Immature olfactory sensory neurons provide behaviourally relevant sensory input to the olfactory bulb

Abstract

Postnatal neurogenesis provides an opportunity to understand how newborn neurons functionally integrate into circuits to restore lost function. Newborn olfactory sensory neurons (OSNs) wire into highly organized olfactory bulb (OB) circuits throughout life, enabling lifelong plasticity and regeneration. Immature OSNs can form functional synapses capable of evoking firing in OB projection neurons. However, what contribution, if any, immature OSNs make to odor processing is unknown. Indeed, because immature OSNs can express multiple odorant receptors, any input that they do provide could degrade the odorant selectivity of input to OB glomeruli. Here, we used a combination of in vivo 2-photon calcium imaging, optogenetics, electrophysiology and behavioral assays to show that immature OSNs provide odor input to the OB, where they form monosynaptic connections with excitatory neurons. Importantly, immature OSNs responded as selectively to odorants as mature OSNs. Furthermore, mice successfully performed odor detection tasks using sensory input from immature OSNs alone. Immature OSNs responded more strongly to low odorant concentrations but their responses were less concentration dependent than those of mature OSNs, suggesting that immature and mature OSNs provide distinct odor input streams to each glomerulus. Together, our findings suggest that sensory input mediated by immature OSNs plays a previously unappreciated role in olfactory-guided behavior.

Developing and maintaining a nose-to-brain map of odorant identity

“…Under constitutive, baseline conditions this map maintenance is rather successful, with only a few glomerular targeting errors occurring in later adult life [ 124 ]. Newly adult-generated immature OSNs can make functional synapses with OB cells to provide downstream circuits with specialized olfactory information [ 49 , 125 ], and this suggests that activity (and possibly synapse-dependent processes) might determine their glomerular targeting. Indeed, expressing tetanus toxin to block glutamate release from OSNs starting from postnatal day (P)21 produces diffuse axonal projections [ 106 ], while lowering spontaneous activity via Kir2.1 overexpression from P21 [ 106 ] or P30 [ 107 ] also leads to a loss of glomerular convergence and the emergence supernumerary glomeruli around after around a month.…”

Neurological Manifestations Associated with SARS-CoV-2 Invasion of the Autonomous Nervous System

“…The virus may also use the olfactory nerve as an alternative retrograde route to access the brain [40]. The olfactory sensory neurons (OSNs) of the olfactory epithelium, including immature neurons, project to the olfactory bulb [41]. From there, the virus can broadly spread within different brain areas as the primary projections of the olfactory bulb are the olfactory nucleus, olfactory tubercle, piriform cortex, the anterior part of the parahippocampal gyrus (entorhinal cortex) and the peri-amygdaloid cortex of the amygdala [42].…”

“…SARS-CoV-2 persistence and associated inflammation in the olfactory neuroepithelium may account for prolonged or relapsing symptoms of COVID-19 such as loss of smell. The way OSNs are infected by SARS-CoV-2 remains still unknown, but as horizontal basal cells are progenitors that continually divide to replace OSNs [55], it is possible that infected horizontal basal cells could produce newly formed OSNs infected by SARS-CoV-2, and by axonal transportation allow the virus to migrate from the sensory epithelium to the olfactory bulb [41], and from there spreads into further central targets [40] (Figure 1).…”

Rapid presynaptic maturation in naturally regenerating axons

“…Olfactory sensory neurons (OSNs) in the nasal olfactory epithelium project axons to the brain, where they terminate in the glomerular layer of the olfactory bulb (OB). After even widespread peripheral damage due to infection, inflammation, toxicity or injury, this entire nose-to-brain axonal projection is capable of natural regeneration throughout life, with OSN axons regrowing, re-connecting with postsynaptic OB neurons, and supporting the recovery of olfactory-driven behaviour (Blanco-Hernández et al, 2012; Cheung et al, 2013; Graziadei and Graziadei, 1979; Huang et al, 2021; Schwob et al, 2017). The re-establishment of the glomerular olfactory map during this process has been well described – overall, this can be very precise but is less accurate when the initial damage to the projection is more severe (Blanco-Hernández et al, 2012; Cheung et al, 2013; Christensen et al, 2001; Costanzo, 2000; Cummings et al, 2000; Gogos et al, 2000; St John et al, 2003).…”

“…The re-establishment of the glomerular olfactory map during this process has been well described – overall, this can be very precise but is less accurate when the initial damage to the projection is more severe (Blanco-Hernández et al, 2012; Cheung et al, 2013; Christensen et al, 2001; Costanzo, 2000; Cummings et al, 2000; Gogos et al, 2000; St John et al, 2003). We also know that, under non-injured conditions of ongoing constitutive replacement, immature OSN axon terminals can make highly dynamic, activity-dependent functional synaptic contacts with OB neurons (Cheetham et al, 2016; Huang et al, 2021). However, the functional presynaptic properties of re-connecting OSN axons remain entirely unstudied.…”