Early survival factor deprivation in the olfactory epithelium enhances activity-driven survival

Abstract

The neuronal olfactory epithelium undergoes permanent renewal because of environmental aggression. This renewal is partly regulated by factors modulating the level of neuronal apoptosis. Among them, we had previously characterized endothelin as neuroprotective. In this study, we explored the effect of cell survival factor deprivation in the olfactory epithelium by intranasal delivery of endothelin receptors antagonists to rat pups. This treatment induced an overall increase of apoptosis in the olfactory epithelium. The responses to odorants recorded by electroolfactogram were decreased in treated animal, a result consistent with a loss of olfactory sensory neurons (OSNs). However, the treated animal performed better in an olfactory orientation test based on maternal odor compared to non-treated littermates. This improved performance could be due to activity-dependent neuronal survival of OSNs in the context of increased apoptosis level. In order to demonstrate it, we odorized pups with octanal, a known ligand for the rI7 olfactory receptor (Olr226). We quantified the number of OSN expressing rI7 by RT-qPCR and whole mount in situ hybridization. While this number was reduced by the survival factor removal treatment, this reduction was abolished by the presence of its ligand. This improved survival was optimal for low concentration of odorant and was specific for rI7-expressing OSNs. Meanwhile, the number of rI7-expressing OSNs was not affected by the odorization in non-treated littermates; showing that the activity-dependant survival of OSNs did not affect the OSN population during the 10 days of odorization in control conditions. Overall, our study shows that when apoptosis is promoted in the olfactory mucosa, the activity-dependent neuronal plasticity allows faster tuning of the olfactory sensory neuron population toward detection of environmental odorants.

The olfactory mucosa, first actor of olfactory detection, is sensitive to glucocorticoid hormone

“…Furthermore, variations in the amplitude of EOG signals do not always predict impact on sensory perception, as some studies show that increased OSN response is not necessarily accompanied by improved odorant detection. For example, we observed an increase in OM sensitivity in young rats treated with endothelin, but olfactory detection behaviour was reduced (Francois et al., ). Conversely, others have identified a reduction in EOG signal coupled with improved odorant detection in response to feeding‐related peptides, insulin and leptin (Savigner et al., ).…”

Variation in olfactory neuron repertoires is genetically controlled and environmentally modulated

“…Both types were marked by phosphorylation of the S6 ribosomal subunit, a feature of activated OSNs (Jiang et al, 2015), indicating that the differential expression is mediated by OSN subtype-specific olfactory stimulation. This may explain why very different conclusions were drawn from previous exposure studies on a small number of ORs (Cadiou et al, 2014, Cavallin et al, 2010, Francois et al, 2013, Watt et al, 2004). Short-term odor exposures (30 min to 24 hr) result in a temporary downregulation of activated OR mRNA (von der Weid et al, 2015), presumably as part of the olfactory adaptation process.…”

“…Therefore each strain of mouse, when housed in homogeneous groups, is exposed to a unique pre- and post-natal olfactory environment. As odor exposure alters the life-span of OSNs in an activity dependent manner (Francois et al, 2013, Santoro and Dulac, 2012, Watt et al, 2004), genetic variation could regulate OSN population dynamics either directly or indirectly, via odortype. We therefore devised an experiment to test and differentiate the influence of the olfactory environment from the genetic background.…”

“…Previous studies have shown that OSNs activated by their cognate ligands have increased life-span (Francois et al, 2013, Santoro and Dulac, 2012, Watt et al, 2004). With time, longer survival rates should translate into enrichment in the neuronal population, compared to those OSN types that are mostly inactive (Santoro and Dulac, 2012).…”

“…The main olfactory epithelium regenerates throughout the life of an animal. It has been suggested that activity-mediated mechanisms may shape the olfactory system by increasing OSN survival (Francois et al, 2013, Santoro and Dulac, 2012, Watt et al, 2004, Zhao and Reed, 2001), though other studies have found that the number of specific OSN subtypes decrease or are unaffected by odor-exposure (Cadiou et al, 2014, Cavallin et al, 2010). Each of these studies focused on one or two OSN subtypes and the odor exposure procedures varied significantly in frequency, persistence and length.…”