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...
Cholinergic neuromodulation in the olfactory bulb has been hypothesized to regulate mitral cell molecular receptive ranges and the behavioral discrimination of similar odorants. We tested the effects of cholinergic modulation in the olfactory bulb of cannulated rats by bilaterally infusing cholinergic agents into the olfactory bulbs and measuring the rats' performances on separate spontaneous and motivated odor-discrimination tasks. Specifically, 6 microL/bulb infusions of vehicle (0.9% saline), the muscarinic antagonist scopolamine (7.6 mM and 38 mM), the nicotinic antagonist mecamylamine hydrochloride (3.8 mM and 19 mM), a combination of both antagonists, or the acetylcholinesterase inhibitor neostigmine (8.7 mM) were made 20 min prior to testing on an olfactory cross-habituation task or a rewarded, forced-choice odor-discrimination task. Spontaneous discrimination between chemically related odorants was abolished when nicotinic receptors were blocked in the olfactory bulb, and enhanced when the efficacy of cholinergic inputs was increased with neostigmine. Blocking muscarinic receptors reduced but did not abolish odor discrimination. Interestingly, no behavioral effects of modulating either nicotinic or muscarinic receptors were observed when rats were trained on a reward-motivated odor-discrimination task. Computational modeling of glomerular circuitry demonstrates that known nicotinic cholinergic effects on bulbar neurons suffice to explain these results.
Neurogenesis, the division, migration, and differentiation of new neurons, occurs throughout life. Brain derived neurotrophic factor (BDNF) has been identified as a potential signaling molecule regulating neurogenesis in the subventricular zone (SVZ), but its functional consequences in vivo have not been well defined. We report marked and unexpected deficits in survival but not proliferation of newly born cells of adult knock-in mice containing a variant form of BDNF [a valine (Val) to methionine (Met) substitution at position 66 in the prodomain of BDNF (Val66Met)], a genetic mutation shown to lead to a selective impairment in activity-dependent BDNF secretion. Utilizing knock-out mouse lines, we identified BDNF and tyrosine receptor kinase B (TrkB) as the critical molecules for the observed impairments in neurogenesis, with p75 knock-out mice showing no effect on cell proliferation or survival. We then localized the activated form of TrkB to a discrete population of cells, type A migrating neuroblasts, and demonstrate a decrease in TrkB phosphorylation in the SVZ of Val66Met mutant mice. With these findings, we identify TrkB signaling, potentially through activity dependent release of BDNF, as a critical step in the survival of migrating neuroblasts. Utilizing a behavioral task shown to be sensitive to disruptions in olfactory bulb neurogenesis, we identified specific impairments in spontaneous olfactory discrimination, but not general olfactory sensitivity or habituation to olfactory stimuli in BDNF mutant mice. Through these observations, we have identified novel links between genetic variant BDNF and adult neurogenesis in vivo, which may contribute to significant impairments in olfactory function.
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.
Odor identity is coded in spatiotemporal patterns of neural activity in the olfactory bulb. Here we asked whether meaningful olfactory information could also be read from the global olfactory neural population response. We applied standard statistical methods of dimensionality-reduction to neural activity from 12 previously published studies using seven different species. Four studies reported olfactory receptor activity, seven reported glomerulus activity, and one reported the activity of projection-neurons. We found two linear axes of neural population activity that accounted for more than half of the variance in neural response across species. The first axis was correlated with the total sum of odor-induced neural activity, and reflected the behavior of approach or withdrawal in animals, and odorant pleasantness in humans. The second and orthogonal axis reflected odorant toxicity across species. We conclude that in parallel with spatiotemporal pattern coding, the olfactory system can use simple global computations to read vital olfactory information from the neural population response.
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.
A number of electrophysiological experiments have shown that odor exposure alone, unaccompanied by behavioral training, changes the response patterns of neurons in the olfactory bulb. As a consequence of these changes, across mitral cells in the olfactory bulb, individual odors should be better discriminated because of previous exposure. We have previously shown that a daily 2-h exposure to odorants during 2 weeks enhances rats' ability to discriminate between chemically similar odorants. Here, we first show that the perception of test odorants is only modulated by enrichment with odorants that activate at least partially overlapping regions of the olfactory bulb. Second, we show that a broad activation of olfactory bulb neurons by daily local infusion of NMDA into both olfactory bulbs enhances the discrimination between chemically related odorants in a manner similar to the effect of daily exposure to odorants. Computational modeling of the olfactory bulb suggests that activity-dependent plasticity in the olfactory bulb can support the observed modulation in olfactory discrimination capability by enhancing contrast and synchronization in the olfactory bulb. Last, we show that blockade of NMDA receptors in the olfactory bulb impairs the effects of daily enrichment, suggesting that NMDA-dependent plasticity is involved in the changes in olfactory processing observed here. discrimination ͉ enrichment ͉ plasticity B ehavioral enrichment is thought to be a major modulator of animals' ability to learn behavioral tasks. It has been shown many times that an enriched environment during development dramatically increases animals' learning and memory abilities during adult life (1, 2). Enrichment during adult life can counteract learning disabilities due to absence of NMDA receptors in genetically modified mice (3), as well as the decrease in learning capabilities seen in older rodents (4,5). Most studies investigating the beneficial effects of enriched housing environments focus on complex learning tasks such as the Morris water maze (5-7) or the Hebb-Williams maze (8) that have been linked to hippocampal function (9-11). In contrast to previous studies, we here focus on sensory perception, a predeterminant of all learning tasks in animals. Using olfactory perception in rats, we have recently shown for the first time that sensory enrichment during a relatively short period improves animals' sensory discrimination capabilities in an odor-unspecific manner (12). Here, we show that the modulation of olfactory discrimination abilities due to daily enrichment with odorants arises in the first olfactory sensory structure, the olfactory bulb (OB). First, we show that enrichment only affects the perception of those odorants that activate at least partially overlapping regions of the OB, suggesting that nonspecific activation of OB neurons suffices to produce lasting changes in perception and that spatial specificity of odor responses is of importance in this process. Second, we show that unspecific activation of OB neurons via l...
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