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Simplified schematic of key central extended amygdala inputs and outputs in humans and other primates. Although this vast literature leaves little doubt that the extended amygdala plays an important role in evaluating and responding to threat, confusion persists about the respective contributions of its major subdivisions. Other work suggests that alterations in the function of this circuit contribute to the development ( Fox and Kalin, 2014 McLaughlin et al., 2014 Fox et al., 2015a Swartz et al., 2015) as well as the maintenance of anxiety and mood disorders in humans ( Sheline et al., 2001 Paulus et al., 2005 Etkin and Wager, 2007 Felmingham et al., 2007 Hamilton et al., 2012 Phan et al., 2013). Studies of rodents, monkeys, and humans demonstrate that the extended amygdala-an anatomical concept encompassing portions of the amygdala and the bed nucleus of the stria terminalis (BST) ( Alheid and Heimer, 1988)-plays a crucial role in assembling states of fear and anxiety in response to a broad spectrum of learned and unlearned threats ( Calhoon and Tye, 2015 Fox et al., 2015a Janak and Tye, 2015 Tovote et al., 2015 Gungor and Paré, 2016 Oler et al., 2016a) ( Fig.
![normal fear vs pathological fear normal fear vs pathological fear](https://image.slideserve.com/1193303/fears-vs-phobias-l.jpg)
Existing treatments are inconsistently effective or associated with significant adverse effects ( Bystritsky, 2006 Insel, 2012 Griebel and Holmes, 2013), underscoring the need to develop a deeper understanding of the neural circuits that control the experience and expression of fear and anxiety in humans. They are the most common family of neuropsychiatric disorders and contribute to the development of depression and comorbid substance abuse ( Kessler et al., 2012). Anxiety disorders impose a staggering impact on public health and the global economy ( Collins et al., 2011 Whiteford et al., 2013 DiLuca and Olesen, 2014). When expressed too intensely or in maladaptive contexts, fear and anxiety can become debilitating ( American Psychiatric Association, 2013).
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These observations compel a reconsideration of the central extended amygdala's contributions to fear and anxiety and its role in neuropsychiatric disease. Mechanistic studies demonstrate that both regions can control the expression of fear and anxiety during sustained exposure to diffuse threat. Both regions are sensitive to a range of aversive challenges, including uncertain or temporally remote threat both covary 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. Imaging studies in humans and monkeys show that the Ce and BST exhibit similar functional profiles. 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. However, new observations encourage a different perspective. Early versions of this hypothesis remain highly influential and have been incorporated into the National Institute of Mental Health Research Research Domain Criteria framework. 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.