Perceptual learning is required for olfactory function to adapt appropriately to changing odor environments. We here show that newborn neurons in the olfactory bulb are not only involved in, but necessary for, olfactory perceptual learning. First, the discrimination of perceptually similar odorants improves in mice after repeated exposure to the odorants. Second, this improved discrimination is accompanied by an elevated survival rate of newborn inhibitory neurons, preferentially involved in processing of the learned odor, within the olfactory bulb. Finally, blocking neurogenesis before and during the odorant exposure period prevents this learned improvement in discrimination. Olfactory perceptual learning is thus mediated by the reinforcement of functional inhibition in the olfactory bulb by adult neurogenesis. discrimination ͉ mice ͉ enrichment ͉ olfactory bulb P erceptual learning is an implicit (nonassociative) form of learning in which discrimination between sensory stimuli is improved by previous experience (1). For instance, animals trained on a tactile discrimination task improve their behavioral performances and in parallel, the neural representation of the stimuli is sharpened (2, 3). In the olfactory modality, perceptual learning has been shown to occur in humans (4), and an experimental model of olfactory perceptual learning has recently been proposed in rats (5). Olfactory perceptual learning is crucial for basic olfactory functions because it sets the degree of discrimination between stimuli, and thus contributes to the perceptual representation of the environment, which guides the animal's behavior. However, neural mechanisms underlying such changes of perception remain elusive. We here show that a modulation of newborn cell survival in the olfactory bulb (OB) underlies olfactory perceptual learning. We show that neurogenesis is not only involved in, but necessary for perceptual learning to occur.We have shown that odor enrichment enhances rats' ability to discriminate between chemically similar odorants in a relatively odor-unspecific manner (5, 6). Indeed, the discrimination of a pair of similar odorants is improved by enrichment with the same odorants or with other odorants that activate regions of the OB partially overlapping with the regions activated by the discriminated pair. Even if the mechanisms underlying this learning remain unclear, it has been shown that infusions of NMDA into the OB improves odor discrimination in a manner similar to odor enrichment indicating that changes in OB processing contribute at least partially to the perceptual plasticity (5). A computational model proposed that activation of OB neurons produces widespread changes in inhibitory processing, which can underlie the observed improvement of odor discrimination (5). In support to this model, odor exposure has been shown to increase inhibition of mitral cells (7) and to increase the responsiveness of the inhibitory granule cells to odorants, as measured by expression of an immediate early gene (8).Inhibitory neuro...

Inhibitory interneurons of the olfactory bulb are subjected to permanent adult neurogenesis. Their number is modulated by learning, suggesting that they could play a role in plastic changes of the bulbar network associated with olfactory memory. Adult male C57BL/6 mice were trained in an associative olfactory task, and we analyzed long-term retention of the task 5, 30, and 90 d post-training. In parallel, we assessed the fate of these newborn cells, mapped their distribution in the olfactory bulb and measured their functional implication using the immediate early gene Zif268. In a second set of experiments, we pharmacologically modulated glutamatergic transmission and using the same behavioral task assessed the consequences on memory retention and neurogenesis. Finally, by local infusion of an antimitotic drug, we selectively blocked neurogenesis during acquisition of the task and looked at the effects on memory retention. First we demonstrated that retrieval of an associative olfactory task recruits the newborn neurons in odor-specific areas of the olfactory bulb selected to survive during acquisition of the task and that it does this in a manner that depends on the strength of learning. We then demonstrated that acquisition is not dependent on neurogenesis if long-term retention of the task is abolished by blocking neurogenesis. Adult-born neurons are thus involved in changes in the neural representation of an odor; this underlies long-term olfactory memory as the strength of learning is linked to the duration of this memory. Neurogenesis thus plays a crucial role in long-term olfactory memory.

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In the main olfactory bulb, stimuli are coded within the spatio-temporal pattern of mitral cells' activity. Granule cells are interneurons that shape the mitral cells' activity, and are continuously generated in the adult main olfactory bulb. However, the role of granule cell renewal remains elusive. We show here that an associative olfactory discrimination task reduces the survival of newborn neurons. However, when the olfactory task involves perceptually related odorants, the learning process is slower and does not induce such a reduction in the number of new neurons. Mapping newborn cells within the granule cell layer of the main olfactory bulb reveals a clustered distribution that evolves with learning as a function of odorant similarity and partly overlaps with the immediate-early gene Zif268 expression pattern. These data provide insight into the functional mechanisms underlying olfactory discrimination learning, and promote the importance of neurogenesis as a cellular basis for the restructuring of odor images in the main olfactory bulb.

Current antidepressants still display unsatisfactory efficacy and a delayed onset of therapeutic action. Here we show that the pharmacological blockade of serotonin 7 (5-HT 7 ) receptors produced a faster antidepressant-like response than the commonly prescribed antidepressant fluoxetine. In the rat, the selective 5-HT 7 receptor antagonist SB-269970 counteracted the anxiogenic-like effect of fluoxetine in the open field and exerted an antidepressant-like effect in the forced swim test. In vivo, 5-HT 7 receptors negatively regulate the firing activity of dorsal raphe 5-HT neurons and become desensitized after long-term administration of fluoxetine. In contrast with fluoxetine, a 1-week treatment with SB-269970 did not alter 5-HT firing activity but desensitized cell body 5-HT autoreceptors, enhanced the hippocampal cell proliferation, and counteracted the depressive-like behavior in olfactory bulbectomized rats. Finally, unlike fluoxetine, early-life administration of SB-269970, did not induce anxious/depressive-like behaviors in adulthood. Together, these findings indicate that the 5-HT 7 receptor antagonists may represent a new class of antidepressants with faster therapeutic action.

In humans, the pleasantness of odors is a major contributor to social relationships and food intake. Smells evoke attraction and repulsion responses, reflecting the hedonic value of the odorant. While olfactory preferences are known to be strongly modulated by experience and learning, it has been recently suggested that, in humans, the pleasantness of odors may be partly explained by the physicochemical properties of the odorant molecules themselves. If odor hedonic value is indeed predetermined by odorant structure, then it could be hypothesized that other species will show similar odor preferences to humans. Combining behavioral and psychophysical approaches, we here show that odorants rated as pleasant by humans were also those which, behaviorally, mice investigated longer and human subjects sniffed longer, thereby revealing for the first time a component of olfactory hedonic perception conserved across species. Consistent with this, we further show that odor pleasantness rating in humans and investigation time in mice were both correlated with the physicochemical properties of the molecules, suggesting that olfactory preferences are indeed partly engraved in the physicochemical structure of the odorant. That odor preferences are shared between mammal species and are guided by physicochemical features of odorant stimuli strengthens the view that odor preference is partially predetermined. These findings open up new perspectives for the study of the neural mechanisms of hedonic perception.

Commonly used experimental paradigms of environmental enrichment combine increased social interactions and sensory inputs and renewal of the objects present in the environment. However, the specific contribution of novelty to the effects of enrichment is unclear. Here, we show that repeated daily exposure to single novel odorants and not to an enriched but stable olfactory environment improves short-term olfactory memory and neurogenesis in the mouse olfactory bulb. In addition, these positive effects are mediated by noradrenalin as they are blocked by a noradrenergic receptor antagonist. These data suggest that novelty recognition and noradrenergic mechanisms are crucial in mediating neural plasticity induced by olfactory enrichment.

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