CRMP5 Regulates Generation and Survival of Newborn Neurons in Olfactory and Hippocampal Neurogenic Areas of the Adult Mouse Brain

The Collapsin Response Mediator Proteins (CRMPs) are highly expressed in the developing brain, and in adult brain areas that retain neurogenesis, ie: the olfactory bulb (OB) and the dentate gyrus (DG). During brain development, CRMPs are essentially involved in signaling of axon guidance and neurite outgrowth, but their functions in the adult brain remain largely unknown. CRMP5 has been initially identified as the target of auto-antibodies involved in paraneoplasic neurological diseases and further implicated in a neurite outgrowth inhibition mediated by tubulin binding. Interestingly, CRMP5 is also highly expressed in adult brain neurogenic areas where its functions have not yet been elucidated. Here we observed in both neurogenic areas of the adult mouse brain that CRMP5 was present in proliferating and post-mitotic neuroblasts, while they migrate and differentiate into mature neurons. In CRMP5−/− mice, the lack of CRMP5 resulted in a significant increase of proliferation and neurogenesis, but also in an excess of apoptotic death of granule cells in the OB and DG. These findings provide the first evidence that CRMP5 is involved in the generation and survival of newly generated neurons in areas of the adult brain with a high level of activity-dependent neuronal plasticity

Consolidation of an Olfactory Memory Trace in the Olfactory Bulb Is Required for Learning-Induced Survival of Adult-Born Neurons and Long-Term Memory

Background: It has recently been proposed that adult-born neurons in the olfactory bulb, whose survival is modulated by learning, support long-term olfactory memory. However, the mechanism used to select which adult-born neurons following learning will participate in the long-term retention of olfactory information is unknown. We addressed this question by investigating the effect of bulbar consolidation of olfactory learning on memory and neurogenesis. Methodology/Principal Findings: Initially, we used a behavioral ecological approach using adult mice to assess the impact of consolidation on neurogenesis. Using learning paradigms in which consolidation time was varied, we showed that a spaced (across days), but not a massed (within day), learning paradigm increased survival of adult-born neurons and allowed long-term retention of the task. Subsequently, we used a pharmacological approach to block consolidation in the olfactory bulb, consisting in intrabulbar infusion of the protein synthesis inhibitor anisomycin, and found impaired learning and no increase in neurogenesis, while basic olfactory processing and the basal rate of adult-born neuron survival remained unaffected. Taken together these data indicate that survival of adult-born neurons during learning depends on consolidation processes taking place in the olfactory bulb. Conclusion/Significance: We can thus propose a model in which consolidation processes in the olfactory bulb determine both survival of adult-born neurons and long-term olfactory memory. The finding that adult-born neuron survival durin

Involvement of Newborn Neurons in Olfactory Associative Learning? The Operant or Non-operant Component of the Task Makes All the Difference

International audienceNew neurons are continuously generated in the adult mammalian olfactory bulb. The role of these newborn neurons in olfactory learning has been debated. Blocking the addition of neurons has been reported either to result in memory alteration or to have no effect at all (Imayoshi et al., 2008; Breton-Provencher et al., 2009; Lazarini et al., 2009; Sultan et al., 2010). These discrepancies may have arisen from differences in the behavioral paradigms used: operant procedures indicated that neurogenesis blockade had substantial effects on long-term memory (Lazarini et al., 2009; Sultan et al., 2010) whereas other methods had little effect (Imayoshi et al., 2008; Breton-Provencher et al., 2009). Surprisingly, while operant learning is known to modulate the survival of new neurons, the effect of non-operant learning on newborn cells is unknown. Here we use mice to show that compared with operant learning, non-operant learning does not affect cell survival, perhaps explaining the current controversy. In addition, we provide evidence that distinct neural substrates at least partly underlie these two forms of learning. We conclude that the involvement of newborn neurons in learning is subtly dependent on the nature of the behavioral task

Newborn Neurons in the Olfactory Bulb Selected for Long-Term Survival through Olfactory Learning Are Prematurely Suppressed When the Olfactory Memory Is Erased

International audienceA role for newborn neurons in olfactory memory has been proposed based on learning-dependent modulation of olfactory bulb neuro-genesis in adults. We hypothesized that if newborn neurons support memory, then they should be suppressed by memory erasure. Using an ecological approach in mice, we showed that behaviorally breaking a previously learned odor-reward association prematurely suppressed newborn neurons selected to survive during initial learning. Furthermore, intrabulbar infusions of the caspase pan-inhibitor ZVAD (benzyloxycarbonyl-Val-Ala-Asp) during the behavioral odor-reward extinction prevented newborn neurons death and erasure of the odor-reward association. Newborn neurons thus contribute to the bulbar network plasticity underlying long-term memory

Acquisition of an olfactory associative task triggers a regionalized down-regulation of adult born neuron cell death

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Neurogenic correlates of an olfactory discrimination task in the adult olfactory bulb

International audienceIn 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

Alteration of olfactory perceptual learning and its cellular basis in aged mice

International audienceOlfactory perceptual learning reflects an ongoing process by which animals learn to discriminate odorants thanks to repeated stimulations by these odorants. Adult neurogenesis is required for this learning to occur in young adults. The experiments reported here showed that olfactory perceptual learning is impaired with aging and that this impairment is associated with a reduction of neurogenesis and a decrease in granule cell responsiveness to the learned odorant in the olfactory bulb. Interestingly, we showed that the pharmacological stimulation of the noradrenergic system using dexefaroxan mimics olfactory perceptual learning in old mice, which is accompanied by an increase of granule cell responsiveness in response to the learned odorant without any improvement in neurogenesis. We provide the first published evidence that, in contrast to young adult mice, the improvement of olfactory performances in old mice is independent of the overall level of neurogenesis. In addition, restoring behavioral performances in old mice by stimulation of the noradrenergic system underlies the importance of this neuromodulatory system in regulating bulbar network plasticity

Action of the Noradrenergic System on Adult-Born Cells Is Required for Olfactory Learning in Mice

International audienceWe have previously shown that an experience-driven improvement in olfactory discrimination (perceptual learning) requires the addition of newborn neurons in the olfactory bulb (OB). Despite this advance, the mechanisms which govern the selective survival of newborn OB neurons following learning remain largely unknown. We propose that activity of the noradrenergic system is a critical mediator providing a top-down signal to control the selective survival of newly born cells and support perceptual learning. In adult mice, we used pharmacological means to manipulate the noradrenergic system and neurogenesis and to assess their individual and additive effects on behavioral performance on a perceptual learning task. We then looked at the effects of these manipulations on regional survival of adult-born cells in the OB. Finally, using confocal imaging and electrophysiology, we investigated potential mechanisms by which noradrenaline could directly influence the survival of adult-born cells. Consistent with our hypotheses, direct manipulation of noradrenergic transmission significantly effect on adult-born cell survival and perceptual learning. Specifically, learning required both the presence of adult-born cell and noradrenaline. Finally, we provide a mechanistic link between these effects by showing that adult-born neurons receive noradrenergic projections and are responsive to noradrenaline. Based upon these data we argue that noradrenergic transmission is a key mechanism selecting adult-born neurons during learning and demonstrate that top-down neuromodulation acts on adult-born neuron survival to modulate learning performance

Olfactory perceptual learning requires action of noradrenaline in the olfactory bulb: comparison with olfactory associative learning

International audienceNoradrenaline contributes to olfactory-guided behaviors but its role in olfactory learning during adulthood is poorly documented. We investigated its implication in olfactory associative and perceptual learning using local infusion of mixed a1-b adrenergic receptor antagonist (labetalol) in the adult mouse olfactory bulb. We reported that associative learning, as opposed to perceptual learning, was not affected by labetalol infusions in the olfactory bulb. Accordingly, this treatment during associative learning did not affect the survival of bulbar adult-born neurons. Altogether, our results suggest that the noradrenergic system plays different parts in specific olfactory learning tasks and their neurogenic correlates