Fear Extinction as a Model for Translational Neuroscience: Ten Years of Progress

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, 02129, USA.
Annual Review of Psychology (Impact Factor: 21.81). 01/2012; 63(1):129-51. DOI: 10.1146/annurev.psych.121208.131631
Source: PubMed


The psychology of extinction has been studied for decades. Approximately 10 years ago, however, there began a concerted effort to understand the neural circuits of extinction of fear conditioning, in both animals and humans. Progress during this period has been facilitated by a high degree of coordination between rodent and human researchers examining fear extinction. Here we review the major advances and highlight new approaches to understanding and exploiting fear extinction. Research in fear extinction could serve as a model for translational research in other areas of behavioral neuroscience.

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    • "It is generally accepted that extinction reflects new learning, rather than unlearning of the initial contingency (Pavlov 1927; Rescorla and Heth 1975; Bouton and King 1983; Bouton and Nelson 1994; Berman and Dudai 2001; Myers and Davis 2002). Extinction has received extensive attention recently, as it has been likened to an animal model of exposure-based therapies used clinically to treat anxiety disorders (Davis 2002; Milad and Quirk 2012). "
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    ABSTRACT: The extinction of delay fear conditioning relies on a neural circuit that has received much attention and is relatively well defined. Whether this established circuit also supports the extinction of more complex associations, however, is unclear. Trace fear conditioning is a better model of complex relational learning, yet the circuit that supports extinction of this memory has received very little attention. Recent research has indicated that trace fear extinction requires a different neural circuit than delay extinction; trace extinction requires the participation of the retrosplenial cortex, but not the amygdala, as noted in a previous study. Here, we tested the roles of the prelimbic and infralimbic regions of the medial prefrontal cortex in trace and delay fear extinction by blocking NMDA receptors during extinction learning. We found that the prelimbic cortex is necessary for trace, but not for delay fear extinction, whereas the infralimbic cortex is involved in both types of extinction. These results are consistent with the idea that trace fear associations require plasticity in multiple cortical areas for successful extinction. Further, the infralimbic cortex appears to play a role in extinction regardless of whether the animal was initially trained in trace or delay conditioning. Together, our results provide new information about how the neural circuits supporting trace and delay fear extinction differ. © 2014 Kwapis et al.; Published by Cold Spring Harbor Laboratory Press.
    Learning & memory (Cold Spring Harbor, N.Y.) 12/2015; 22(1):39-46. DOI:10.1101/lm.036517.114 · 3.66 Impact Factor
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    • "Milad et al. (2013) reported impaired fear extinction recall in OCD patients, derived from skin conductance measurements, and found reduced activations in the caudate and hippocampus during fear conditioning and in the posterior cingulate cortex and putamen during extinction recall. Cognitive-behavioral therapy with exposure to threat-provoking stimuli and situations as a core intervention may be viewed as a clinical application of fear extinction (Milad and Quirk, 2012). Successful treatment partly relies on fear extinction learning during exposure to reduce the fear response. "
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    ABSTRACT: Background: Obsessive-compulsive disorder (OCD) is a psychiatric disorder which is characterized by recurrent intrusive thoughts (obsessions) and ritualized, repetitive behaviors or mental acts (compulsions). The gold standard for the treatment of OCD is cognitive behavioral therapy (CBT) with exposure and response prevention. This is the first study exploring the predictive value of resting-state functional connectivity for the outcome of CBT. Methods: We assessed whole-brain resting-state functional connectivity in a group of 17 un-medicated OCD inpatients prior to CBT compared to 19 healthy controls using functional magnetic resonance imaging. The graph theoretical metric degree centrality served as indicator for altered voxel-wise whole-brain functional connectivity. The relative change in the Yale-Brown Obsessive Compulsive Scale (YBOCS) score was used to evaluate treatment outcome. Results: The degree centrality of the right basolateral nuclei group of the amygdala was positively correlated with the response to subsequent CBT. OCD patients showed a lower degree centrality of the superficial amygdala (bilateral). Conclusions: Our results suggest that two different sub-regions of the amygdala and their respective neural networks are affected in OCD: The superficial amygdala and networks related to evaluation of reinforcers and risk anticipation and the basolateral amygdala which is implicated in fear processing. The diminished CBT response in patients showing a lower degree centrality of the basolateral amygdala reflects a deficient fear circuit in these patients which may impact fear extinction as a core mechanism of exposure-based CBT.
    Biological psychology 09/2015; DOI:10.1016/j.biopsycho.2015.09.004 · 3.40 Impact Factor
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    • "Similar to fear memory formation, neuronal circuits in the amygdala are required to mediate the extinction of fear memory (Cammarota et al., 2005; Sotres-Bayon and Quirk, 2010; Sierra-Mercado et al., 2011; Jasnow et al., 2013; Duvarci and Pare, 2014). Other reports have shown that this extinction is also controlled by a series of networks, including the hippocampus and medial prefrontal cortex (Herry et al., 2010; Pape and Pare, 2010; Milad and Quirk, 2012; Maren et al., 2013; Duvarci and Pare, 2014; Herry and Johansen, 2014). On the other hand, few studies have been performed to investigate the mechanisms of fear memory in higher animals such as nonhuman primates. "
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    ABSTRACT: Fear is an emotion that is well-studied due to its importance for animal survival. Experimental animals, such as rats and mice, have been widely used to model fear. However, higher animals such as nonhuman primates have rarely been used to study fear due to ethical issues and high costs. Tree shrews are small mammals that are closely related to primates; they have been used to model human-related psychosocial conditions such as stress and alcohol tolerance. Here, we describe an experimental paradigm to study the formation and extinction of fear memory in tree shrews. We designed an experimental apparatus of a light/dark box with a voltage foot shock. We found that tree shrews preferred staying in the dark box in the daytime without stimulation and showed avoidance to voltage shocks applied to the footplate in a voltage-dependent manner. Foot shocks applied to the dark box for 5 days (10 min per day) effectively reversed the light-dark preference of the tree shrews, and this memory lasted for more than 50 days without any sign of memory decay (extinction) in the absence of further stimulation. However, this fear memory was reversed with 4 days of reverse training by applying the same stimulus to the light box. When reducing the stimulus intensity during the training period, a memory extinction and subsequently reinstatement effects were observed. Thus, our results describe an efficient method of monitoring fear memory formation and extinction in tree shrews.
    Frontiers in Behavioral Neuroscience 08/2015; 9:204. DOI:10.3389/fnbeh.2015.00204 · 3.27 Impact Factor
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