An egr-1 (zif268) antisense oligodeoxynucleotide infused into the amygdala disrupts fear conditioning.
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.
Program in Behavioral Neuroscience, Department of Psychology, University of Delaware, Newark, Delaware 19716, USA.
Seema
S
Malkani
Karin J
KJ
Wallace
Melanie P
MP
Donley
Jeffrey B
JB
Rosen
D000679:Amygdala / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001245:Association Learning / Q000187:drug effects / Q000502:physiology; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology*; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1; D004777:Environment; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D017874:Immediate-Early Proteins / Q000008:administration & dosage; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008845:Microinjections; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000008:administration & dosage
D002352:Carrier Proteins; C400751:Cuzd1 protein, rat; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D014157:Transcription Factors