Mahan AL, Ressler KJ. Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder. Trends Neurosci 35: 24-35

Center for Behavioral Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University School of Medicine, 954 Gatewood Drive, Atlanta, GA 30329, USA.
Trends in Neurosciences (Impact Factor: 13.56). 07/2011; 35(1):24-35. DOI: 10.1016/j.tins.2011.06.007
Source: PubMed


Posttraumatic stress disorder (PTSD) is an anxiety disorder that can develop after a traumatic experience such as domestic violence, natural disasters or combat-related trauma. The cost of such disorders on society and the individual can be tremendous. In this article, we review how the neural circuitry implicated in PTSD in humans is related to the neural circuitry of fear. We then discuss how fear conditioning is a suitable model for studying the molecular mechanisms of the fear components that underlie PTSD, and the biology of fear conditioning with a particular focus on the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB), GABAergic and glutamatergic ligand-receptor systems. We then summarize how such approaches might help to inform our understanding of PTSD and other stress-related disorders and provide insight to new pharmacological avenues of treatment of PTSD.

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Available from: Kerry Ressler, Aug 19, 2014
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    • "Molecular changes underlying fear extinction can occur in the amygdala, hippocampus, or medial prefrontal cortex (mPFC; Quirk and Mueller, 2008; Mahan and Ressler, 2012; Maren et al., 2013). Since reduced fear extinction in adolescents involves a reduced activation of infralimbic cortex (IL; Kim et al., 2011), it is likely that gene expression changes in IL, which mediate consolidation of extinction memory, may be different during adolescence . "
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    ABSTRACT: Adolescent rats are prone to impaired fear extinction, suggesting that mechanistic differences in extinction could exist in adolescent and adult rats. Since the infralimbic cortex (IL) is critical for fear extinction, we used PCR array technology to identify gene expression changes in IL induced by fear extinction in adolescent rats. Interestingly, the ephrin type B receptor 2 (EphB2), a tyrosine kinase receptor associated with synaptic development, was downregulated in IL after fear extinction. Consistent with the PCR array results, EphB2 levels of mRNA and protein were reduced in IL after fear extinction compared with fear conditioning, suggesting that EphB2 signaling in IL regulates fear extinction memory in adolescents. Finally, reducing EphB2 synthesis in IL with shRNA accelerated fear extinction learning in adolescent rats, but not in adult rats. These findings identify EphB2 in IL as a key regulator of fear extinction during adolescence, perhaps due to the increase in synaptic remodeling occurring during this developmental phase.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2015; 35(36):12394-403. DOI:10.1523/JNEUROSCI.4254-14.2015 · 6.34 Impact Factor
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    • "It had been proposed that drugs designed to modulate these neurotransmitter systems might enhance fear learning and the extinction of inappropriate associations (Mahan & Ressler, 2012). Alcohol generates the opposite of the desired effect on neurotransmission, blocking NMDA receptors and enhancing GABA-mediated inhibition , and is disruptive to extinction learning in our experiments. "
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    ABSTRACT: Alcohol is frequently involved in psychological trauma and often used by individuals to reduce fear and anxiety. We examined the effects of alcohol on fear acquisition and extinction within a virtual environment. Healthy volunteers were administered alcohol (0.4 g/kg) or placebo and underwent acquisition and extinction from different viewpoints of a virtual courtyard, in which the conditioned stimulus, paired with a mild electric shock, was centrally located. Participants returned the following day to test fear recall from both viewpoints of the courtyard. Skin conductance responses were recorded as an index of conditioned fear. Successful fear acquisition under alcohol contrasted with impaired extinction learning evidenced by persistent conditioned responses (Experiment 1). Participants' impairments in extinction under alcohol correlated with impairments in remembering object-locations in the courtyard seen from one viewpoint when tested from the other viewpoint. Alcohol-induced extinction impairments were overcome by increasing the number of extinction trials (Experiment 2). However, a test of fear recall the next day showed persistent fear in the alcohol group across both viewpoints. Thus, alcohol impaired extinction rather than acquisition of fear, suggesting that extinction is more dependent than acquisition on alcohol-sensitive representations of spatial context. Overall, extinction learning under alcohol was slower, weaker and less context-specific, resulting in persistent fear at test that generalized to the extinction viewpoint. The selective effect on extinction suggests an effect of alcohol on prefrontal involvement, while the reduced context-specificity implicates the hippocampus. These findings have important implications for the use of alcohol by individuals with clinical anxiety disorders. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Neurobiology of Learning and Memory 07/2015; 125. DOI:10.1016/j.nlm.2015.07.014 · 3.65 Impact Factor
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    • "Children and adolescents also succumb to PTSD after trauma at rates somewhat lower than that experienced by adults (Kessler et al, 2012). Given the exceptional individual and societal costs of PTSD, there has been a considerable effort aimed at understanding the psychological and neurobiological mechanisms underlying this disorder (Liberzon and Sripada, 2008; Mahan and Ressler, 2012; Pitman et al, 2012; Goswami et al, 2013; Rau et al, 2005). This effort has led to enormous gains in understanding not only the brain circuits mediating stress and fear responses in the face of threat, but also those that are involved in dampening fear and anxiety once threats have passed (Ehrlich et al, 2009; Pape and Pare, 2010; Milad and Quirk, 2012; Duvarci and Paré, 2014). "
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    ABSTRACT: Stress plays a critical role in the development and expression of many psychiatric disorders, and is a defining feature of post-traumatic stress disorder (PTSD). Stress also limits the efficacy of behavioral therapies, such as exposure therapy, aimed at limiting pathological fear. Here we examine emerging evidence that stress impairs recovery from trauma by impairing fear extinction, a form of learning thought to underlie the suppression of trauma-related fear memories. We describe the major structural and functional abnormalities in brain regions that are particularly vulnerable to stress, including the amygdala, prefrontal cortex, and hippocampus, which may underlie stress-induced impairments in extinction. We also discuss some of the stress-induced neurochemical and molecular alterations in these brain regions that are associated with extinction deficits, and the potential for targeting these changes to prevent or reverse impaired extinction. A better understanding of the neurobiology of deleterious stress effects on extinction promises to yield novel approaches to improving therapeutic outcomes for PTSD and other anxiety and trauma-related disorders.Neuropsychopharmacology accepted article preview online, 24 June 2015. doi:10.1038/npp.2015.180.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.180 · 7.05 Impact Factor
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