Distribution and development of β‐adrenergic receptors in the rat olfactory bulb

100

103

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.

Section: Yuan Et Almentioning

confidence: 97%

Section: Yuan Et Almentioning

confidence: 99%

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

Yuan¹,

Harley²,

McLean³

2003

100

103

“…1). Both ␣ and ␤ adrenergic receptors are expressed by cells in the MOB (Pieribone et al 1994;Woo and Leon 1995;Day et al 1997). Current evidence suggests that the LC-NA system has a behaviorally meaningful role within the MOB of adult animals engaged in olfactory learning tasks.…”

mentioning

confidence: 99%

Adrenergic modulation of olfactory bulb circuitry affects odor discrimination

Doucette¹,

Milder²,

Restrepo³

2007

132

A rodent's survival depends upon its ability to perceive odor cues necessary to guide mate selection, sexual behavior, foraging, territorial formation, and predator avoidance. Arguably, the need to discriminate odor cues in a complex olfactory environment requires a highly adaptable olfactory system. Indeed, it has been proposed that context-dependent modulation of the initial sensory relay could alter olfactory perception. Interestingly, 40% of the adrenergic innervation from the locus coeruleus, fibers that are activated by contextual cues, innervates the first relay station in the olfactory system (the main olfactory bulb). Here we utilize restricted pharmacological inhibition of olfactory bulb noradrenergic receptors in awake-behaving animals. We show that combined blockade of ␣ and ␤ adrenergic receptors does not impair two-odor discrimination behavior per se but does impair the ability to discriminate perceptually similar odors. Thus, contextual cues conveyed by noradrenergic fibers alter processing before the second synapse in the olfactory cortex, resulting in tuning of the ability to discriminate between similar odors.Particularly intriguing, but poorly understood, is the potential role of adrenergic modulation of the main olfactory bulb (MOB) in adults. The MOB receives strong innervation from the locus coeruleus (LC)-noradrenaline (NA) system, and in rodents ∼40% of LC fibers target the MOB. The fibers are known to be densest in the internal plexiform and granule cell layers, less dense in the external plexiform layer, and sparse in the glomerular layer (McLean et al. 1989) (Fig. 1). Both ␣ and ␤ adrenergic receptors are expressed by cells in the MOB (Pieribone et al. 1994;Woo and Leon 1995;Day et al. 1997). Current evidence suggests that the LC-NA system has a behaviorally meaningful role within the MOB of adult animals engaged in olfactory learning tasks. There is a modest but reproducible release of NA in the MOB during operant conditioning in adult mice (Brennan et al. 1998). In addition, detection of the rewarded odor, presumably relayed from the prefrontal cortex to LC, triggers a brief phasic increase in firing of LC neurons (Bouret and Sara 2004). Gray and coworkers also find that the topical application of propranolol, a ␤ adrenergic antagonist, to the MOB abolished changes in ␥ frequency (40-100 Hz) oscillations in the local field potential elicited by the rewarded odor in an odor discrimination task (Gray et al. 1986). The modulation of odor-induced local field potential oscillations has been postulated to play a role in olfactory learning (Martin et al. 2006). Surprisingly, although the adrenergic effect on odor-induced changes in local field potential oscillations found by Gray and coworkers was robust, propranolol did not change the ability of rabbits to discriminate between odors. Data presented in this paper provide an explanation for the paradoxical observation of Gray and coworkers, as we show that blockade of both ␣ and ␤ adrenergic receptors in the MOB is necessary to attain a chan...

“…Norepinephrine released by locus coeruleus activation would interact with all adrenoceptor subtypes present in the olfactory bulb. Both ␤1-and ␤2-adrenoceptor subtypes are present in the olfactory bulb (Nicholas et al 1993;Woo and Leon 1995) and would be activated by isoproterenol. ␣-Adrenoceptor subtypes also occur in the olfactory bulb (McCune et al 1993).…”

mentioning

confidence: 99%

“…These groups were tested against the learning effective dose of phenylephrine (1 mg/kg) as well as the usual controls (six litters, 46 pups). This added condition was required because ␣1-adrenoceptors are present in both the locus coeruleus (McCune et al 1993) and olfactory bulb (McCune et al 1993;Pieribone et al 1994), while ␤-adrenoceptors are present in the olfactory bulb (Woo and Leon 1995) but not in the locus coeruleus (Nicholas et al 1993). Thus, blocking the ␤-adrenoceptors in the olfactory bulb, while activating ␣1-adrenoceptors, would rule out ␤-adrenoceptor involvement in learning in the presence of ␣1-adrenoceptor activation.…”

mentioning

confidence: 99%

β1-Adrenoceptor or α1-adrenoceptor activation initiates early odor preference learning in rat pups: Support for the mitral cell/cAMP model of odor preference learning

Harley¹,

Darby‐King²,

McCann³

et al. 2006

We proposed that mitral cell ␤1-adrenoceptor activation mediates rat pup odor preference learning. Here we evaluate ␤1-, ␤2-, ␣1-, and ␣2-adrenoceptor agonists in such learning. The ␤1-adrenoceptor agonist, dobutamine, and the ␣1-adrenoceptor agonist, phenylephrine, induced learning, and both exhibited an inverted U-curve dose-response relationship to odor preference learning. Phenylephrine-induced learning occurred in the presence of propranolol to prevent indirect activation of ␤-adrenoceptors. ␣1-Adrenoceptor mediation may represent a novel mechanism inducing learning or may increase cAMP in mitral cells via indirect activation of GABA B receptors. Neither the ␤2-adrenoceptor agonist, salbutamol, nor the ␣2-adrenoceptor agonist, clonidine, induced learning.Since initial ground breaking studies in Aplysia (for a review, see Pittenger and Kandel 2003) and later Drosophila (Yin and Tully 1996), there has been interest in the hypothesis that the cyclic adenosine monophosphate/protein kinase A/cyclic adenosine monophosphate response element binding protein (cAMP/PKA/ CREB) cascade might be a universal mechanism underlying learning and memory. In mammalian models there is also supporting evidence for such an assertion, but in adult rat models the associative pathways involved in recruiting cAMP activation in learning are difficult to identify (Alberini 1999). The rat pup odor preference learning model offers an advantage in that respect as the role of ␤-adrenoceptor activation as an unconditioned stimulus is well established (Sullivan et al. 1989(Sullivan et al. , 1991aSullivan and Wilson 1991;Langdon et al. 1997), and more recently, a causal role for cAMP in this form of associative learning has been demonstrated .In 2003, we proposed that early odor preference learning in the week-old rat pup induced by pairing a novel odor with tactile stimulation (stroking), or with injection of the nonselective ␤-agonist isoproterenol, was mediated by the activation of ␤1-adrenoceptors on mitral cells that interacted with glutamatergic odor input to the same cells (Yuan et al. 2003b). This interaction was proposed to produce alterations in mitral cell connectivity that altered the pup's memory of, and preference for, the novel odor. We showed that ␤1-adrenoceptors are predominantly localized on mitral cells and that they are colocalized there with 5-HT 2A receptors (Yuan et al. 2003b), which facilitate learning by potentiating the cAMP response initiated by ␤1-adrenoceptors. We have also found that cAMP has a causal role in odor preference learning consistent with our hypothesis (Yuan et al. 2003a,b).All previous work with odor preference learning and ␤-adrenoceptor activation has used the nonselective ␤-adrenoceptor agonist isoproterenol. It has not been demonstrated that selective ␤1-adrenoceptor activation produces learning. Isoproterenol, infused directly into the olfactory bulb (Sullivan et al. 2000) or given systemically (Sullivan et al. 1991a;Langdon et al. 1997), induces odor preference learning when paired with a nov...