Learned stressor resistance requires extracellular signal-regulated kinase in the prefrontal cortex.

John P Christianson,Linda R Watkins,Allison R Foilb,Steven F Maier,Robert C Drugan,Johanna G Flyer-Adams,Jose Amat,Rachel A Daut

doi:10.3389/fnbeh.2014.00348

Abstract

Behaviorally controllable stressors confer protection from the neurochemical and behavioral consequences of future uncontrollable stressors, a phenomenon termed “behavioral immunization”. Recent data implicate protein synthesis within the ventromedial prefrontal cortex (mPFC) as critical to behavioral immunization. Adult, male Sprague-Dawley rats were exposed to a series of controllable tailshocks and 1 week later to uncontrollable tailshocks, followed 24 h later by social exploration and shuttlebox escape tests. To test the involvement of N-methyl-D-aspartate receptors (NMDARs) and the extracellular signal-regulated kinase (ERK) cascade in behavioral immunization, either D-AP5 or the MEK inhibitor U0126 was injected to the prelimbic (PL) or infralimbic (IL) mPFC prior to controllable stress exposure. Phosphorylated ERK and P70S6K, regulators of transcription and translation, were quantified by Western blot or immunohistochemistry after controllable or uncontrollable tailshocks. Prior controllable stress prevented the social exploration and shuttlebox performance deficits caused by the later uncontrollable stressor, and this effect was blocked by injections of D-AP5 into mPFC. A significant increase in phosphorylated ERK1 and ERK2, but not P70S6K, occurred within the PL and IL in rats exposed to controllable stress, but not to uncontrollable stress. However, U0126 only prevented behavioral immunization when injected to the PL. We provide evidence that NMDAR and ERK dependent signaling within the PL region is required for behavioral immunization, a learned form of stressor resistance.

Highlights

Stressor exposure is a trigger for a number of psychopathologies, yet some individuals appear to either avoid or recuperate from stressor-induced changes more readily than do others (Southwick et al, 2005; Southwick and Charney, 2012)
The dorsomedial striatum (DMS) was included because we recently reported that intra-DMS AP5 injections prevented the protective effects of controllable stressor exposure (Amat et al, 2014) and extracellular signal-regulated kinase (ERK) phosphorylation in this region might indicate that DMS, in addition to the medial prefrontal cortex (mPFC), is a neuroanatomical locus of memory required for behavioral immunization
INTRA-PFC AP5 PREVENTED BEHAVIORAL IMMUNIZATION Experimental timeline, cannula placements, social exploration and mean shuttle escape latency are depicted in Figure 1; baseline social exploration values are shown as a reference and were not included in the analysis

Summary

Introduction

Stressor exposure is a trigger for a number of psychopathologies, yet some individuals appear to either avoid or recuperate from stressor-induced changes more readily than do others (Southwick et al, 2005; Southwick and Charney, 2012). The degree to which an individual can manipulate the onset, offset, or intensity of a stressor gives rise to the perception of behavioral control, and behavioral control is one factor that mitigates the impact of stressors (Maier and Watkins, 2010; Hammack et al, 2012; Christianson and Greenwood, 2014). Behavioral control causes a longlasting, learned form of stressor resistance termed “behavioral immunization” in which one exposure to ES prevents the consequences of IS that may occur several days later (Williams and Maier, 1977; Amat et al, 2006, 2010; Christianson et al, 2008)

Methods

Results

Conclusion