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. 2008 Jul 17;154(4):1178-86.
doi: 10.1016/j.neuroscience.2008.04.005. Epub 2008 Apr 18.

Activation of the ventral medial prefrontal cortex during an uncontrollable stressor reproduces both the immediate and long-term protective effects of behavioral control

J Amat  1 , E Paul, L R Watkins, S F Maier
Affiliations

Activation of the ventral medial prefrontal cortex during an uncontrollable stressor reproduces both the immediate and long-term protective effects of behavioral control

J Amat et al. Neuroscience. .

Abstract

The degree of behavioral control that an organism has over a stressor determines the behavioral and neurochemical sequelae of the stressor, with the presence of control preventing the typical outcomes that occur when the stressor is uncontrollable (e.g. failure to learn, exaggerated fear, dorsal raphe nucleus (DRN) 5-HT activation). Furthermore, an experience with a controllable stressor blocks the consequences of later uncontrollable stressors ("immunization"). These effects of control have been argued to be mediated by control-induced activation of ventral medial prefrontal cortex (mPFCv) output to the DRN. The experiments that have led to this interpretation have all involved the inactivation of the mPFCv with muscimol, showing that inactivation during the stressor eliminates the stressor-resistance produced by control, with the controllable stressor now acting as if it were uncontrollable. The present experiments in rats employed the opposite strategy, activating the mPFCv during the stressor. mPFCv microinjection of picrotoxin during the stressor eliminated the DRN 5-HT activation that normally occurs during the uncontrollable stressor, as well as the escape learning deficit and exaggerated fear that normally follows uncontrollable stress. Furthermore, mPFCv activation during an initial exposure to an uncontrollable stressor led the uncontrollable stressor to produce behavioral and neurochemical immunization when the subjects were later exposed to an uncontrollable stressor. That is, the conjoint activation of the mPFCv and exposure to an uncontrollable stressor led the uncontrollable stressor to act as if it were controllable. These results provide strong support for the argument that behavioral control produced stress-resistance by activating the mPFCv.

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Figures

Fig. 1
Fig. 1
Efficiency of wheel-turn escape behavior during exposure to controllable tail shock measured as number of quarter turns (mean±S.E.M.) of the wheel attained as the escape requirement on each trial. The rats had received mPFCv microinjections of PIC (closed circles) or VEH (open circles) 60 min before the shock session.
Fig. 2
Fig. 2
Placements of microinjection cannulae in the mPFCv. Numerals indicate distance from bregma in mm.
Fig. 3
Fig. 3
Placements of microdialysis probes in the DRN. Numerals indicate distance from bregma in mm.
Fig. 4
Fig. 4
5-HT as a mean (±S.E.M.) percentage of baseline in the DRN in groups that received IS. IS occurred during the gray bar. Open squares received VEH and closed squares PIC in the vPFCm at Time 0.
Fig. 5
Fig. 5
5-HT as a mean percentage (±S.E.M.) of baseline in the DRN in groups that received ES. ES occurred during the gray bar. Open circles received VEH and closed circles PIC in the vPFCm at Time 0.
Fig. 6
Fig. 6
5-HT as a mean percentage (±S.E.M.) of baseline in the DRN in groups that received IS. IS occurred during the gray. Closed squares received PIC in the vPFCm and open squares received PIC 2 mm caudal at Time 0.
Fig. 7
Fig. 7
The mean (±S.E.M.) number of 8-s intervals spent freezing, in 2-min blocks, after two foot shocks 24 h following stressor exposure. Squares represent IS, circles ES and triangles HCC. Open symbols VEH, closed symbols PIC given before day 1 treatment.
Fig. 8
Fig. 8
The mean (±S.E.M.) shuttle-box escape latencies across blocks of five shuttle-box FR-2 escape trials 24 h after stressor exposure. Squares represent IS, circles ES and triangles HCC. Open symbols VEH, closed symbols PIC given before day 1 treatment.
Fig. 9
Fig. 9
5-HT as a mean (±S.E.M.) percentage of baseline in the DRN in groups that received IS. IS occurred during the gray bar. These rats had received PIC and IS (closed squares), VEH and IS (open squares), or VEH and ES (open circles) 7 days earlier.
Fig. 10
Fig. 10
The mean (±S.E.M.) shuttle-box escape latencies across blocks of five shuttle-box FR-2 escape trials 24 h after IS exposure. The rats had received VEH (open symbols) or PIC (closed symbols) in the vPFCm before either IS (squares), ES (circles) or HCC (triangles), 7 days before IS.
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