An egr-1 (zif268) Antisense Oligodeoxynucleotide Infused Into the Amygdala Disrupts Fear Conditioning

Abstract

Studies of gene expression following fear conditioning have demonstrated that the inducible transcription factor, egr-1, is increased in the lateral nucleus of the amygdala shortly following fear conditioning. These studies suggest that egr-1 and its protein product Egr-1 in the amygdala are important for learning and memory of fear. To directly test this hypothesis, an egr-1 antisense oligodeoxynucleotide (antisense-ODN) was injected bilaterally into the amygdala prior to contextual fear conditioning. The antisense-ODN reduced Egr-1 protein in the amygdala and interfered with fear conditioning. A 250-pmole dose produced an 11% decrease in Egr-1 protein and reduced long-term memory of fear as measured by freezing in a retention test 24 h after conditioning, but left shock-induced freezing intact. A larger 500-pmole dose produced a 25% reduction in Egr-1 protein and significantly decreased both freezing immediately following conditioning and freezing in the retention test. A nonsense-ODN had no effect on postshock or retention test freezing. In addition, 500 pmole of antisense-ODN infused prior to the retention test in previously trained rats did not reduce freezing, indicating that antisense-ODN did not suppress conditioned fear behavior. Finally, rats infused with 500 pmole of antisense-ODN displayed unconditioned fear to a predator odor, demonstrating that unconditioned freezing was unaffected by the antisense-ODN. The data indicate that the egr-1 antisense-ODN interferes with learning and memory processes of fear without affecting freezing behavior and suggests that the inducible transcription factor Egr-1 within the amygdala plays important functions in long-term learning and memory of fear.

Disrupting Reconsolidation of Conditioned Withdrawal Memories in the Basolateral Amygdala Reduces Suppression of Heroin Seeking in Rats

“…Our results also suggest a selective involvement of the BLA in regulating reconsolidation of CS-withdrawal memories, because Zif268 was not upregulated in the CeN after reactivation with the CS, and Zif268 ASO infusion reduced expression selectively in the BLA. This latter finding extends the data in previous reports not only by confirming that Zif268 ASO attenuates Zif268 upregulation in the BLA (Lee et al, 2005) and whole amygdala (Malkani et al, 2004) but also providing the novel finding that the effect is selective to the BLA, because there is no reduction of Zif268 protein in the CeN. The amygdalar nuclei form part of an interconnected circuit that has been suggested to underlie the aversive aspects of opiate withdrawal (Frenois et al, 2002(Frenois et al, , 2005.…”

The Activity-Regulated Cytoskeletal-Associated Protein (Arc/Arg3.1) Is Required for Memory Consolidation of Pavlovian Fear Conditioning in the Lateral Amygdala

“…Although the use of ODNs has proven successful in the hippocampus (Guzowski and McGaugh, 1997;Guzowski et al, 2000;Taubenfeld et al, 2001), fewer studies have used ODNs to manipulate gene expression in the amygdala (but see Malkani et al, 2004;Milekic et al, 2007). In our experiments, we show that intra-LA infusion of a biotinylated Arc/Arg3.1 ODN exhibits significant spread within the LA.…”

Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats

“…Activity-regulated genes contribute to the promotion and maintenance of synaptic plasticity (Lu 2003, Rial Verde et al 2006, associative learning , Liu et al 2004, Malkani et al 2004, and long-term storage and retrieval of memories (Guzowski et al 2000;Hall et al 2001; Thomas et al 2002;Bozon et al 2003;Davis et al 2003;Liu et al 2004;Plath et al 2006). Furthermore, manipulation of BDNF levels in the brain alters cocaine seeking (Horger et al 1999;Lu et al 2004;Berglind et al 2007;Graham et al 2007).…”