Mitral Cell β₁ and 5-HT_2A Receptor Colocalization and cAMP Coregulation: A New Model of Norepinephrine-Induced Learning in the Olfactory Bulb

Abstract

In the present study we assess a new model for classical conditioning of odor preference learning in rat pups. In preference learning ␤ 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 ␤ 1 -adrenoceptors and 5-HT 2A receptors colocalize primarily on mitral cells. Using a cAMP assay and cAMP immunocytochemistry, we find that ␤-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.

Locus Ceruleus Activation Initiates Delayed Synaptic Potentiation of Perforant Path Input to the Dentate Gyrus in Awake Rats: A Novel β-Adrenergic- and Protein Synthesis-Dependent Mammalian Plasticity Mechanism

“…In rat pup olfactory preference learning, ␤-adrenoceptor stimulation in the olfactory bulb paired with glutamatergic input from olfactory neurons produces an odor preference 24 hr later (Sullivan et al, 2000). This olfactory memory depends on cAMP elevation (Yuan et al, 2003) and the phosphorylation of cAMP response elementbinding protein (CREB) at the time of acquisition (Yuan et al, 2000). Both cAMP and phosphorylation of CREB are widely implicated in memory formation (Bernabeu et al, 1996;Silva et al, 1998).…”

Ontogeny of odor-LiCl vs. odor-shock learning: Similar behaviors but divergent ages of functional amygdala emergence

“…Previous data on infant odor learning indicate that the olfactory bulb exhibits robust learning-associated changes in early life, regardless of pups learning an odor preference or odor aversion (Sullivan and Leon 1986;Wilson et al 1987;Sullivan et al 1990;Woo et al 1996;McLean et al 1999;Yuan et al 2003;Roth et al 2006). The role of the olfactory bulb changes with development since older pups and adults do not usually show odor learning-induced changes in this brain area (Hamrick et al 1993;Woo et al 1996;Sevelinges et al 2007).…”

Molecular Biology Of Early Olfactory Memory: Figure 1.

“…A particular strength of the early olfactory learning paradigm, and one taken full advantage of by Yuan et al (2003) in their work presented here, is its dependence on a relatively reduced neural circuitry. While olfactory memory in adults is associated with changes in the hippocampus (Staubli et al 1986;Alvarez et al 2002), amygdala (Rosenkranz and Grace 2002;Tronel and Sara, 2002), piriform cortex (Roman et al 1987;Litaudon et al 1997;Zinyuk et al 2001;Saar et al 2002), perirhinal cortex (Herzog and Otto 1998), and orbitofrontal cortex (Ramus and Eichenbaum, 2000;Rolls 2001) among elsewhere, many of these structures are not anatomically mature or effectively activated by odors during the first postnatal week in the rat.…”

“…One behavioral model that has proven useful for identifying circuit, cellular, and now molecular mechanisms of learning is early olfactory associative learning, a form of mammalian olfactory imprinting. In this issue of Learning & Memory, Yuan et al (2003) make use of the many advantages of the early olfactory learning paradigm to shed light on the underlying molecular events that occur within the olfactory bulb and support this type of associative learning.…”