Lesions of the basolateral amygdala reverse the long-lasting interference with shuttle box escape produced by uncontrollable stress

Abstract

Exposure to an uncontrollable, but not a controllable, stressor produces a constellation of behaviors called learned helplessness. In rodents, uncontrollable stress interferes with the ability to learn to escape from escapable shocks delivered in a shuttle box. The stress-induced shuttle box escape deficit is a common screening tool for potential antidepressant strategies. Inconsistencies in the literature exist regarding the time-course of, and mechanisms underlying, stress-induced escape deficits. When no common cues are shared between the stressor and testing environment, the escape deficit is short lived and independent of conditioned freezing. In contrast, when stress and testing occur in the same or similar environments, the escape deficit is very long lasting. The current studies address the hypothesis that the long-lived escape deficit produced by uncontrollable stress is dependent upon conditioned fear and the basolateral amygdala (BLA). Rats received bilateral excitotoxic lesions of the BLA 2 weeks following uncontrollable foot shocks. One week after surgery, rats were tested for conditioned freezing and escape behavior in the same shuttle boxes in which prior foot shocks were delivered. Stressed rats with sham lesions displayed robust conditioned freezing and failed to escape during shuttle box testing. Lesions of the BLA eliminated conditioned freezing and completely restored stressed rats' ability to perform the escape contingency. These data indicate that the long-lived stress-induced escape deficit produced under conditions in which the stressor and testing environments share common cues is dependent upon conditioned freezing elicited by the BLA. Results have important implications for the mechanisms underlying learned helplessness phenomena.

Figure 1

Schematic representation of the extent of damage produced by NMDA infused into the region of the basolateral amygdala for the animal showing the minimum amount of damage (dark gray) and the animal showing the maximum amount of damage (light gray). Values represent distance from bregma. Coronal brain section images adapted from Paxinos and Watson (1998).

Figure 2

Representative coronal brain slices showing the extent of the NMDA lesion of the basolateral amygdala. The box outline in (A) shows the region magnified in the photomicrographs from a sham animal (B) and a lesioned animal (C) stained with NeuN.

Figure 3

Freezing behavior of rats following sham surgery or post-stress lesions of the basolateral amygdala (BLA). One week following no shocks (No Stress) or uncontrollable shocks in the shuttle box (Stress), rats either received sham surgery (Sham) or NMDA infusion bilaterally into the BLA. Two weeks later, rats were re-exposed to the shuttle box for assessment of freezing behavior. Data are expressed as A) 1-min freezing blocks or B) the average freezing score across the entire observation period. Data represent group means ± SEM. * p ≤ .05 relative to all other groups.

Figure 4

Fixed ratio-1 (FR-1) escape performance of rats following sham surgery or post-stress lesions of the basolateral amygdala (BLA). One week following no shocks (No Stress) or uncontrollable shocks in the shuttle box (Stress), rats received either sham surgery (Sham) or NMDA infusion bilaterally into the BLA. Two weeks later, rats were re-exposed to the shuttle box and FR-1 escape latency was recorded. Data represent group means ± SEM. * p ≤ .05 relative to all other groups.

Figure 5

Shock-elicited (post-fixed ratio-1; FR-1) freezing behavior of rats following sham surgery or post-stress lesions of the basolateral amygdala (BLA). One week following no shocks (No Stress) or uncontrollable shocks in the shuttle box (Stress), rats received either sham surgery (Sham) or NMDA infusion bilaterally into the BLA. Two weeks later, rats were re-exposed to the shuttle box and shock-elicited freezing was scored immediately following a single FR-1 trial. Data represent group means ± SEM.

Figure 6

Fixed ratio-2 (FR-2) escape performance of rats following sham surgery or post-stress lesions of the basolateral amygdala (BLA). One week following no shocks (No Stress) or uncontrollable shocks in the shuttle box (Stress), rats received either sham surgery (Sham) or NMDA infusion bilaterally into the BLA. Two weeks later, rats were re-exposed to the shuttle box and FR-2 escape latency was recorded. Data are expressed as A) blocks of 5 FR-2 escape trials and B) the average escape latency across all 25 FR-2 trials. Data represent group means ± SEM. * p ≤ .05 relative to all other groups.