Neural and cellular mechanisms of fear and extinction memory formation

Abstract

Over the course of natural history, countless animal species have evolved adaptive behavioral systems to cope with dangerous situations and promote survival. Emotional memories are central to these defense systems because they are rapidly acquired and prepare organisms for future threat. Unfortunately, the persistence and intrusion of memories of fearful experiences are quite common and can lead to pathogenic conditions, such as anxiety and phobias. Over the course of the last thirty years, neuroscientists and psychologists alike have attempted to understand the mechanisms by which the brain encodes and maintains these aversive memories. Of equal interest, though, is the neurobiology of extinction memory formation as this may shape current therapeutic techniques. Here we review the extant literature on the neurobiology of fear and extinction memory formation, with a strong focus on the cellular and molecular mechanisms underlying these processes.

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory

“…Instead, the different impact of the global A 2A R blockade compared with the blockade of A 2A Rs selectively in the amygdala indicates that the impact of A 2A Rs on fear memory is unlikely to be restricted to the amygdala, in accordance with the previously reported ability of hippocampal A 2A Rs to interfere with contextual fear and the opposite effect of amygdala and striatal A 2A Rs on the control of the expression of fear memory (Wei et al, 2014), as summarized in Figure 5d. In fact, the acquisition and recall of conditioned fear also involves other limbic and neocortical areas in partially redundant circuits (Orsini and Maren, 2012). Similarly, it is possible that the selective deletion of A 2A Rs in the amygdala might bolster the impact of otherwise less relevant A 2A Rs in other brain regions, as we have previously observed to occur for the recruitment of striatal DARPP-32 (Shen et al, 2013), behavioral sensitization , or emotional responses (Wei et al, 2014) using cell-type-selective genetic eliminations of A 2A Rs.…”

“…Similarly, it is possible that the selective deletion of A 2A Rs in the amygdala might bolster the impact of otherwise less relevant A 2A Rs in other brain regions, as we have previously observed to occur for the recruitment of striatal DARPP-32 (Shen et al, 2013), behavioral sensitization , or emotional responses (Wei et al, 2014) using cell-type-selective genetic eliminations of A 2A Rs. In fact, several studies have dissected the involvement of different brain regions in the processing of contextual and cued fear memory (Orsini and Maren, 2012), albeit the expression of both forms of contextual fear mostly depend on amygdala circuits (Goosens and Maren, 2001). This is heralded by the differential impact on cued and contextual fear memory upon manipulation of different molecular targets (eg, Sui et al, 2006;Burghart and Bauer, 2013) or lesions/inactivation (eg, Duvarci et al, 2009;Baldi et al, 2013) in different brain regions.…”

Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

“…Interestingly, the inhibition of protein synthesis during the late phase after extinction significantly reduced the persistence of extinction LTM, suggesting that breceptor/PKA-independent new protein synthesis is needed for the late consolidation of extinction. Several molecules in the hippocampus have been shown to be involved in both fear conditioning and fear extinction, including cyclindependent kinase-5, protein kinase C, PKA, and ErK1/2 (Orsini and Maren, 2012;Tronson et al, 2012). Among these kinases, only ErK1/2 is activated in both processes (Atkins et al, 1998;Fischer et al, 2007;Irvine et al, 2005;Kimura et al, 2008;Tronson et al, 2012).…”

Generation and Characterization of Humanized Mice Carrying COMT158 Met/Val Alleles

“…Our initial characterization of this line focused on phenotypes that have homologous measures in humans shown to be affected by COMT genotype, exploration, sensorimotor gating, fear learning/extinction, and working memory (see discussion for references). These behaviors are modulated by catecholamine signaling in the frontal cortex (for review see Swerdlow et al 2001;Orsini and Maren, 2012;Lalonde, 2002), which is the suggested mechanism for Val158Met phenotype associations in humans. Here we report that humanized COMT Met/Met mice displayed better working memory than sibling COMT Val/Val mice and increased cued fear learning with reduced fear extinction.…”