Extinction of cued fear memory involves a distinct form of depotentiation at cortical input synapses onto the lateral amygdala

Abstract

The amygdala is known to be a critical storage site of conditioned fear memory. Among the two major pathways to the lateral amygdala (LA), the cortical pathway is known to display a presynaptic long-term potentiation which is occluded with fear conditioning. Here we show that fear extinction results in a net depression of conditioning-induced potentiation at cortical input synapses onto the LA (C-LA synapses). Fear conditioning induced a significant potentiation of excitatory postsynaptic currents at C-LA synapses compared with naïve and unpaired controls, whereas extinction apparently reversed this potentiation. Paired-pulse low-frequency stimulation (pp-LFS) induced synaptic depression in the C-LA pathway of fear-conditioned rats, but not in naïve or unpaired controls, indicating that the pp-LFS-induced depression is specific to associative learning-induced changes (pp-LFS-induced depotentiation(ex vivo)). Importantly, extinction occluded pp-LFS-induced depotentiation(ex vivo), suggesting that extinction shares some mechanisms with the depotentiation. pp-LFS-induced depotentiation(ex vivo) required NMDA receptor (NMDAR) activity, consistent with a previous finding that blockade of amygdala NMDARs impaired fear extinction. In addition, pp-LFS-induced depotentiation(ex vivo) required activity of group II metabotropic glutamate receptors (mGluRs), known to be present at presynaptic terminals, but not AMPAR internalization, consistent with a presynaptic mechanism for pp-LFS-induced depotentiation(ex vivo). This result is in contrast with another form of ex vivo depotentiation in the thalamic pathway that requires both group I mGluR activity and AMPAR internalization. We thus suggest that extinction of conditioned fear involves a distinct form of depotentiation at C-LA synapses, which depends upon both NMDARs and group II mGluRs.

Long-Term Neural Correlates of Reversible Fear Learning in the Lateral Amygdala

“…3E-G). Collectively, these results suggest that the average LA ensemble activity represents updated CS-US association strength in reversible fear learning and maintains this representation beyond memory consolidation, consistent with previous reports (Maren, 2000;Hong et al, 2011).…”

“…These fear neurons amount to only 10ϳ30% of all the LA neurons, suggesting a rather sparse and restricted encoding of CS-US associations (Quirk et al, 1995;Repa et al, 2001;Han et al, 2007). In contrast, fear learninginduced synaptic potentiation has been observed in the general population of LA neurons (McKernan and Shinnick-Gallagher, 1997; Kim et al, 2007;Zhou et al, 2009), leading to the previously suggested possibility that the majority of LA neurons are strongly inhibited by GABAergic interneurons (Paré and Gaudreau, 1996) and are thus virtually undetectable by either in vivo recordings or immediate-early gene staining methods. Interestingly, a previous report demonstrated that targeted ablation of the ϳ15% of LA neurons that preferentially participated in learning can significantly impair auditory fear memory, whereas ablating a similarly sized random population had no effect (Han et al, 2009).…”

“…Fear extinction recruits the infralimbic cortex to exert inhibitory influence on the medial subnuclei of the central amygdala (CeM) via the basal amygdala (BA) and amygdala-intercalated neurons (Maren and Quirk, 2004;Haubensak et al, 2010;Pape and Pare, 2010;Amir et al, 2011). Extinction also induces depotentiation at LA input synapses (Kim et al, 2007;Dalton et al, 2008;Hong et al, 2009) and enhances local inhibition (Chhatwal et al, 2005;Lin et al, 2009), all leading to decreased fear expression. Interestingly, NMDA receptor blockers infused into the LA impair both fear conditioning and extinction, suggesting that neuronal plasticity in the LA is crucial for both events (Miserendino et al, 1990;Falls et al, 1992;Sotres-Bayon et al, 2007).…”

Extinction reverses olfactory fear-conditioned increases in neuron number and glomerular size

“…Thus, whereas regions such as the amygdala, hippocampus, or prefrontal cortex may allow for the inhibition of fear expression or the modulation of that inhibition (12,21), the primary olfactory sensory system likely plays a major role in the CS sensitivity and responsiveness following a learning event and its extinction. A growing body of literature suggests that alterations in synaptic transmission within the basolateral amygdala (BLA) play an important role in the suppression of conditioned fear following extinction learning (22,23); in fact, there is evidence of depotentiation of conditioning-related amygdala synaptic transmission that occurs following extinction training (24)(25)(26)(27). These data are in line with our observation that extinction reverses aspects of conditioning-related effects, although the contribution of regions such as the amygdala in the regulation of primary sensory system structural changes remains an important area for future investigation.…”

Extinction of fear memory during development: lesson for a better exposure therapy?

“…Amygdala LTP requires activation of N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, and extinction training leads to depotentiation of LTP by inducing AMPA receptor endocytosis [28]. Thus, fear conditioning and extinction are accompanied by an increase and decrease in synaptic activity in amygdale, respectively [29]. Density of dendritic spines was significantly increased in the fear conditioned group compared to the fear extinction group in BLA [30].…”