ReviewThe Role of the Amygdala in the Extinction of Conditioned Fear
Section snippets
Evidence for Amygdaloid Involvement in Fear Extinction
There are several ways to localize the control of a behavior to a specific brain location. These include lesion studies, in vivo electrophysiology studies, local infusion studies, biochemical or immunohistochemical studies of changes in molecules that correlate to behavioral changes, and studies of physiological correlates to behavior in slices of the target region in brain after behavioral training.
Electrical or neurotoxic lesions of candidate regions have been the classical approach to
N-methyl-D-aspartate Receptors and L-type Voltage-Gated Calcium Channels in BLA
The first data implicating the BLA in extinction came from infusion of the N-methyl-D-aspartate (NMDA) antagonist, 2-amino-5-phosphonopentanoic acid (APV), into that structure through chronically implanted cannulae in rats (Falls et al 1992). These researchers used stereotaxic surgery to implant cannulae directed at basolateral amygdala on both sides, allowed the animals to recover, and then fear-conditioned the animals with 10 light CS-shock US pairings. Measuring fear with the
Endocannabinoids
The endocannabinoid system (Piomelli 2003)—which comprises the endocannabinoids, lipid signaling molecules, and their endogenous receptors, the cannabinoid receptors—has recently emerged as an important player in the regulation of emotionality (for review, see Wotjak 2005), including fear extinction learning (Marsicano et al 2002). Cannabinoid receptor type 1 (CB1 receptor)-deficient mice were strongly impaired in both short-term and long-term extinction of cue-conditioned fear (Marsicano et al
Does Fear Extinction Involve Erasure of Changes That Occur With Fear Conditioning?
A series of experiments combining basolateral amygdala infusions, electrophysiology, and correlative molecular studies of BLA tissue has added substantially to the data supporting a role for the BLA in extinction learning (Lin et al 2003, Lin et al 2003b, Lin et al 2003c). In addition to providing substantial support for the role of the BLA in extinction learning, these experiments provide strong evidence that extinction does involve reversal of at least some of the changes that underlie the
The Expression of Extinction Memory
Consistent with the view of extinction as, at least in part, a reversal of the changes seen with fear conditioning itself, several other molecular changes that follow fear conditioning in basolateral amygdala seem to reverse with extinction training. Specifically, the expression of two molecules involved with GABAergic inhibitory learning are changed by fear conditioning, and those changes are reversed by extinction training. In particular, the mRNA that encodes the GABAA receptor clustering
Physiological Correlates of Extinction in the Amygdala
A substantial contribution to our understanding of the role of LA in fear extinction came from two in vivo electrophysiology experiments. In one, short latency (<20 msec after tone onset) cell spiking in LA was increased by fear conditioning and reduced by extinction (Quirk et al 1995). Although increases in spiking during aversive conditioning had previously been seen in recordings from the basolateral (Maren et al 1991) and central nuclei (Pascoe and Kapp 1985), the findings from Quirk et al
Physiological Models of Extinction Involving the Amygdala
As we have seen, substantial physiological evidence indicates that extinction learning involves and depends on changes in neurotransmission within the basolateral amygdala, perhaps corresponding to alterations of the synaptic excitation of cells there. This idea maps closely onto the common view of a mechanistic relationship between changes in synaptic strength, learning, and behavior. However, as noted in the introduction, substantial behavioral evidence indicates that extinction is inhibitory
Summary
Extinction of fear is clearly some form of new learning superimposed on a more or less intact fear association. Fear extinction, like its acquisition, depends on the amygdala. Numerous studies demonstrate that various molecular mechanisms acting within the basolateral amygdala are essential for extinction learning. These mechanisms include NMDA receptors (Falls et al 1992), calcineurin (Lin et al 2003b), MAP kinase (Lin et al 2003c, Lu et al 2001), translation, PI3 kinase (Lin et al 2003c), CB1
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2020, Behavioural Brain ResearchCitation Excerpt :The necessity for beta - adrenergic receptor activation seems to depend on its ability to modulate protein synthesis necessary for plastic changes related to fear memory formation [58]. The medial prefrontal cortex and the amygdala are considered as two important regions related to fear extinction [59,60]. Mueller et al., have reported that norepinephrine is involved in extinction learning.