disorders and depression (Fox et al, 2005). This trait, defined as the tendency to withdraw and avoid novel situations, demonstrates stability over time in both non-human primates (Kalin and Shelton, 2003) and children (Fox et al, 2005). Behavioral inhibition has been linked to anxiety disorders in family studies and in prospective longitudinal studies of young children who have been followed through childhood (Hirshfeld et al, 1992;Rosenbaum et al, 1988) and into adolescence (Prior et al, 2000;Schwartz et al, 1999).…”

The serotonin transporter genotype is associated with intermediate brain phenotypes that depend on the context of eliciting stressor

“…Furthermore, the impacts of different types of ethologically relevant stressors on behavioral, neurochemical, physiological and brain functional responses have been well characterized in this species. [26][27][28] We have been performing highresolution FDG microPET scans in rhesus monkeys to explore the relation between patterns of brain metabolic activity and individual differences in anxiety-related traits. For example, we previously demonstrated that when threatened by a human intruder for a 30-min period, monkeys' individual differences in metabolic activity in the bed nucleus of the stria terminalis (BNST) are strongly predictive of individual differences in monkeys' anxiety-related freezing responses.…”

Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates

“…To this end, we have optimized a model of anxious temperament (AT), the conserved at-risk phenotype, in young developing rhesus monkeys (1)(2)(3)(4). The rhesus monkey is ideal for studying the origin of human AT because these species share the genetic, neural, and phenotypic underpinnings of complex social and emotional functioning (5)(6)(7)(8)(9)(10). Importantly, the rhesus developmental model bridges the critical gap between human psychopathology and rodent models, allowing for translation to humans by using in vivo imaging measures and translation to rodents by using ex vivo molecular methods.…”