Controllable versus uncontrollable stressors bi-directionally modulate conditioned but not innate fear

Abstract

Fear conditioning and fear extinction play key roles in the development and treatment of anxiety-related disorders, yet there is little information concerning experiential variables that modulate these processes. Here we examined the impact of exposure to a stressor in a different environment on subsequent fear conditioning and extinction, and whether the degree of behavioral control that the subject has over the stressor is of importance. Rats received a session of either escapable (controllable) tail shock (ES), yoked inescapable (uncontrollable) tail shock (IS), or control treatment (home cage, HC) 7 days before fear conditioning in which a tone and foot shock were paired. Conditioning was measured 24 h later. In a second experiment rats received ES, IS or HC 24 h after contextual fear conditioning. Extinction then occurred every day beginning 7 days later until a criterion was reached. Spontaneous recovery of fear was assessed 14 days after extinction. IS potentiated fear conditioning when given before fear conditioning, and potentiated fear responding during extinction when given after conditioning. Importantly, ES potently interfered with later fear conditioning, decreased fear responding during fear extinction, and prevented spontaneous recovery of fear. Additionally, we examined if the activation of the ventral medial prefrontal cortex (mPFCv) by ES is critical for the protective effects of ES on later fear conditioning. Inactivation of the mPFCv with muscimol at the time of the initial experience with control prevented ES-induced reductions in later contextual and auditory fear conditioning. Finally, we explored if the protective effects of ES extended to an unconditioned fear stimulus, ferret odor. Unlike conditioned fear, prior ES increased the fear response to ferret odor to the same degree as did IS.

Fig. 1

(A) Mean percent freezing in the conditioning context for groups given escapable (ES), yoked inescapable (IS), or no shock (HC) before fear conditioning. (B) Mean percent freezing to the altered experimental context (pretone) and to the tone CS for groups given ES, IS, or HC before fear conditioning.

Fig. 2

(A) Mean percent freezing to the conditioning context on each day of extinction, and 2 weeks after meeting the extinction criterion (spontaneous recovery, SR). Groups received escapable (ES), yoked inescapable (IS), or no shock (HC) 24 h after fear conditioning. (B) Mean percent freezing to the conditioning context during each minute of the first day of extinction.

Fig. 3

Microinjection cannula placements in the mPFCv. The black circles represent the sites of the injection cannula tips. Numerals indicate distance from bregma (mm).

Fig. 4

(A) Mean percent freezing in the conditioning context for groups given escapable (ES), yoked inescapable (IS), or no shock (HC) one week before fear conditioning. (B) Mean percent freezing to the altered experimental context (pretone) and to the tone CS for groups given ES, IS, HC one week before fear conditioning. Muscimol or vehicle saline was microinjected into the mPFCv 30 min before onset of tailshock. Site specificity controls for ES were injected with muscimol or vehicle saline into the ventral orbital cortex (ES-VO).

Fig. 5

Graphs showing mean behavior in defensive withdrawal apparatus that contained a ferret odor towel (Days 1–7). On Day 8, the ferret odor towel was replaced with a strawberry (S) odor towel. (A) Group means for time (seconds, s) spent with the ferret odor towel for subjects given escapable (ES), yoked inescapable (IS), or no shock (HC) the previous day. (B) Group means for the number of rears for subjects given ES, IS, or HC the previous day.