Excessive fear, a central component of many anxiety disorders, can have deleterious effects on both psychological and physical wellbeing. Treatments for anxiety disorders often endeavor to supplant fear-based reactions with instrumental actions that can be thought of as active coping strategies. Thus, the capacity to transition from reactive fear to active coping has clear clinical significance ? understanding the biological basis of this process could provide a sound platform for advancements in the treatment of anxiety-related psychopathologies. Signaled active avoidance learning can offer important insights into this transitional process. In this form of conditioning, subjects are trained to avoid an unconditioned stimulus (US) by performing an instrumental action when a predictive conditioned stimulus (CS) is presented. Interestingly, an initial Pavlovian fear reaction, freezing, predominates through early training and constrains the development of active behaviors during CS presentation. Over the course of learning freezing is suppressed, allowing active avoidance responses to become manifest. It is this very suppression of freezing that this proposal seeks to examine, as it represents a compelling model of the transition from reactive to active behavioral states. A neurobiological understanding of this phenomenon could shed light on the substrates of anxiety and resilience, and thus has ample translational potential. The ventromedial prefrontal cortex (vmPFC) is involved in the suppression of maladaptive or inappropriate behaviors, whereas the central nucleus of the amygdala (CeA) is crucial for CS evoked freezing. vmPFC cells form synapses on the neurons that comprise the intercalated cell masses of the amygdala (ITC), which are an inhibitory population that in turn project to the cells of the CeA. The basic hypothesis that this proposal will pursue is that vmPFC exerts feed-forward inhibition on CeA during signaled avoidance learning, thus suppressing CS-evoked freezing and allowing the subject to execute an instrumental avoidance response when the CS is presented. To explore this hypothesis, three specific aims are proposed: 1) to ascertain the role of vmPFC and Cea in the suppression of freezing during signaled avoidance learning, 2) to identify the role of the ITC, and of the vmPFC projection to those neurons, and 3) to determine the timing and nature of vmPFC involvement in the suppression of freezing. Experiments proposed under the first two aims will involve traditional lesion techniques, while the final aim will be explored using the light-activated inhibitory molecule Archaerhodopsin-3. This blend of conventional (lesion) and cutting edge (optogenetic) methodologies will allow for a detailed and precise exploration of the proposed model, thus shedding light on the neuroboiogical substrates of a clinically relevant behavioral phenomenon.

Public Health Relevance

The transition from fear-based reactions to instrumental actions represents a key strategy for the management of anxiety disorders. By studying the substrates of the transition from Pavlovian fear to active instrumental avoidance in a rodent model, the current proposal seeks to illuminate the neurobiology by which organisms move from reactive to active behavioral responses. The examination of this clinically significant neural pathway, involving projections from frontal cortices to the amygdala, will produce novel data that could provide therapeutic targets for the treatment of anxiety disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F02A-J (20))
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Li, Ingrid Y
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New York University
Schools of Arts and Sciences
New York
United States
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Martinez, Raquel C R; Gupta, Nikita; Lázaro-Muñoz, Gabriel et al. (2013) Active vs. reactive threat responding is associated with differential c-Fos expression in specific regions of amygdala and prefrontal cortex. Learn Mem 20:446-52
Moscarello, Justin M; LeDoux, Joseph E (2013) Active avoidance learning requires prefrontal suppression of amygdala-mediated defensive reactions. J Neurosci 33:3815-23