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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

ABSTRACT

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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    • "Yet, despite these concerns very little is known of how PTSD might affect brain network organization in adolescents. Whereas multiple lines of research suggest amygdala subregional defects in the pathophysiology of adult PTSD [Brown et al., 2014; Jovanovic and Ressler, 2010; Mahan and Ressler, 2012; Nicholson et al., 2015; Patel et al., 2012], no study has yet examined the functional architecture of amygdala subregional networks in adolescent PTSD. Knowledge on how major amygdalar circuits might be compromised in adolescent PTSD is crucial in gaining insight into the underlying pathophysiology, ultimately informing the development of reliable biomarkers and potential therapeutic targets. "
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    ABSTRACT: Posttraumatic stress disorder (PTSD) is a prevalent, debilitating, and difficult to treat psychiatric disorder. Very little is known of how PTSD affects neuroplasticity in the developing adolescent brain. Whereas multiple lines of research implicate amygdala-centered network dysfunction in the pathophysiology of adult PTSD, no study has yet examined the functional architecture of amygdala subregional networks in adolescent PTSD. Using intrinsic functional connectivity analysis, we investigated functional connectivity of the basolateral (BLA) and centromedial (CMA) amygdala in 19 sexually abused adolescents with PTSD relative to 23 matched controls. Additionally, we examined whether altered amygdala subregional connectivity coincides with abnormal grey matter volume of the amygdaloid complex. Our analysis revealed abnormal amygdalar connectivity and morphology in adolescent PTSD patients. More specifically, PTSD patients showed diminished right BLA connectivity with a cluster including dorsal and ventral portions of the anterior cingulate and medial prefrontal cortices (p < 0.05, corrected). In contrast, PTSD patients showed increased left CMA connectivity with a cluster including the orbitofrontal and subcallosal cortices (p < 0.05, corrected). Critically, these connectivity changes coincided with diminished grey matter volume within BLA and CMA subnuclei (p < 0.05, corrected), with CMA connectivity shifts additionally relating to more severe symptoms of PTSD. These findings provide unique insights into how perturbations in major amygdalar circuits could hamper fear regulation and drive excessive acquisition and expression of fear in PTSD. As such, they represent an important step toward characterizing the neurocircuitry of adolescent PTSD, thereby informing the development of reliable biomarkers and potential therapeutic targets. Hum Brain Mapp, 2016.
    Full-text · Article · Jan 2016 · Human Brain Mapping
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    • "Accordingly, ICV administered PACAP could recapitulate a condition where elevated levels of endogenous PACAP—putatively increased by exposure to chronic stress—affects multiple brain areas thereby sensitizing (or protecting) the brain to the consequences of exposure to a traumatic event. Considering that preclinical fear conditioning paradigms have been useful tools to help understand the neurobiology of psychiatric conditions such as post-traumatic stress disorder (PTSD; Mahan and Ressler, 2012), a disorder where dysfunction within PACAP systems has been implicated (Ressler et al., 2011), the current study may have useful face and construct validity. Our data indicate that ICV PACAP can induce a profound but temporary amnestic-like effect early after fear conditioning that evolves into a hypermnestic phenotype after multiple re-exposures to the conditioned cues. "
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    ABSTRACT: Pituitary adenylate cyclase-activating polypeptide (PACAP) is implicated in stress regulation and learning and memory. PACAP has neuromodulatory actions on brain structures within the limbic system that could contribute to its acute and persistent effects in animal models of stress and anxiety-like behavior. Here, male Sprague-Dawley rats were implanted with intracerebroventricular (ICV) cannula for infusion of PACAP-38 (0.5, 1, or 1.5μg) or vehicle followed 30min later by fear conditioning. Freezing was measured early (1, 4, and 7 days) or following a delay (7, 10, and 13 days) after conditioning. PACAP (1.5μg) produced a bi-phasic response in freezing behavior across test days: relative to controls, PACAP-treated rats showed a reduction in freezing when tested 1 or 7 days after fear conditioning that evolved into a significant elevation in freezing by the third test session in the early, but not delayed, group. Corticosterone (CORT) levels were significantly elevated in PACAP-treated rats following fear conditioning, but not at the time of testing (Day 1). Brain c-Fos expression revealed PACAP-dependent alterations within, as well as outside of, areas typically implicated in fear conditioning. Our findings raise the possibility that PACAP disrupts fear memory consolidation by altering synaptic plasticity within neurocircuits normally responsible for encoding fear-related cues, producing a type of dissociation or peritraumatic amnesia often seen in people early after exposure to a traumatic event. However, fear memories are retained such that repeated testing and memory reactivation (e.g., re-experiencing) causes the freezing response to emerge and persist at elevated levels. PACAP systems may represent an axis on which stress and exposure to trauma converge to promote maladaptive behavioral responses characteristic of psychiatric illnesses such as post-traumatic stress disorder (PTSD).
    Full-text · Article · Nov 2015 · Psychoneuroendocrinology
    • "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.
    No preview · Article · Sep 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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