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Freezing is an adaptive defensive behavior that is expressed in response to an imminent threat. In prior studies with rhesus monkeys, stable individual differences in animals' propensities to freeze have been demonstrated. To understand the factors associated with these individual differences, freezing behavior was examined in infant rhesus monkeys and their mothers, in conjunction with levels of the stress-related hormone cortisol. In both mothers and infants, basal cortisol levels were positively correlated with freezing duration. Additionally, the number of offspring a mother had was negatively correlated with her infant's cortisol level. These findings suggest a link between basal cortisol levels and an animal's propensity to freeze, as well as a mechanism by which maternal experience may affect infants' cortisol levels.
Children with an anxious temperament (AT) are at risk for developing psychiatric disorders along the internalizing spectrum, including anxiety and depression. Like these disorders, AT is a multidimensional phenotype and children with extreme anxiety show varying mixtures of physiological, behavioral, and other symptoms. Using a well-validated juvenile monkey model of AT, we addressed the degree to which this phenotypic heterogeneity reflects fundamental differences or similarities in the underlying neurobiology. The rhesus macaque is optimal for studying AT because children and young monkeys express the anxious phenotype in similar ways and have similar neurobiology. Fluorodeoxyglucose (FDG)-positron emission tomography (FDG-PET) in 238 freely behaving monkeys identified brain regions where metabolism predicted variation in three dimensions of the AT phenotype: hypothalamic-pituitary-adrenal (HPA) activity, freezing behavior, and expressive vocalizations. We distinguished brain regions that predicted all three dimensions of the phenotype from those that selectively predicted a single dimension. Elevated activity in the central nucleus of the amygdala and the anterior hippocampus was consistently found across individuals with different presentations of AT. In contrast, elevated activity in the lateral anterior hippocampus was selective to individuals with high levels of HPA activity, and decreased activity in the motor cortex (M1) was selective to those with high levels of freezing behavior. Furthermore, activity in these phenotype-selective regions mediated relations between amygdala metabolism and different expressions of anxiety. These findings provide a framework for understanding the mechanisms that lead to heterogeneity in the clinical presentation of internalizing disorders and set the stage for developing improved interventions.
BACKGROUND: Excessive behavioral inhibition during childhood marks anxious temperament and is a risk factor for the development of anxiety and affective disorders. Studies in nonhuman primates can provide important information related to the expression of this risk factor, since threat-induced freezing in rhesus monkeys is a trait-like characteristic analogous to human behavioral inhibition. The orbitofrontal cortex (OFC) and amygdala are part of a circuit involved in the processing of emotions and associated physiological responses. Earlier work demonstrated involvement of the primate central nucleus of the amygdala (CeA) in mediating anxious temperament. This study assessed the role of the primate OFC in mediating anxious temperament and its involvement in fear responses. METHODS: Twelve adolescent rhesus monkeys were studied (six lesion and six control monkeys). Lesions were targeted at regions of the OFC that are most interconnected with the amygdala. Behavior and physiological parameters were assessed before and after the lesions. RESULTS: The OFC lesions significantly decreased threat-induced freezing and marginally decreased fearful responses to a snake. The lesions also resulted in a leftward shift in frontal brain electrical activity consistent with a reduction in anxiety. The lesions did not significantly decrease hypothalamic-pituitary-adrenal (HPA) activity or cerebrospinal fluid (CSF) concentrations of corticotrophin-releasing factor (CRF). CONCLUSIONS: These findings demonstrate a role for the OFC in mediating anxious temperament and fear-related responses in adolescent primates. Because of the similarities between rhesus monkey threat-induced freezing and childhood behavioral inhibition, these findings are relevant to understanding mechanisms underlying anxious temperament in humans.