Shackman, A. J. & Fox, A. S. (2016). Contributions of the central extended amygdala to fear and anxiety. Journal of Neuroscience, 36, 8050-63.

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ABSTRACT

It is widely thought that phasic and sustained responses to threat reflect dissociable circuits centered on the central nucleus of the amygdala (Ce) and the bed nucleus of the stria terminalis (BST), the two major subdivisions of the central extended amygdala. Early versions of this hypothesis remain highly influential and have been incorporated into the National Institute of Mental Health (NIMH) Research Research Domain Criteria (RDoC) framework. However, new observations encourage a different perspective. Anatomical studies show that the Ce and BST form a tightly interconnected unit, where different kinds of threat-relevant information can be integrated and used to assemble states of fear and anxiety. Imaging studies in humans and monkeys show that the Ce and BST exhibit similar functional profiles. Both regions are sensitive to a range of aversive challenges, including uncertain or temporally remote threat; both co-vary with concurrent signs and symptoms of fear and anxiety; both show phasic responses to short-lived threat; and both show heightened activity during sustained exposure to diffusely threatening contexts. Mechanistic studies demonstrate that both regions can control the expression of fear and anxiety during sustained exposure to diffuse threat. These observations compel a reconsideration of the central extended amygdala’s contributions to fear and anxiety and its role in neuropsychiatric disease.

SIGNIFICANCE STATEMENT

Anxiety disorders impose a staggering burden on public health, underscoring the need to develop a deeper understanding of the underlying neurobiology. The central extended amygdala plays a key role in prominent models of fear and anxiety, yet confusion persists about the respective roles of its two major subdivisions, the Ce and the BST. Anatomical work demonstrates that these two regions are tightly interconnected and uniquely poised to trigger fearful and anxious states. Neuroimaging studies reveal that the Ce and BST are marked by similar functional profiles. Mechanistic evidence indicates that both regions are involved in controlling defensive responses elicited by diffuse or uncertain threat. These observations challenge longstanding ideas about the contributions of the extended amygdala to fear and anxiety and have important implications for our understanding of psychopathology.

Key words: affective neuroscience, anxiety disorders, emotion, individual differences, neuroimaging, nonhuman primate