Numerous studies demonstrate that the rhesus monkey is an excellent species with which to investigate mechanisms underlying human emotion and psychopathology. To examine the role of the central nucleus of the amygdala (CeA) in mediating the behavioral and physiological responses associated with fear and anxiety, we used rhesus monkeys to assess the effects of excitotoxic lesions of the CeA. Behavioral and physiological responses of nine monkeys with bilateral CeA destruction (ranging from 46 to 98%) were compared with five animals with asymmetric lesions (42-86.5% destruction on the most affected side) and with 16 unoperated controls. Results suggest that similar to rodent species, the primate CeA plays a role in mediating fear-and anxiety-related behavioral and endocrine responses. Compared with controls and the asymmetric-lesion group, bilaterally lesioned monkeys displayed significantly less fear-related behavior when exposed to a snake and less freezing behavior when confronted by a human intruder. In addition, bilaterally lesioned monkeys had decreased levels of CSF corticotrophin-releasing factor (CRF), and both lesioned groups had decreased plasma ACTH concentrations. In contrast to these findings, patterns of asymmetric frontal brain electrical activity, as assessed by regional scalp EEG, did not significantly differ between control and lesioned monkeys. These findings suggest that in primates, the CeA is involved in mediating fear-and anxiety-related behavioral and pituitary-adrenal responses as well as in modulating brain CRF activity.

To survive, primates must detect danger in time to activate appropriate defensive behaviors. In this study, the defensive behaviors of infant rhesus monkeys exposed to humans were characterized. It was observed that the direction of the human's gaze is a potent cue for the infant. Infants separated from their mothers were active and emitted frequent distress vocalizations. When a human entered the room but did not look at the infant, it became silent and froze in one position. If the human stared at the infant, it responded with aggressive barking. Alterations of the opiate system affected the frequency of the infant's distress calls without affecting barking and freezing, whereas benzodiazepine administration selectively reduced barking and freezing. This suggests that opiate and benzodiazepine systems regulate specific defensive behaviors in primates and that these systems work together to mediate behavioral responses important for survival.

Anxious temperament (AT) in human and non-human primates is a trait-like phenotype evident early in life that is characterized by increased behavioural and physiological reactivity to mildly threatening stimuli 1–4. Studies in children demonstrate that AT is an important risk factor for the later development of anxiety disorders, depression, and comorbid substance abuse 5. Despite its importance as an early predictor of psychopathology, little is known about the factors that predispose vulnerable children to develop AT and the brain systems that underlie its expression. To characterize the neural circuitry associated with AT and the extent to which the function of this circuit is heritable, we performed a study in a large sample of rhesus monkeys phenotyped for AT. Using 238 young monkeys from a multigenerational single-family pedigree, we simultaneously assessed brain metabolic activity and AT while monkeys were exposed to the relevant ethological condition that elicits the phenotype. High-resolution 18F-deoxyglucose positron emission tomography (FDG-PET) was selected as the imaging modality since it provides semi-quantitative indices of absolute glucose metabolic rate, allows for simultaneous measurement of behaviour and brain activity, and has a time course suited to assess temperament-associated sustained brain responses. Results demonstrated that the central nucleus region of amygdala and the anterior hippocampus are key components of the neural circuit predictive of AT. Quantitative genetic analysis demonstrated significant heritability of the AT phenotype. Additionally, a voxelwise analysis revealed significant heritability of metabolic activity in AT-associated hippocampal regions. However, activity in the amygdala region predictive of AT was not significantly heritable. Furthermore, the heritabilities of the hippocampal and amygdala regions significantly differed from each other. Even though these structures are closely linked, the results suggest differential influences of genes and environment on how these brain regions mediate AT and the ongoing risk to develop anxiety and depression.

Temperamentally anxious individuals can be identified in childhood and are at risk to develop anxiety and depressive disorders. In addition, these individuals tend to have extreme asymmetric right prefrontal brain activity. Although common and clinically important, little is known about the pathophysiology of anxious temperament. Regardless, indirect evidence from rodent studies and difficult to interpret primate studies is used to support the hypothesis that the amygdala plays a central role. In previous studies using rhesus monkeys, we characterized an anxious temperament endophenotype that is associated with excessive anxiety and fear-related responses and increased electrical activity in right frontal brain regions. To examine the role of the amygdala in mediating this endophenotype and other fearful responses, we prepared monkeys with selective fiber sparing ibotenic acid lesions of the amygdala. Unconditioned trait-like anxiety-fear responses remained intact in monkeys with Ͼ95% bilateral amygdala destruction. In addition, the lesions did not affect EEG frontal asymmetry. However, acute unconditioned fear responses, such as those elicited by exposure to a snake and to an unfamiliar threatening conspecific were blunted in monkeys with Ͼ70% lesions. These findings demonstrate that the primate amygdala is involved in mediating some acute unconditioned fear responses but challenge the notion that the amygdala is the key structure underlying the dispositional behavioral and physiological characteristics of anxious temperament. Key words: rhesus monkey; anxiety; fear; amygdala; temperament; EEGThe amygdala is a structure that is located in the medial temporal lobe and is composed of numerous subnuclei. The basolateral regions receive information from areas such as the cortex and thalamus, and the central nucleus sends efferents to projection sites that are important in mediating the behavioral, autonomic, and endocrine responses to stressors. Since the early studies of Kluver and Bucy (1939) and Weiskrantz (1956) the amygdala has been hypothesized to be a critical structure in mediating fear, anxiety, and other defensive behaviors. These studies, performed in rhesus monkeys with large lesions of the temporal lobe, reported dramatic effects such that monkeys with feral behavior became tame. These initial studies were a major impetus for numerous other investigators to explore amygdala functions in relation to emotion and behavior. Studies in rodents demonstrated that the amygdala is a key component of the neural circuitry underlying acute fear responses, as well as in the acquisition and expression of conditioned fear (Blanchard and Blanchard, 1972;Ledoux et al., 1988;Davis, 1992). However, the rodent data are difficult to interpret in relation to human behavior and psychopathology because there are important differences between rodents and primates in behavior, amygdala anatomy, and amygdala-prefrontal cortical circuitry (Amaral et al., 1992;Kalin, 1993). A small number of studies have been performed in nonhuman...