Functional recovery of odor representations in regenerated sensory inputs to the olfactory bulb

Abstract

The olfactory system has a unique capacity for recovery from peripheral damage. After injury to the olfactory epithelium (OE), olfactory sensory neurons (OSNs) regenerate and re-converge on target glomeruli of the olfactory bulb (OB). Thus far, this process has been described anatomically for only a few defined populations of OSNs. Here we characterize this regeneration at a functional level by assessing how odor representations carried by OSN inputs to the OB recover after massive loss and regeneration of the sensory neuron population. We used chronic imaging of mice expressing synaptopHluorin in OSNs to monitor odor representations in the dorsal OB before lesion by the olfactotoxin methyl bromide and after a 12 week recovery period. Methyl bromide eliminated functional inputs to the OB, and these inputs recovered to near-normal levels of response magnitude within 12 weeks. We also found that the functional topography of odor representations recovered after lesion, with odorants evoking OSN input to glomerular foci within the same functional domains as before lesion. At a finer spatial scale, however, we found evidence for mistargeting of regenerated OSN axons onto OB targets, with odorants evoking synaptopHluorin signals in small foci that did not conform to a typical glomerular structure but whose distribution was nonetheless odorant-specific. These results indicate that OSNs have a robust ability to reestablish functional inputs to the OB and that the mechanisms underlying the topography of bulbar reinnervation during development persist in the adult and allow primary sensory representations to be largely restored after massive sensory neuron loss.

Distorted Coarse Axon Targeting and Reduced Dendrite Connectivity Underlie Dysosmia after Olfactory Axon Injury

“…However, these OSN axons formed small glomerular-like structures within the glomerular layer in the anterior part of the OB ( Fig. 1 F , G ), which is consistent with earlier studies performed with chemical lesions ( St John and Key, 2003 ; Cheung et al, 2014 ). Compared with the control, OSN axons tended to be scarcer in the posterior part of the dorsal OB ( Fig.…”

“…It has been demonstrated that the regenerated OSNs after injury are functional and respond to odors ( Cheung et al, 2014 ). However, the anatomy and odor responses in mitral cells have not been investigated so far.…”

“…For example, a single intraperitoneal injection of methimazole results in the loss of most (though not all) mature OSNs, but they can re-establish the correct glomerular map without any defects ( Blanco-Hernández et al, 2012 ). An injection of dichlobenil or the inhalation of methyl bromide causes more severe damage to OSNs, and regenerated OSN axons show mistargeting to the OB in the initial stage; however, in many cases, the glomerular map is largely recovered after a sufficient recovery period ( Schwob et al, 1999 ; St John and Key, 2003 ; Carr et al, 2004 ; Cheung et al, 2014 ). In contrast, the glomerular map was poorly recovered when OSNs were injured by OSN axon transections ( Costanzo, 2000 ; Christensen et al, 2001 ).…”

Stem and progenitor cells of the mammalian olfactory epithelium: Taking poietic license

“…). Unlike other parts of the nervous system, the OE retains a lifetime capacity for wholesale anatomical and functional recovery after injury (Nagahara, ; Schultz, ; Graziadei, ; Monti Graziadei and Graziadei, ; Morrison and Costanzo, ; Schwob et al, ; Costanzo, ; Cummings et al, ; Christensen et al, ; Schwob, ; Iwema et al, ; Schwob and Costanzo, ; Cheung et al, ; Holbrook et al, ). This regenerative capacity implies the lifelong persistence of stem cells, i.e., cells that are able to progress through intermediate progenitor cell stages to generate all of the differentiated cell types of the epithelium, including neurons, and that maintain that tissue totipotency through unlimited self‐renewal (Schwob et al, ).…”

Odorant Receptors Signaling Instructs the Development and Plasticity of the Glomerular Map

“…It has been proven that, in a control olfactory environment, the number of M72 OSNs almost is reestablished and the formation and position of M72 glomeruli are very similar to control mice ( Figure 5(c) ; [ 10 ]). Likewise in another study it was shown that there is a recovery of the functional topography of odor representations in the OB after OE degeneration [ 73 ]. However, under chronic exposure to pure acetophenone for 35 days (from day 15 to day 45 after methimazole treatment), M72 glomeruli cannot be formed again; also there is an incorrect regional targeting of M72 axons, like the incursion into the anterior-medial region ( Figure 5(d) ).…”