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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    • "Thus, the mechanisms mediating the changes in emotionality and cognition likely differ between these models. The reduction in extinction learning may be caused by impaired inhibitory learning mechanisms in the medial prefrontal cortex and amygdala relevant to human anxiety disorders such as post-traumatic stress disorder (Milad and Quirk, 2012;Herry and Johansen, 2014). "
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    ABSTRACT: Behavioural, neurological, and genetic similarities exist in epilepsies, their psychiatric comorbidities, and various psychiatric illnesses, suggesting common etiological factors. Rodent models of epilepsy are used to characterize the co-morbid symptoms apparent in epilepsy and their neurobiological mechanisms. The present study was designed to assess Pavlovian fear conditioning and latent inhibition in a polygenetic rat model of absence epilepsy, Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and the Non-Epileptic Control (NEC) strain. Electrophysiological recordings confirmed the presence of spike-wave discharges in young adult GAERS but not NEC rats. A series of behavioural tests designed to assess anxiety-like behaviour (elevated plus maze, open field, acoustic startle response) and cognition (Pavlovian conditioning and latent inhibition) were subsequently conducted on male and female offspring. Results showed that GAERS exhibited significantly higher anxiety-like behaviour, a characteristic reported previously. In addition, using two protocols that differed on shock intensity, we found that both sexes of GAERS displayed exaggerated cued and contextual Pavlovian fear conditioning and impaired fear extinction. Fear reinstatement to the CS following unsignaled footshocks did not differ between the strains. Male GAERS also showed impaired latent inhibition in a paradigm using Pavlovian fear conditioning suggesting that they may have altered attention, particularly related to previously irrelevant stimuli in the environment. Neither the female GAERS nor NECs showed evidence of latent inhibition in our paradigm. Together, the results suggest that GAERS may be a particularly useful model for assessing therapeutics designed to improve the emotional and cognitive disturbances associated with absence epilepsy. This article is protected by copyright. All rights reserved.
    European Journal of Neuroscience 10/2015; DOI:10.1111/ejn.13110 · 3.18 Impact Factor
    • "The temporal pole has been suggested to be involved in the association of sensory input with emotional responses (Olson et al., 2007), while the connections between the amygdala and the vmPFC are critical in the acquisition of conditioned fear as well as in the extinction learning and extinction memory recall (Milad and Quirk, 2012). Our finding of enhanced LB amygdala-vmPFC connectivity in men relative to women is consistent with our recent data showing enhanced functional activation of the vmPFC in men relative to women during extinction recall (Lebron-Milad et al., 2012). There are also data indicating that estrogen variance affects the activity of the amygdala and vmPFC during fear extinction (Milad et al., 2009, 2010; Zeidan et al., 2011). "
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    ABSTRACT: The amygdala is a hub in emotional processing, including that of negative affect. Healthy men and women have distinct differences in amygdala responses, potentially setting the stage for the observed sex differences in the prevalence of fear, anxiety, and pain disorders. Here, we examined how amygdala subnuclei resting-state functional connectivity is affected by sex, as well as explored how the functional connectivity is related to estrogen levels. Resting-state functional connectivity was measured using functional magnetic resonance imaging (fMRI) with seeds placed in the left and right laterobasal (LB) and centromedial (CM) amygdala. Sex differences were studied in 48 healthy men and 48 healthy women, matched for age, while the association with estrogen was analyzed in a subsample of 24 women, for whom hormone levels had been assessed. For the hormone analyses, the subsample was further divided into a lower and higher estrogen levels group based on a median split. We found distinct sex differences in the LB and CM amygdala resting-state functional connectivity, as well as preliminary evidence for an association between estrogen levels and connectivity patterns. These results are potentially valuable in explaining why women are more afflicted by conditions of negative affect than are men, and could imply a mechanistic role for estrogen in modulating emotion.
    Psychoneuroendocrinology 09/2015; 63:34-42. DOI:10.1016/j.psyneuen.2015.09.012 · 4.94 Impact Factor
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