The Primate Amygdala Mediates Acute Fear But Not the Behavioral and Physiological Components of Anxious Temperament

Abstract

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...

Prepared stimuli enhance aversive learning without weakening the impact of verbal instructions

“…Consistent with these population-based findings, experimental work has shown that prepared stimuli elicit increased arousal and preferential attention relative to neutral stimuli (for review, see Ohman and Mineka (2001)). Neurobiologically, their effects are thought to be mediated by the amygdala as well as the orbitofrontal cortex (Meunier et al 1999;Kalin et al 2001;Murray and Izquierdo 2007). Our quantitative models reveal that discriminative fear conditioning occurred faster when humans were exposed to images of snakes or spiders than when they were exposed to images of abstract fractals, replicating prior work (Ho and Lipp 2014).…”

“…Relative to fearirrelevant stimuli (e.g., flowers, mushrooms), fear-relevant stimuli have been shown to facilitate classical conditioning (Ho and Lipp 2014) and slow extinction learning (Fredrikson et al 1976; Ohman et al 1975a,b). Work in nonhuman primates suggests that innate responses to fear-relevant stimuli are mediated by the amygdala and orbitofrontal cortex (Meunier et al 1999;Kalin et al 2001;Murray and Izquierdo 2007). These structures play crucial roles in fear acquisition (Davis 1992; Maren 2001), extinction (Schiller andDelgado 2010;Milad and Quirk 2012), and value-based learning (Schoenbaum et al 1998;Holland and Gallagher 2004), and thus their preferential recruitment by prepared stimuli might enhance dynamic aversive learning.…”

“…Prepared stimuli such as the snakes and spiders we used here are thought to draw on basic evolutionarily conserved mechanisms (Seligman 1971;Mineka and Ohman 2002). They elicit preferential attention and enhanced learning early in development in human infants (LoBue and DeLoache 2010) and primates (Cook and Mineka 1989;Kalin et al 2001;Murray and Izquierdo 2007), and the specific phobia rate for such stimuli is elevated relative to nonprepared stimuli (de Silva et al 1977;de Silva 1988;Fredrikson et al 1996). Consistent with these population-based findings, experimental work has shown that prepared stimuli elicit increased arousal and preferential attention relative to neutral stimuli (for review, see Ohman and Mineka (2001)).…”

Bilateral neurotoxic amygdala lesions in rhesus monkeys (Macaca mulatta): Consistent pattern of behavior across different social contexts.

“…We believe this evidence suggests that heightened affiliative social interactions following amygdala lesions stems from a more general inability to properly perceive danger or threat in the environment and use such information to modulate social behavior adaptively. In line with this view, deficits in threat detection or fear reactivity have been specifically demonstrated for monkeys with bilateral neurotoxic amygdala lesions in both social (Machado & Bachevalier, 2006) and nonsocial settings (Izquierdo, Suda, & Murray, 2005;Kalin, Shelton, & Davidson, 2004;Kalin, Shelton, Davidson, & Kelley, 2001;Mason et al, 2006;Meunier, Bachevalier, Murray, Málková, & Mishkin, 1999). These abnormalities are not restricted to nonhuman primates, since humans with amygdala lesions also demonstrate specific deficits in identifying fearful facial expressions (Adolphs et al, 1999), rating the magnitude of fearful expressions (Adolphs, Tranel, Damasio, & Damasio, 1995) and assessing the approachability or trustworthiness of unfamiliar individuals (Adolphs, Tranel, & Damasio, 1998).…”

Comparison of the Effects of Bilateral Orbital Prefrontal Cortex Lesions and Amygdala Lesions on Emotional Responses in Rhesus Monkeys

“…One tool that might be used to investigate this issue relies on monkeys' innate emotional responses to snakes. Macaques, even snake-naive ones, exhibit marked defensive responses in the presence of fake or real snakes (Mineka, 1987;Nelson et al, 2003), and elicitation of these responses requires an intact amygdala (Aggleton and Passingham, 1981;Meunier et al, 1999, Kalin et al, 2001. Another commonly used tool relies on monkeys responses to an unfamiliar human observer.…”