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.

Download full-text


Available from: Kerry Ressler, Aug 19, 2014
1 Follower
126 Reads
    • "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 . "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "These failures may be the result of damage, genetic, epigenetic, or environment risk factors (Callaghan and Richardson, 2012, 2014; Dias et al., 2013; Morrison and Ressler, 2014; Maren and Homes, 2015). Identifying these factors is the source of a great deal of research in this area (Callaghan and Richardson, 2012, 2014; Mahan and Ressler, 2012; Dias et al., 2013; Maren and Homes, 2015). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Emerging evidence suggests that mild traumatic brain injury (mTBI) resulting from blast exposure may contribute to the occurrence of posttraumatic stress disorder (PTSD) and related affective sequelae, such as anxiety and depression. Many studies have used survey techniques to describe blast exposure leading to comorbid mTBI and related persistent postconcussive symptoms (PPCS) with PTSD in military populations. Despite this, there is a lack of literature that examines possible biological mechanisms by which blast exposure contributes to the development of PTSD sequelae. This Mini-Review addresses the current literature on potential neurophysiological changes that may contribute to PTSD-like traits as a result of a single or multiple exposures to blast events. Evidence from clinical blast-induced mTBI populations and animal models of blast-induced mTBI was evaluated with an emphasis on behavioral and physiological symptoms similar to those seen in PTSD populations and models. From the analysis, we propose potential mechanisms that merit further investigation for better understanding of how blast exposures may produce a higher rate of comorbid PPCS, PTSD, and affective phenomena. An improved understanding of PTSD-like outcomes resulting from blast exposure will ultimately help facilitate the development of future treatments and contribute to a better understanding of PTSD sequelae that develop from physical trauma. © 2015 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 09/2015; DOI:10.1002/jnr.23641 · 2.59 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
Show more