Activation of the cyclic AMP response element-binding protein signaling pathway in the olfactory bulb is required for the acquisition of olfactory aversive learning in young rats.
Long-term memory formation requires both gene expression and protein synthesis. Phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB) is thought to be important in processes underlying long-term memory. To clarify the role of CREB in olfactory aversive learning in young rats, we carried out behavioral pharmacology and Western blot analyses. On postnatal day 11, oligodeoxynucleotides were infused directly into the bilateral olfactory bulbs through cannulae implanted prior to training in a classical conditioning paradigm with citral odor and foot shock. On the following day the odor preference test was performed. After training, saline-infused animals spent significantly shorter time over the citral odor zone. Infusion of CREB antisense oligodeoxynucleotides 6 h before or during training, however, prevented olfactory aversive learning without affecting memory retention 1 h after training. CREB scrambled oligodeoxynucleotides infusions had no effect on olfactory learning. When infused 6 h after training, none of oligodeoxynucleotides had an effect on time spent over the odor zone. Using Western blotting, we analyzed CREB in nuclear extracts obtained from the young rats after training. Marked increases in phosphorylated CREB were sustained from 10 to 360 min after the odor-shock pairing in animals which were subjected to both, in comparison with levels 30 min in animals which were subjected to odor only or no stimulation. Total CREB levels showed no differences among groups. Infusion of CREB antisense oligodeoxynucleotides significantly reduced the expression of phosphorylated and total CREBs in the olfactory bulb. These results show that the synthesis and phosphorylation of CREB are required for the acquisition of olfactory aversive learning in young rats, and that this requirement for the CREB signaling pathway has a critical time window.
Zhang
J-J
JJ
Department of Neuropsychiatry, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.
Okutani
F
F
Inoue
S
S
Kaba
H
H
D000818:Animals; D000831:Animals, Newborn; D001067:Appetite Depressants / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western / Q000379:methods; D003214:Conditioning, Classical; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D008098:Litter Size / Q000502:physiology; D009830:Olfactory Bulb / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D015398:Signal Transduction / Q000502:physiology*; D012903:Smell / Q000502:physiology*; D013997:Time Factors
D001067:Appetite Depressants; D017362:Cyclic AMP Response Element-Binding Protein; D016376:Oligonucleotides, Antisense