Fear extinction learning can be impaired or enhanced by modulation of the CRF system in the basolateral nucleus of the amygdala

Abstract

The neuropeptide corticotropin-releasing factor (CRF) is released during periods of anxiety and modulates learning and memory formation. One region with particularly dense concentrations of CRF receptors is the basolateral nucleus of the amygdala (BLA), a critical structure for both Pavlovian fear conditioning and fear extinction. While CRF has the potential to modify amygdala-dependent learning, its effect on fear extinction has not yet been assessed. In the present study, we examined the modulatory role of CRF on within-session extinction and fear extinction consolidation. Intra-BLA infusions of the CRF binding protein ligand inhibitor CRF(6-33) which increases endogenous levels of free CRF, or intra-BLA infusions of exogenous CRF made prior to fear extinction learning did not affect either fear expression or within-session extinction learning. However, when these animals were tested twenty-four hours later, drug free, they showed impairments in extinction memory. Conversely, intra-BLA infusions of the CRF receptor antagonist α-helical CRF(9-41) enhanced memory of fear extinction. These results suggest that increased CRF levels within the BLA at the time of fear extinction learning actively impair the consolidation of long-term fear extinction.

Keywords: Amygdala; Anxiety; Corticotropin-releasing factor; Fear extinction; Fear learning.

Figure 1

Histological verification of cannula placements.

Figure 2

Intra-BLA infusions of the CRF binding protein ligand inhibitor CRF(6-33) impair fear extinction. A: Schematic of behavioral protocol. B: Mean ± SE % freezing to three CS tones during fear conditioning. C: Mean ± SE % freezing to 10 CS tones 24 hr after training in rats given intra-BLA infusions of saline vehicle (n=8), 0.1 μg CRF(6-33) (n=4) or 1.0 μg CRF (6-33) (n=8) 15 min prior to training. D: Mean ± SE % freezing to the 30 sec pre-CS period (PRE) and 1 CS tone (CS) 24 hr after extinction training, drug-free. Animals that previously received infusions of CRF(6-33) showed impaired extinction memory.

Figure 3

Intra-BLA infusions of CRF impair fear extinction, while infusions of a CRF receptor antagonist enhance fear extinction. A: Schematic of behavioral protocol. B: Mean ± SE % freezing to three CS tones during fear conditioning. C: Mean ± SE % freezing to 10 CS tones 24 hr after training in rats given intra-BLA infusions of saline vehicle (n=11), 15ng CRF (n=8) or 1.0 μg α-helical CRF (9-41) (n=8) 15 min prior to training. D: Mean ± SE % freezing to the 30 sec pre-CS period (PRE) and 1 CS tone (CS) 24 hr after extinction training, drug-free. Animals that previously received infusions of CRF showed impaired extinction memory; animals that had received a CRF receptor antagonist showed enhanced extinction memory.