Previous experience with behavioral control over stress blocks the behavioral and dorsal raphe nucleus activating effects of later uncontrollable stress: role of the ventral medial prefrontal cortex

Abstract

Previous experience with stressors over which the subject has behavioral control blocks the typical behavioral consequences of subsequent exposure to stressors over which the organism has no behavioral control. The present experiments explored the involvement of the ventral medial prefrontal cortex (mPFCv) in mediating this "immunizing" or resilience producing effect of an initial experience with control. Behavioral immunization was blocked by inactivation of the mPFCv with muscimol at the time of the initial experience with control, as well as at the time of the later exposure to uncontrollable stress. Inhibition of protein synthesis within the mPFCv by anisomycin also blocked immunization when administered at the time of the initial controllable stress but had no effect when administered at the time of the later uncontrollable stress. Additional experiments found that the initial experience with control blocks the intense activation of serotonergic cells in the dorsal raphe nucleus that would normally be produced by uncontrollable stress, providing a mechanism for behavioral immunization. Furthermore, mPFCv activity during the initial controllable stressor was required for this effect to occur. These results suggest that the mPFCv is needed both to process information about the controllability of stressors and to utilize such information to regulate responses to subsequent stressors. Moreover, the mPFCv may be a site of storage or plasticity concerning controllability information. These results are consistent with recent research in other domains that explore the functions of the mPFCv.

Figure 1.

A, Microinjection cannula placements. The black circles represent the sites of the injection cannula tips. B, Microdialysis probe placements. Black bars represent the placement of microdialysis probes. Numerals indicate distance from bregma (in millimeters).

Figure 2.

A, 5-HT as percentage of baseline in caudal DRN during IS from groups of rats receiving VEH and different stress treatments 7 d earlier. The dotted line represents 5-HT in rats exposed to ES from a previous study, for comparative purposes. Squares received previous V-IS, circles received previous V-ES, and diamonds are pooled data of previous V or M-HC. B, 5-HT as percentage of baseline in caudal DRN during IS from groups of rats receiving MUS and different stress treatments 7 d earlier. Black squares received previous M-IS, black circles received previous M-ES, and diamonds are pooled data of previous V or M-HC. The gray bar represents the time of stressor exposure in the wheel-turn boxes in A and B.

Figure 3.

Photomicrographs (20×) of coronal DRN sections at −8 mm from bregma (D, dorsal; V, ventral; L, lateral) of rats exposed to IS ending 2 h before death. The section in A is from a subject microinjected with VEH into the vPFCm and exposed to ES 7 d earlier. In B, a similar microinjection was made, and the subject was exposed to IS. In C, the subject received a microinjection of MUS followed by ES. The sections were double labeled for c-Fos (small black particles) and serotonin (larger brown-reddish particles).

Figure 4.

Percentage of 5-HT-labeled cells expressing c-Fos in caudal (A) and middle (B) DRN. All groups received IS ending 2 h before death, and either VEH or MUS and ES, IS, or HC 7 d earlier, as indicated below each bar.

Figure 5.

Effect of muscimol administration in the vPFCm before the immunization phase treatment (treatment 1). The graph in this figure and in Figures 6–9, 11, and 12, shows the mean shuttle-box escape latencies across blocks of five shuttle-box FR-2 escape trials (third experimental treatments). □, V-IS/IS; ■, M-IS/IS; ○, V-ES/IS; ●, M-ES/IS; ◇, V-HC/IS; ▴, M-HC/IS; ▵, V-HC/V-HC (for an explanation of the treatment group abbreviations, see Table 1).

Figure 6.

Shuttle-box escape latencies showing the effect of intra-vPFCm muscimol administration given after the immunization phase treatment. ○, ES-V/IS; ●, ES-M/IS; ◇, V-HC/IS; ▵, V-HC/V-HC.

Figure 7.

Shuttle-box escape latencies showing the effect of vPFCm muscimol administration before IS at treatment 2. □, IS/V-IS; ■, IS/M-IS; ○, ES/V-IS; ●, ES/M-IS; ◇, V-HC/IS, ▴, V-HC/V-HC.

Figure 8.

Shuttle-box escape latencies showing the effect of vPFCm muscimol administration before both ES at treatment 1 and IS at treatment 2. ●, M-ES/M-IS; ◇, V-HC/IS; ▵, V-HC/V-HC.

Figure 9.

Shuttle-box escape latencies showing the effect of vPFCm muscimol administration before shuttle-box testing. ○, ES/IS/V-T; ●, ES/IS/M-T; ◇, V-HC/IS; ▵, V-HC/V-HC.

Figure 10.

Efficiency of wheel-turn escape behavior during exposure to controllable tail shock in subjects that had received vPFCm anisomycin (ANIS) or vehicle (VEH) 60 min before the shock session. The “state” is the mean number of one-quarter turns of the wheel attained as the escape requirement on each trial.

Figure 11.

Shuttle-box escape latencies showing the effect of vPFCm anisomycin administration before ES at treatment 1 or IS at treatment 2. ○, V-ES/IS; ●, A-ES/IS; ♦, A-ES/A-IS; ▾, ES-A/IS; ◇, V-HC/IS; ▵, V-HC/V-HC.

Figure 12.

Shuttle-box escape latencies showing the effect of vPFCm anisomycin before IS at treatment 2. ●, V-ES/A-IS; ◇, V-HC/IS; ▵, V-HC/V-HC.