New Neurons in the Postnatal Olfactory System: Functions in the Healthy and Regenerating Brain

Abstract

The rodent olfactory system is unique in harboring two distinct postnatal neurogenic niches, the olfactory epithelium and the subventricular zone. This results in the ongoing generation of both olfactory sensory neurons (OSNs), which provide odor input to the brain, and multiple molecularly distinct populations of GABAergic interneurons that modulate both input to and output from the olfactory bulb, continuing throughout life for some neuronal types. Here, we review the roles played by these postnatally generated neurons in olfactory processing, plasticity and regeneration. We identify specific roles for individual types of postnatally generated neurons, as well as identifying overarching principles that span multiple neuronal types.

Keywords: learning; olfactory epithelium; postnatal neurogenesis; regeneration; subventricular zone.

Figure 1

Overview of postnatal neurogenesis in the rodent olfactory epithelium (OE) and subventricular zone (SVZ). (A) Pseudostratified organization of the OE showing basal cells, immature and mature olfactory sensory neurons (OSNs). An axon fascicle projecting through the lamina propria to the OB is also shown. (B) In the healthy OE, globose basal cells (GBCs) generate immature OSNs, which migrate apically as they mature. Horizontal basal cells (HBCs) are typically quiescent but undergo cell division following large-scale OSN loss to replace OSNs and sustentacular cells. Markers are based on [5,6,10,20,21,22,23,24,25]. (C) Neural stem cells in the SVZ generate neuroblasts, which migrate via the rostral migratory stream (RMS) to reach the olfactory bulb (OB), where they migrate radially and differentiate into multiple molecularly defined subtypes of granule cells (GCs) and inhibitory juxtaglomerular neurons (JGNs). Inset: different regions of the SVZ generate distinct subclasses of postnatally born OB neurons [26]. (D) Schematic of cell types involved in postnatal SVZ neurogenesis. Created with BioRender. Modified from Figure 1 of [27].

Figure 2

Schematic of the nose to brain pathway for odor information in rodents. (A) OSNs located in the OE at the back of the nose project through the cribriform plate to the ipsilateral OB. The axons of OSNs expressing the same odorant receptor (OR) coalesce together to form glomeruli, thereby generating a highly organized odor input map to the OB. Note that only a single glomerulus per OR is shown here, whereas OSNs expressing each OR form on average two glomeruli per OB in mice. The inset on the right shows an expanded view of a glomerulus, containing OSN axons and dendrites of mitral/tufted cells and inhibitory JGNs. Note that glomeruli are compartmentalized into axodendritic and dendrodendritic domains [28]. Created with BioRender. (B) Schematic showing coronal view of the left side of the OE and left OB. The shading illustrates the classical zonal organization of the OE: OSNs expressing each OR are typically scattered within a single zone or longitudinal band of the OE [29,30,31]. Note, however, that not all ORs are restricted to a single zone; rather, expression domains for each OR are continuous and overlapping [32,33,34]. Nevertheless, projections from the OE to the OB are topographic, with the position of glomeruli along the dorsal to ventral axis of the OB corresponding to the location of OSNs along the dorsomedial to ventrolateral axis of the OE [33,35].

Figure 3

Cell types in the OSN lineage. The schematic shows markers expressed by OE basal cells and key OSN maturational stages, as well as the major functions of those genes. Markers are based on data from [7,9]. Created with BioRender.

Figure 4

Different experimental manipulations to reduce OSN sensory input to the OB result in differing degrees of recovery. (A) Techniques that cause irreversible damage to the OE (OSN axotomy, zinc sulfate and dichlobenil) or permanently block OSN sensory input to the OB (nasal cauterization). Recovery of OSN projections to the OB is limited or absent, resulting in significant olfactory deficits. See text for applications of these techniques. (B) Techniques that ablate OSNs but do not damage OE stem cells, enabling substantial OSN repopulation and regeneration of OSN projections to the OB. However, axonal targeting may be error prone. (C) OSNs immediately recover from optogenetic or chemogenetic silencing. Nasal plug removal restores sensory input to the OB after a period of naris occlusion. Chemogenetics schematic BioRender. Adapted from [106]. Figure created with BioRender.

Figure 5

Postnatally generated inhibitory neurons in the OB. The major postnatally born inhibitory JGN subtypes can be distinguished by their non-overlapping expression of the markers calretinin, calbindin and tyrosine hydroxylase. Postnatally born GCs are found in the mitral cell layer (MCL), internal plexiform layer (IPL) and granule cell layer (GCL). While there are some studies of GC subtypes that express specific molecular markers, there is considerable overlap between some markers, and most studies have focused on the postnatally generated GC population as a whole. Partially created with BioRender.