Research on fear learning has transformed the way we think about the etiology and treatment of anxiety disorders such as post-traumatic stress disorder (PTSD). Much of what we know is derived from animal models measuring freezing as a fear response, which resembles exaggerated fear in PTSD sufferers. However people suffering from PTSD also show persistent avoidance of cues associated with their traumatic event. Persistent avoidance interferes with the daily activities, and reduces the opportunity for extinction, thus prolonging PTSD symptoms. Studies in the previous cycle of this grant have shown that the prelimbic prefrontal cortex (PL) drive freezing via projections to the basolateral amygdala (BLA), whereas the infralimbic prefrontal cortex (IL) mediates extinction via projections to inhibitory interneurons within the amygdala. To study avoidance, we have developed a platform-mediated avoidance task (PA) were rats avoid footshock by stepping onto a nearby platform. The platform protects the rat from shock, but also prevents the rat's access to food, similar to clinical avoidance. Furthermore, approximately 30% of rats are unable to extinguish this avoidance response, showing persistent avoidance even after extinction of fear. Preliminary data shows that PL, BLA and the nucleus accumbens (NAc) are necessary for expression of avoidance. However, inactivation of PL and NAc causes rats to revert to freezing behavior. Comparing the effects of manipulations on different behaviors (freezing and avoidance) can help distinguish fear-generating circuits from avoidance-generating circuits.
In Aim 1, we will investigate the circuits mediating avoidance using pharmacological, single-unit recording and optogenetic tools.
In Aim 2, we will study the neural circuits mediating the extinction of avoidance responses.
In Aim 3 we will characterize the neural circuits involved in extinction failure (persistent avoidance). We plan to use optogenetic techniques to silence and/or activate pathways involved in avoidance expression and extinction in order to repair circuits in persistent avoiders.

Public Health Relevance

This research will explore the neural mechanisms of avoidance expression and extinction. Understanding normal and persistent avoidance is necessary for anxiety disorders such as PTSD and OCD, in which patients show persistent avoidance. This research could also lead to new ways to increase the effectiveness of pharmacological and extinction-based therapies for the treatment of these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH058883-18
Application #
8722627
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Vicentic, Aleksandra
Project Start
1998-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
18
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Puerto Rico Med Sciences
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
San Juan
State
PR
Country
United States
Zip Code
00936
Do Monte, F H; Quirk, G J; Li, B et al. (2016) Retrieving fear memories, as time goes by…. Mol Psychiatry 21:1027-36
Rodriguez-Romaguera, Jose; Greenberg, Benjamin D; Rasmussen, Steven A et al. (2016) An Avoidance-Based Rodent Model of Exposure With Response Prevention Therapy for Obsessive-Compulsive Disorder. Biol Psychiatry 80:534-40
Rodriguez-Romaguera, Jose; Do-Monte, Fabricio H; Tanimura, Yoko et al. (2015) Enhancement of fear extinction with deep brain stimulation: evidence for medial orbitofrontal involvement. Neuropsychopharmacology 40:1726-33
Do-Monte, Fabricio H; Quiñones-Laracuente, Kelvin; Quirk, Gregory J (2015) A temporal shift in the circuits mediating retrieval of fear memory. Nature 519:460-3
Do-Monte, Fabricio H; Manzano-Nieves, Gabriela; Quiñones-Laracuente, Kelvin et al. (2015) Revisiting the role of infralimbic cortex in fear extinction with optogenetics. J Neurosci 35:3607-15
Bravo-Rivera, Christian; Roman-Ortiz, Ciorana; Montesinos-Cartagena, Marlian et al. (2015) Persistent active avoidance correlates with activity in prelimbic cortex and ventral striatum. Front Behav Neurosci 9:184
Rosas-Vidal, Luis E; Do-Monte, Fabricio H; Sotres-Bayon, Francisco et al. (2014) Hippocampal--prefrontal BDNF and memory for fear extinction. Neuropsychopharmacology 39:2161-9
Bravo-Rivera, Christian; Roman-Ortiz, Ciorana; Brignoni-Perez, Edith et al. (2014) Neural structures mediating expression and extinction of platform-mediated avoidance. J Neurosci 34:9736-42
Padilla-Coreano, Nancy; Do-Monte, Fabricio H; Quirk, Gregory J (2012) A time-dependent role of midline thalamic nuclei in the retrieval of fear memory. Neuropharmacology 62:457-63
Sierra-Mercado, Demetrio; Padilla-Coreano, Nancy; Quirk, Gregory J (2011) Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear. Neuropsychopharmacology 36:529-38

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