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

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.

Previous Ketamine Produces an Enduring Blockade of Neurochemical and Behavioral Effects of Uncontrollable Stress

“…It is known that that the reduced social investigation produced by IS is mediated by increased 5-HT release in the BLA produced by IS (Amat et al, 1998;Christianson et al, 2010). Thus, the present experiments assessed whether ketamine administered before IS would block or reduce the 5-HT increase in the BLA produced by IS.…”

“…Social investigation testing was conducted 24 h after the stress procedure, as described previously (Christianson et al, 2010). Any rats showing signs of injury after the stress session were excluded (these include irritated/inflamed hindpaws and sometimes toenails).…”

“…Inescapable tail shock was administered as described previously (Amat et al, 2005;Christianson et al, 2010). Briefly, rats were placed in a loose Plexiglas restraint tube (8 ϫ 18 cm, diameter ϫ length) with a rod extending from the rear to which the tail was taped and affixed with copper electrodes.…”

“…Peripheral injections of low dose of ketamine reduce depressivelike behavior in a variety of paradigms, including the forced swim test (Garcia et al, 2008;Engin et al, 2009) and the tail suspension test (da Silva et al, 2010). Ketamine has also been shown to reduce anxiety-like behavior (Engin et al, 2009).…”

“…We have shown that the activation of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) is necessary and sufficient for the production of the behavioral sequelae of IS (for review, see Maier and Watkins, 2005). More specifically, increases in 5-HT in the basolateral amygdala (BLA), a DRN projection region, is critical in the production of the behavioral endpoint measured here, juvenile social investigation (JSI; Amat et al, 1998;Christianson et al, 2010). Thus, we measured extracellular levels of 5-HT in the BLA during IS.…”