This proposal addresses a fundamental issue in emotion research, namely, what are the neural circuits of fear extinction? Fear extinction is the decrease in fear responses that normally occurs when a conditioned stimulus (CS) is repeatedly presented in the absence of the unconditioned stimulus (US). Since Pavlov, we have known that extinction does not erase the CS-US association but is new learning. While the neural circuits of fear conditioning are well understood, little is known about the neural circuits of fear extinction, which are thought to be compromised in post-traumatic stress disorder (PTSD) and other anxiety disorders. Using auditory fear conditioning in rats, we will investigate the neural circuits of fear extinction. While the amygdala is critical for acquisition and expression of conditioned fear, the medial prefrontal cortex (mPFC), which is reciprocally connected with the amygdala, has been implicated in the consolidation and expression of extinction learning. The central hypothesis of this proposal is that the prefrontal - amygdala system mediates the acquisition, consolidation, and expression of fear extinction.
Specific Aim 1 will examine the prefrontal-amygdala system in the acquisition phase of fear extinction, using lesion techniques and single-unit recording in behaving rats (hypothesis: the basal nucleus of the amygdala is responsible for short-term memory for fear extinction, as indicated by lesion deficits and a sub-population of basal neurons that increase their tone responses during extinction).
Specific Aim 2 will examine the prefrontal-amygdala system in the consolidation phase of fear extinction, using pharmacological inactivation, local inhibition of protein synthesis and NMDA receptors, and single-unit recording in behaving rats (hypothesis: extinction triggers subsequent NMDA activation and protein synthesis resulting in increased prefrontal tone responses and long-term extinction memory).
Specific Aim 3 will examine the prefrontal-amygdala system in the expression phase of fear extinction, using electrical stimulation, and single-unit recording in anesthetized rats (hypothesis: increased activity of prefrontal neurons after extinction reduces freezing by inhibiting the response of amygdala central neurons to conditioned tones). A detailed knowledge of the circuits and pharmacology of fear extinction could improve current exposure-based treatments for PTSD and phobias, which rely on extinction learning. ? ?
| 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 |
| 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 |
| Quiñones-Laracuente, Kelvin; Hernández-Rodríguez, Marán Y; Bravo-Rivera, Christian et al. (2015) The effect of repeated exposure to ethanol on pre-existing fear memories in rats. Psychopharmacology (Berl) 232:3615-22 |
| Rodriguez-Romaguera, Jose; Greenberg, Benjamin D; Haber, Suzanne N et al. (2015) A Cross Species Approach to Understanding DBS Modulation of Fear. Brain Stimul 8:986-8 |
| 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 |
| Pendyam, Sandeep; Bravo-Rivera, Christian; Burgos-Robles, Anthony et al. (2013) Fear signaling in the prelimbic-amygdala circuit: a computational modeling and recording study. J Neurophysiol 110:844-61 |
| Burgos-Robles, Anthony; Bravo-Rivera, Hector; Quirk, Gregory J (2013) Prelimbic and infralimbic neurons signal distinct aspects of appetitive instrumental behavior. PLoS One 8:e57575 |
| 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 |
| Rodriguez-Romaguera, Jose; Do Monte, Fabricio H M; Quirk, Gregory J (2012) Deep brain stimulation of the ventral striatum enhances extinction of conditioned fear. Proc Natl Acad Sci U S A 109:8764-9 |
| Sotres-Bayon, Francisco; Sierra-Mercado, Demetrio; Pardilla-Delgado, Enmanuelle et al. (2012) Gating of fear in prelimbic cortex by hippocampal and amygdala inputs. Neuron 76:804-12 |
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