Inhibition of Spontaneous Recovery of Fear by mGluR5 after Prolonged Extinction Training

Abstract

Fear behavior is vital for survival and involves learning contingent associations of non-threatening cues with aversive stimuli. In contrast, excessive levels of fear can be maladaptive and lead to anxiety disorders. Generally, extensive sessions of extinction training correlates with reduced spontaneous recovery. The molecular mechanisms underlying the long-term inhibition of fear recovery following repeated extinction training are not fully understood. Here we show that in rats, prolonged extinction training causes greater reduction in both fear-potentiated startle and spontaneous recovery. This effect was specifically blocked by metabotropic glutamate receptor 5 (mGluR5), but not by mGluR1 antagonists and by a protein synthesis inhibitor. Similar inhibition of memory recovery following prolonged extinction training was also observed in mice. In agreement with the instrumental role of mGluR5 in the prolonged inhibition of fear recovery, we found that FMR1−/− mice which exhibit enhanced mGluR5-mediated signaling exhibit lower spontaneous recovery of fear after extinction training than wild-type littermates. At the molecular level, we discovered that prolonged extinction training reversed the fear conditioning-induced increase in surface expression of GluR1, AMPA/NMDA ratio, postsynaptic density-95 (PSD-95) and synapse-associated protein-97 (SAP97). Accordingly, delivery of Tat-GluR23Y, a synthetic peptide that blocks AMPA receptor endocytosis, inhibited prolonged extinction training-induced inhibition of fear recovery. Together, our results demonstrate that prolonged extinction training results in the mGluR5-dependent long-term inhibition of fear recovery. This effect may involve the degradation of original memory and may explain the beneficial effects of prolonged exposure therapy for the treatment of phobias.

Amount of fear extinction changes its underlying mechanisms

“…In contrast, the erasure mechanism has been supported by previous studies using both single- and multiple-session extinction training (Rescorla and Wagner, 1972; Lin et al, 2003; Kim et al, 2007; Dalton et al, 2008; Mao et al, 2013). These findings provide a hint that the inhibition mechanism is involved primarily in the early phase of extinction training.…”

Acute inhibition of mGluR5 disrupts behavioral flexibility

“…How mGluR5 regulates the extinction of fear and spatial memory remains largely unknown. It has been demonstrated that repeated extinction sessions over days trigger up-regulation of mGluR5 expression in the hippocampus (Riedel, Casabona, Platt, Macphail, and Nicoletti, 2000), which may lead to reduction in subsequent recall or spontaneous recovery of fear (Mao, Chang, Wu, Orejarena, Manzoni, and Gean, 2013). At the cellular level, it is suggested that mGluR5 activity supports the extinction-induced changes in AMPA receptor/NMDA receptor ratio and intrinsic excitability in prefrontal cortex (Sepulveda-Orengo, Lopez, Soler-Cedeno, and Porter, 2013).…”

Environmental variables that ameliorate extinction learning deficits in the 129S1/SvlmJ mouse strain

“…1,2 Rodent models of fear learning (ie, fear conditioning) and fear extinction learning have enriched our understanding of genes and neural circuits involved in the expression of GAD and PTSD symptoms (reviewed in Fenster et al 1 ). [12][13][14][15][16] In humans, extinction learning is a main component of exposure therapy, which is often used in the treatment of PTSD. 3 Following one or more CS-US pairings, rodents will typically display a fearful response to the CS alone (conditioned response).…”

“…Extinction learning involves both forming new associations [4][5][6][7][8][9][10][11] and degradation of the originally learned CS-US pairing. [12][13][14][15][16] In humans, extinction learning is a main component of exposure therapy, which is often used in the treatment of PTSD.…”