Prefrontal infusion of PD098059 immediately after fear extinction training blocks extinction-associated prefrontal synaptic plasticity and decreases prefrontal ERK2 phosphorylation

Abstract

A previous study has demonstrated that disruption of fear extinction-induced long-term potentiation (LTP) in the medial prefrontal cortex (mPFC) is associated with the return of fear responding. Given that immediate posttraining infusion of PD098059, an inhibitor of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) cascade, into the mPFC also promotes recovery of fear, we investigated whether impairment of mPFC ERK/MAPK cascade also interferes with development of extinction-related LTP in the mPFC in rats. In Experiment 1, extinction training consisting of repetitive presentations of a tone previously associated with eyelid-shock application induced LTP-like changes at hippocampal inputs to the mPFC that were evident for approximately 2 h following fear extinction. Infusion of PD098059 into the mPFC immediately after extinction training abolished training-related prefrontal LTP and impaired retention of extinction memory tested on the following day. In Experiment 2, immunoblotting assays revealed that posttraining infusion of PD098059 into the mPFC produced a significant reduction of mPFC ERK2. These data, along with previous findings, suggest that low levels of ERK2 phosphorylation in the mPFC may interfere with mechanisms of retention of extinction training. The involvement of mPFC LTP in fear extinction is discussed.

Mechanisms of fear extinction

“…In most experiments there is no effect of these manipulations 112,113,118 but there is one report of a decrease in freezing across an extinction training session following pretraining electrolytic lesions 113 and one report of a disruption of within-session extinction following pre-extinction training infusions of muscimol. 114 Two recent physiological studies by Garcia and co-workers indicate that long-term potentiation (LTP) is induced in the output pathways of the dorsal 119 and ventral 120 hippocampus by extinction training; that extinction is impaired by application of depotentiation-inducing low-frequency stimulation to the dorsal hippocampus following extinction training; 119 and that application of LTP-inducing high-frequency stimulation to the dorsal hippocampus shortly after depotentiation induction restores extinction behavior. 119 It remains unclear which targets of hippocampal projections are important for these effects, because even though LTP and depotentiation were observed as modulation of field potential amplitudes in medial prefrontal cortex, prefrontal cortical lesions had no effect on extinction 119,121 or on the modulation of extinction by hippocampal lowfrequency stimulation 119 in studies by this group.…”

“…A number of studies employing a large variety of techniques have implicated mPFC, and particularly the infralimbic (IL) cortex, in retention and/or expression of fear extinction. mPFC recordings show increased CS-related unit activity 122 and induction of synaptic plasticity 119,120,[123][124][125][126] following extinction training. Microstimulation of mPFC during extinction training reduces conditioned freezing and facilitates later retention of extinction.…”

“…129 Immunocytochemistry shows increased expression of immediate early genes within mPFC following extinction training 125,130 (but see Morrow et al 131 ). Finally, intra-PFC infusion of a D4 dopamine receptor antagonist 132 or a protein synthesis inhibitor 130 before extinction training, or a mitogen-activated protein kinase (MAPK) inhibitor immediately postextinction training, 120,133 impairs extinction retention tested later in the absence of the drug.…”

“…171 In the former study infusions both before and after extinction training were effective, suggesting a role for MAPK in consolidation of extinction memory. Finally, Hugues et al 120,133 reported that immediate but not delayed (2 or 4 h) postextinction training infusions of PD98059 into medial prefrontal cortex impaired later extinction retention, using freezing as a measure of fear following pairings of a tone and eyelid shock US in acquisition.…”

Changing Fear: The Neurocircuitry of Emotion Regulation

“…A subsequent study pointed to the infralimbic (IL) region of the vmPFC as a potential site of extinction consolidation, reporting that pre-training IL lesions left within-session acquisition of extinction intact, but impaired extinction retrieval on the following day (Quirk et al, 2000). Infusion studies showing that disruption of protein synthesis (Santini et al, 2004), MAPk blockade (Hugues et al, 2006), and administration of an NMDA antagonist (Burgos-Robles et al, 2007) within the vmPFC all impair retrieval of extinction suggest that the plasticity in this region supports extinction consolidation. Electrophysiological evidence suggests that the IL inhibits the expression of conditioned fear during extinction through reciprocal connections with the amygdala.…”