Olfactory learning in humans leads to enhanced perceptual discrimination of odor cues. Examining mouse models of both aversive and appetitive conditioning, we demonstrate a mechanism which may underlie this adult learning phenomenon. Topographically unique spatial wiring of the olfactory system allowed us to demonstrate that emotional learning of odor cues alters the primary sensory representation within the nose and brain of adult mice. Transgenic mice labeled at the M71 odorant receptor (specifically activated by the odorant acetophenone) were behaviorally trained with olfactory-dependent fear conditioning or conditioned place preference using acetophenone. Odor-trained mice had larger M71-specific glomeruli and an increase in M71-specific sensory neurons within the nose compared with mice that were untrained, trained to a non-M71 activating odorant, or had nonassociative pairings of acetophenone. These data indicate that the primary sensory neuron population and its projections may remain plastic in adults, providing a structural mechanism for learning-enhanced olfactory sensitivity and discrimination.
Olfactory receptors (ORs) comprise more than half of the large class I G protein-coupled receptor (GPCR) superfamily. Although cloned over a decade ago, little is known about their properties because wild-type ORs do not efficiently reach the cell surface following heterologous expression. Receptor-receptor interactions strongly influence surface trafficking of other GPCRs, and we examined whether a similar mechanism might be involved in OR surface expression. Olfactory neurons are known to express -adrenergic receptors (ARs), and we found that coexpression with  2 -ARs, but not any other AR subtypes, dramatically increased mouse 71 (M71) OR surface expression in human embryonic kidney 293 cells. A persistent physical interaction between M71 ORs and 2-ARs was shown by coimmunoprecipitation and by cointernalization of the two receptors in response to their specific ligands. Also, coexpression of wild-type M71 ORs with 2-ARs resulted in cAMP responses to the M71 ligand acetophenone. Finally, in situ hybridization studies showed extensive colocalization of M71 OR and 2-AR expression in mouse olfactory epithelium. These data demonstrate the successful heterologous surface expression of a functional wild-type OR and reveal that persistent physical association with other GPCRs can control OR surface expression. P erception of smell begins with stimulation of olfactory receptors (ORs) on neurons within the olfactory epithelium, leading to excitation and propagation of currents to the main olfactory bulb (1, 2). ORs are class I G protein-coupled receptors (GPCRs) that signal through stimulation of G␣ olf , which leads to activation of type III adenylyl cyclase and opening of cAMPgated cation channels (3). Since the completion of the human and mouse genome sequencing projects, Ϸ350 receptors in humans (4) and Ϸ1,000 receptors in mice (5) have been identified, presumably to aid in the selective recognition of Ͼ100,000 different odors. However, the mechanism by which the olfactory system selectively recognizes specific odors remains unclear. It was initially hypothesized that each olfactory neuron expresses a single OR and that the axons of olfactory neurons expressing the same OR then converge in the main olfactory bulb (6, 7). However, increasing evidence suggests that detection is substantially more complex than previously thought. For example, olfactory neurons are not restricted to expression of a single OR subtype (8). In addition to ORs, olfactory neurons can express many other receptors, which facilitate modulation of olfactory responses by hormones and neurotransmitters. For example, epinephrine stimulation of endogenous -adrenergic receptors (ARs) modifies the signaling of coexpressed ORs within olfactory neurons (9). Furthermore, multiple OR subtypes can respond to the same ligand, a single OR can respond to multiple ligands (10-12), and structurally similar odorant ligands can act as either agonists or antagonists (13). Thus, as the complexity of the olfactory system becomes increasingly clear, the need t...
We examined brain-derived neurotrophic factor (BDNF) mRNA expression across the olfactory system following fear conditioning. Mice received 10 pairings of odor with footshock or equivalent unpaired odors and shocks. We found increased BDNF mRNA in animals receiving paired footshocks in the multiple regions examined including the posterior piriform cortex (PPC) and basolateral amygdala (BLA). This was in contrast to the unpaired and odor-alone treatments, where BDNF mRNA was increased in the olfactory bulb (OB) and anterior piriform cortex (APC) only, but not the higher olfactory areas. We propose that odor exposure increases expression of BDNF in the OB and APC while the PPC and BLA increase BDNF mRNA only when associative learning occurs.Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that has been shown to play a role in learning and memory (Tyler et al. 2002;Rattiner et al. 2005). Besides its neurotrophic activity, BDNF, working through its primary receptor TrkB, is involved in a number of downstream effects related to learning including long-term synaptic plasticity (Lohof et al. 1993;Korte et al. 1995), morphological changes in dendritic spines (Tyler and Pozzo-Miller 2003;Rex et al. 2007), gene transcription via CREB (Minichiello et al. 2002), and the recruitment of PSD-95 to the synapse (Yoshii and Constantine-Paton 2007).In the hippocampus, BDNF mRNA increases with hippocampal-dependent tasks such as the Morris Water Maze (Falkenberg et al. 1992) and contextual learning (Hall et al. 2000;Mizuno et al. 2000). Locally blocking the action of BDNF prevents learning in hippocampal-dependent tasks as shown by infusion of antisense BDNF oligonucleotides (Mizuno et al. 2000) and by regional knock-out of BDNF (Heldt et al. 2007). In the amygdala, expression of a truncated form of the TrkB receptor, which blocks the activity of the full-length receptor, blocks both the acquisition of a cued fear (Rattiner et al. 2004b) and extinction of fear (Chhatwal et al. 2006).Although many studies of BDNF in sensory systems have focused on its developmental role, few studies have linked BDNF to learning in the olfactory system, even though the olfactory system at multiple levels shows signs of learning-induced change, including LTP (Ennis et al. 1998;Lebel et al. 2001), dendritic spine plasticity (Knafo et al. 2001), and c-fos activation (Funk and Amir 2000;Schettino and Otto 2001;Illig 2007). In the olfactory system, BDNF is expressed in the olfactory bulb and piriform cortex, and is upregulated in these areas following kainic acid-induced seizures (Katoh-Semba et al. 1999). In slice preparations of the main olfactory bulb, BDNF has been shown to cause an increase in dendritic spines in granule cells (Berghuis et al. 2006). In the piriform cortex, deficits in BDNF have been linked to a decrease in dendritic spine number (Nanobashvili et al. 2005). BDNF is also essential to the differentiation of regenerating cells within the olfactory bulb (Benraiss et al. 2001).No study has yet investigated a...
Studies on olfactory receptor (OR) pharmacology have been hindered by the poor plasma membrane localization of most ORs in heterologous cells. We previously reported that association with the  2 -adrenergic receptor ( 2 -AR) facilitates functional expression of the OR M71 at the plasma membrane of HEK-293 cells. In the present study, we examined the specificity of M71 interactions with other G protein-coupled receptors (GPCRs). M71 was co-expressed in HEK-293 cells with 42 distinct GPCRs, and the vast majority of these receptors had no significant effect on M71 surface expression. However, co-expression with three subtypes of purinergic receptor (P2Y 1 R, P2Y 2 R, and A 2A R) resulted in markedly enhanced plasma membrane localization of M71. Agonist stimulation of M71 co-expressed with P2Y 1 R and P2Y 2 R activated the mitogen-activated protein kinase pathway via coupling of M71 to G␣ o . We also examined the ability of  2 -AR, P2Y 1 R, P2Y 2 R, and A 2A R to interact with and regulate ORs beyond M71. We found that coexpression of  2 -AR or the purinergic receptors enhanced the surface expression for an M71 subfamily member but not for several other ORs from different subfamilies. In addition, through chimeric receptor studies, we determined that the second transmembrane domain of  2 -AR is necessary for  2 -AR facilitation of M71 plasma membrane localization. These studies shed light on the specificity of OR interactions with other GPCRs and the mechanisms governing olfactory receptor trafficking.
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