Egr-1 increases in the prefrontal cortex following training in the context preexposure facilitation effect (CPFE) paradigm

Abstract

The context pre-exposure facilitation effect (CPFE) is a modified form of standard contextual fear conditioning that dissociates learning about the context during a preexposure phase from learning the context-shock association during an immediate shock training phase conducted on separate days. Fear conditioning in the CPFE is an associative process in which only animals that are preexposed to the same context they are later given an immediate shock in demonstrate freezing when tested for conditioned fear memory. Previous research has shown that the hippocampus and amygdala are necessary for different phases of the CPFE, but whether other brain regions are also involved is unknown. The present study examined expression of the immediate-early gene early growth response gene 1 (Egr-1; also called Zif268, Ngfi-a, Krox-24) in the dorsal hippocampus, lateral nucleus of the amygdala, retrosplenial cortex, and several prefrontal cortex regions (infralimbic and prelimbic medial prefrontal cortex, anterior cingulate, and orbitofrontal cortex) following each phase of the CPFE in juvenile rats. Animals preexposed to the conditioning context displayed fear conditioned freezing during a retention test whereas rats preexposed to an alternate context did not. Following context preexposure, Egr-1 mRNA was elevated in context and alternate context exposed animals compared to homecaged control rats in almost all regions analyzed. Following the context-shock training phase, fear conditioned rats displayed significantly more Egr-1 mRNA expression in the infralimbic, prelimbic, and orbitofrontal cortices compared to the alternate context preexposed control rats. These differences in Egr-1 expression were not found in amygdala between the preexposed context and alternate context rats. No sex differences were observed following preexposure or training in any regions analyzed. The findings suggest that increased expression of Egr-1 within the prefrontal cortex is associated with contextual fear conditioning in the CPFE paradigm.

Variants of contextual fear conditioning induce differential patterns of Egr-1 activity within the young adult prefrontal cortex

“…However, Egr-1 mRNA is also increased following exposure to unpredictable situations and exposure to novel contexts – suggesting its role in learning contextual information may be quite complex [15, 16, 25–27]. While a number of studies have examined the functional role and molecular changes occurring within the hippocampus and amygdala during different phases of learning in sCFC and the CPFE, recent evidence has begun to point to a role for the prefrontal cortex (PFC) in contextual fear learning [10, 19, 20, 28, 29]. Although the neuroanatomical pathways between the PFC, hippocampus, and amygdala are fairly well characterized, the function of the PFC in contextual fear conditioning is just starting to be explored [30–33].…”

“…Recently, we have begun examining activation of the PFC during contextual fear learning using the CPFE paradigm in developing rats [29, 34]. We have found rats that learn the CPFE via preexposure to the training context (relative to rats preexposed to an alternate context) show increased Egr-1 mRNA levels in the prelimbic and infralimbic regions of the PFC following the context-shock learning phase.…”

Amygdaloid zif268 participated in the D-cycloserine facilitation effect on the extinction of conditioned fear

“…Recently, Asok and colleagues demonstrated that increased expression of zif268 within the prefrontal cortex is associated with contextual fear conditioning in the context of the pre-exposure facilitation effect paradigm. They also found fear-conditioned rats displayed significantly more zif268 mRNA expression in the infralimbic, prelimbic, and orbitofrontal cortices than the alternate context pre-exposed control rats (Asok et al 2013). Further experiments are needed to clarify the role of zif268 in these structures on extinction.…”

NMDA receptor antagonism disrupts acquisition and retention of the context preexposure facilitation effect in adolescent rats

“…In addition to possible differential involvement of the hippocampus and amygdala, it is possible that NMDA receptor antagonism disrupts mPFC plasticity occurring during the CPFE. Our lab has previously reported an increase in the immediate early-growth response gene 1 ( Egr-1 ) in the mPFC in PD31 rats after context-shock association training in the CPFE [5, 6]. It is possible that there may be differential contributions of NMDA receptors in the BLA, DHPC, and mPFC in postshock and retention test freezing within the CPFE.…”

“…We have shown that the CPFE emerges between postnatal day (PD) 17 and 24 in the rat [14], at which point it depends on hippocampal NMDA receptors and on conjunctive-rather than feature-based context representations in developing rats [15]. We have also shown that the CPFE engages plasticity and drives immediate early gene expression in the hippocampus, amygdala, and prefrontal cortex in adolescent rats [5, 6]. …”