Barad M. Fear extinction in rodents: basic insight to clinical promise. Curr Opin Neurobiol 15: 710-715

ArticleinCurrent Opinion in Neurobiology 15(6):710-5 · January 2006with4 Reads
DOI: 10.1016/j.conb.2005.10.005 · Source: PubMed
Abstract
Fear extinction, the reduction of fear by repeated exposure to the object of fear, is a crucial paradigm of inhibitory learning and the acknowledged preclinical model for behavior therapy of human anxiety. Recent insights have clarified roles for infralimbic prefrontal cortex, hippocampus and periaqueductal gray in extinction learning, while maintaining a central role for the basolateral amygdaloid nucleus in the acquisition and storage of this learning. Simultaneously, molecular insights have implicated several neurotransmitter and second messenger systems in extinction learning, and revealed that extinction is surprisingly easy to improve, yielding the promise of a novel approach to improved psychiatric treatments for a variety of human anxiety disorders.
    • "Within the framework of the present work, we show that adult RER males have a superior performance in olfactory discrimination and contextual fear extinction, 2 tasks which are dependent on the PFC noradrenergic system, both the levels of NE and β adrenergic receptors (Tronel et al. 2004; Mueller et al. 2008; Do-Monte et al. 2010). More specifically, in the former task RER animals remembered better the cue-reward association and in the latter they extinguished learned fear more effectively, processes that are controlled by the PrL (Tronel et al. 2004) and IL (Barad 2005; Do-Monte et al. 2010 ), respectively. Notably , in both of these PFC subregions the RER experience resulted in increased ADRB1 levels and function. "
    [Show abstract] [Hide abstract] ABSTRACT: The noradrenergic system plays an important role in prefrontal cortex (PFC) function. Since early life experiences play a crucial role in programming brain function, we investigated the effects of a neonatal experience involving reward through maternal contact on the noradrenergic system of the rat PFC. Rat pups were exposed during Postnatal days (PNDs) 10-13, to a T-maze in which contact with the mother was used as a reward (RER). RER males had higher norepinephrine levels in the PFC both on PND 13 and in adulthood. The RER experience resulted in adulthood in increased levels of the active demethylase GADD45b, hypomethylation of the β1 adrenergic receptor (ADRB1) gene promoter, and consequent enhanced expression of its mRNA in the PFC. In addition, protein and binding levels of the ADRB1, as well as those of its downstream effector phosphorylated cAMP response element-binding protein were elevated in RER males. The higher activity of the PFC noradrenergic system of the RER males was reflected in their superior performance in the olfactory discrimination and the contextual fear extinction, 2 PFC noradrenergic system-dependent behavioral tasks. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    Full-text · Article · Aug 2015
    • "While it is likely that other epigenetic mechanisms (such as histone methylation and nucleosome remodeling) are also required for successful memory reconsolidation, these mechanisms have not yet been tested and are ripe for future study. Epigenetic mechanisms in fear memory extinction PTSD and other anxiety disorders are commonly treated using exposure-based therapy, a form of extinction in which the individual is exposed to the frightening stimulus in the absence of an aversive outcome [79,80]. As the person learns that the cue no longer predicts danger, his or her fear to that stimulus will gradually diminish. "
    [Show abstract] [Hide abstract] ABSTRACT: Post-traumatic stress disorder (PTSD) and other anxiety disorders stemming from dysregulated fear memory are problematic and costly. Understanding the molecular mechanisms that contribute to the formation and maintenance of these persistent fear associations is crucial to developing treatments for PTSD. Epigenetic mechanisms, which control gene expression to produce long-lasting changes in cellular function, may support the formation of fear memory underlying PTSD. We address here the role of epigenetic mechanisms in the formation, storage, updating, and extinction of fear memories. We also discuss methods of targeting these epigenetic mechanisms to reduce the initial formation of fear memory or to enhance its extinction. Epigenetic mechanisms may provide a novel target for pharmaceutical and other treatments to reduce aversive memory contributing to PTSD.
    Full-text · Article · Sep 2014
    • "The ability to reverse or extinct a previously acquired task is an important adaptation mechanism to a different environmental context. The adaptive learning processes, or inhibitory learning, are involved in retasking, being particularly relevant to anxiety disorders in humans such as phobias and post-traumatic stress disorder [Barad, 2005; Bouton, 1993; Xu et al., 2009). Our analyses of anxiety disorders focused on agoraphobia, generalized anxiety, and social phobia since they represent those anxiety disorders with higher prevalence and clinical significance [Gadermann et al., 2012]. "
    [Show abstract] [Hide abstract] ABSTRACT: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder with a strong genetic component. The glutamate metabotropic receptor genes (GRMs) have been considered potential candidates for ADHD susceptibility. The aim of the present study was to investigate if copy number variants (CNVs) in GRM1, GRM5, and GRM8 genes are overrepresented in ADHD subjects. A total of 1038 individuals with ADHD and 1057 subjects without this disorder were investigated. No significant difference in the total number of CNVs was found comparing the entire ADHD sample and the population sample without ADHD (P = 0.326, OR = 1.112, 95% CI = 0.762–1.624). The presence of CNVs was associated with lower intelligence quotient (IQ) scores in ADHD samples (P = 0.026, OR = 1.824, 95% CI = 1.066–3.121) but not in the sample of individuals without ADHD. CNVs in GRM5 were associated with presence of anxiety disorders in ADHD cases (P = 0.002, OR = 3.915, 95% CI = 1.631–9.402), but not in individuals without ADHD. Taken together, our results suggest a role for glutamate in ADHD as CNVs in the glutamatergic genes investigated herein were associated with cognitive and clinical characteristics of ADHD individuals. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Sep 2014
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