Mitral cell beta1 and 5-HT2A receptor colocalization and cAMP coregulation: a new model of norepinephrine-induced learning in the olfactory bulb.
In the present study we assess a new model for classical conditioning of odor preference learning in rat pups. In preference learning beta(1)-adrenoceptors activated by the locus coeruleus mediate the unconditioned stimulus, whereas olfactory nerve input mediates the conditioned stimulus, odor. Serotonin (5-HT) depletion prevents odor learning, with 5-HT(2A/2C) agonists correcting the deficit. Our new model proposes that the interaction of noradrenergic and serotonergic input with odor occurs in the mitral cells of the olfactory bulb through activation of cyclic adenosine monophosphate (cAMP). Here, using selective antibodies and immunofluorescence examined with confocal microscopy, we demonstrate that beta(1)-adrenoceptors and 5-HT(2A) receptors colocalize primarily on mitral cells. Using a cAMP assay and cAMP immunocytochemistry, we find that beta-adrenoceptor activation by isoproterenol, at learning-effective and higher doses, significantly increases bulbar cAMP, as does stroking. As predicted by our model, the cAMP increases are localized to mitral cells. 5-HT depletion of the olfactory bulb does not affect basal levels of cAMP but prevents isoproterenol-induced cAMP elevation. These results support the model. We suggest the mitral-cell cAMP cascade converges with a Ca(2+) pathway activated by odor to recruit CREB phosphorylation and memory-associated changes in the olfactory bulb. The dose-related increase in cAMP with isoproterenol implies a critical cAMP window because the highest dose of isoproterenol does not produce learning.
Yuan
Qi
Q
Division of Basic Medical Sciences, Memorial University of Newfoundland, St John's, Newfoundland, Canada A1B 3V6.
Harley
Carolyn W
CW
McLean
John H
JH
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D003214:Conditioning, Classical / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism* / Q000502:physiology; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D007545:Isoproterenol / Q000494:pharmacology; D007858:Learning / Q000502:physiology*; D008125:Locus Coeruleus / Q000502:physiology; D018613:Microscopy, Confocal; D009638:Norepinephrine / Q000378:metabolism* / Q000502:physiology; D009812:Odorants; D009830:Olfactory Bulb / Q000378:metabolism* / Q000502:physiology; D009832:Olfactory Nerve / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism* / Q000502:physiology
D000318:Adrenergic beta-Agonists; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D018342:Receptors, Adrenergic, beta-1; D011985:Receptors, Serotonin; D012701:Serotonin; D000242:Cyclic AMP; D007545:Isoproterenol; D009638:Norepinephrine