The role of medial prefrontal cortex in active avoidance behavior
Principal Investigator: Justin M Moscarello
Abstract: 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 [unreadable] 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.
Funding Period: 2011-12-20 - 2014-12-19
more information: NIH RePORT
- Active avoidance learning requires prefrontal suppression of amygdala-mediated defensive reactionsJustin M Moscarello
Center for Neural Science, New York University, New York, New York 10003, USA
J Neurosci 33:3815-23. 2013..Thus, ilPFC functions as an inhibitory interface, allowing instrumental control over an aversive outcome to attenuate the expression of freezing and other reactions to conditioned threat...
- Active vs. reactive threat responding is associated with differential c-Fos expression in specific regions of amygdala and prefrontal cortexRaquel C R Martinez
University of Sao Paulo, Medical School, Surgery Department LIM 26 HCFMUSP, Sao Paulo 01246 903, Brazil
Learn Mem 20:446-52. 2013..Individual differences in AA behavior, long considered a nuisance by researchers, may be the key to elucidating the AA neurocircuit and understanding pathological response profiles. ..
- Neural Substrates of Contextual Memory in Fear ExtinctionStephen Maren; Fiscal Year: 2013..g., exposure therapy). ..
- Neural mechanisms of extinction-resistant avoidance behaviorKevin D Beck; Fiscal Year: 2013..Counteracting the neurobiological processes sub-serving enhanced processing of threat and safety in the medial prefrontal cortex will reduce avoidance to tolerable levels. ..
- Central Neuropeptide Y (NPY): A Novel Target for PTSD PathophysiologyRenu Sah; Fiscal Year: 2013..Relevance: This preclinical study will provide the rationale to proceed with the development of NPY analogs for PTSD pharmacotherapy and as a potential biomarker for predicting trauma outcomes. ..
- Understanding Pain of Gastrointestinal Origin in Women that Serve in OEF/OIFBeverley Greenwood-Van Meerveld; Fiscal Year: 2013..Moreover, we will examine whether rats exposed to ELS show altered behavioral responses to chronic stress in adulthood compared to age-matched controls ..
- Neural substrates of affective style and emotion regulationRichard J Davidson; Fiscal Year: 2013..This work will provide critical new information on the neurobiology of affective style. These new data will further our understanding of endophenotypes of affective processing that are associated with vulnerability to psychopathology. ..
- Role of intercalated amygdala neurons in the extinction of conditioned fearDENIS PARE; Fiscal Year: 2013..If supported, the hypothesis tested here would open new strategies for the treatment of anxiety disorders. ..