Alterations of threat processing in brain circuits contribute to a variety of psychiatric problems. Much has been learned about the neural basis of threat processing through studies of Pavlovian threat (fear) conditioning, a procedure in which an emotionally neutral conditioned stimulus (CS), such as a tone, is paired with an aversive unconditioned stimulus (US), typically electric shock. Following pairing, the CS acquires the capacity to elicit conditioned defensive responses (CRs), such as freezing behavior. In addition to eliciting these reactions, an aversive CS also alters instrumental behaviors (actions). For example, people with anxiety disorders go to great lengths to avoid stimuli and situations that might elicit fear or anxiety. But these avoidant actions are detrimental as they can be disruptive to daily life, and also prevent the opportunity to learn what is safe and what is harmful. Further, in the presence of threatening, stressful stimuli or situations, avoidance is enhanced. We seek to understand how threats facilitate avoidance. To do this we use a Pavlovian-to-instrumental transfer (PIT) task. In PIT, the CS-US association is conditioned first and then used to alter the vigor with which the subject performs a separately trained instrumental avoidance response. These tasks thus provide ways to study motivation of actions. The studies take advantage of a relatively new technique for inhibiting neural activity-D READD technology (Designer Receptors Exclusively Activated by Designer Drugs). DREADDs will be used to examine the contribution of distinct amygdala nuclei and extra-amygdala targets to PIT. Given existing findings and preliminary results we hypothesize that inhibition of lateral (LA) and central (CeA) amygdala, but not basal amygdala (BA), will interfere with the motivation to perform PIT. New data suggest that the connections the medial amygdala (MeA) may be an intermediate link in between LA and CeA in motivation of PIT. We hypothesize that MeA plays a key role in determining whether CeA outputs will control freezing or facilitation of avoidance behavior. We also hypothesize that connections from the CeA to the ventral tegmental area (VTA) is a key output of the CeA in PIT. VTA outputs, in turn, release dopamine (DA) in the nucleus accumbens (NAcc). DA in the NAcc has long been implicated in the invigoration of behavior. CeA driving of DA release in NAcc is thus proposed to be the way that a CS processed by the amygdala modulates avoidance. Given that anxiety disorders involve both pathological reactions and actions, the results of this work should greatly extend our understanding of brain circuits relevant to these common psychiatric conditions. Better appreciation of aversive instrumental behavior may also provide insight into the relationship between aversive and appetitive processes, and thus may also be relevant to understanding how threat processing may contribute to eating, addiction, and other disorders that are traditionally viewed as primarily involving appetitive motivation.

Public Health Relevance

Anxiety disorders involve alterations in threat processing, mediated in part by changes in amygdala function, and are characterized by pathological instrumental actions, such as avoidance, as well as exaggerated defensive reactions. This proposal builds on findings about how a Pavlovian aversive stimulus controls reactions to understand how the same stimulus modulates actions such as avoidance. Findings will help understand basic processes that contribute to anxiety disorders and hopefully lead to improved treatments of these debilitating conditions.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Neurobiology of Learning and Memory Study Section (LAM)
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Vicentic, Aleksandra
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New York University
Schools of Arts and Sciences
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LeDoux, Joseph; Daw, Nathaniel D (2018) Surviving threats: neural circuit and computational implications of a new taxonomy of defensive behaviour. Nat Rev Neurosci 19:269-282
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