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.
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.
| Rosas-Vidal, Luis E; Lozada-Miranda, Valeria; Cantres-Rosario, Yisel et al. (2018) Alteration of BDNF in the medial prefrontal cortex and the ventral hippocampus impairs extinction of avoidance. Neuropsychopharmacology 43:2636-2644 |
| Diehl, Maria M; Bravo-Rivera, Christian; Rodriguez-Romaguera, Jose et al. (2018) Active avoidance requires inhibitory signaling in the rodent prelimbic prefrontal cortex. Elife 7: |
| Do-Monte, Fabricio H; Minier-Toribio, Angélica; Quiñones-Laracuente, Kelvin et al. (2017) Thalamic Regulation of Sucrose Seeking during Unexpected Reward Omission. Neuron 94:388-400.e4 |
| Quirk, Gregory J (2017) Less fear, more diversity. PLoS Biol 15:e2002079 |
| Paré, Denis; Quirk, Gregory J (2017) WHEN SCIENTIFIC PARADIGMS LEAD TO TUNNEL VISION: LESSONS FROM THE STUDY OF FEAR. NPJ Sci Learn 2: |
| 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 |
| Do Monte, F H; Quirk, G J; Li, B et al. (2016) Retrieving fear memories, as time goes by…. Mol Psychiatry 21:1027-36 |
| Heilbronner, Sarah R; Rodriguez-Romaguera, Jose; Quirk, Gregory J et al. (2016) Circuit-Based Corticostriatal Homologies Between Rat and Primate. Biol Psychiatry 80:509-21 |
| 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 |
| 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 |
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