Morphological Diversity of Calretinin Interneurons Generated From Adult Mouse Olfactory Bulb Core Neural Stem Cells

Abstract

Neural stem cells (NSCs) in the olfactory bulb (OB) core can generate mature interneurons in the adult mice brain. The vast majority of these adult generated cells express the calcium-binding protein Calretinin (CalR), and they migrate towards different OB layers. However, these cells have yet to be fully characterized and hence, to achieve this we injected retroviral particles expressing GFP into the OB core of adult animals and found that the CalR+ neurons generated from NSCs mainly migrate to the granule cell layer (GCL) and glomerular layer (GL) in similar proportions. In addition, since morphology and function are closely related, we used three-dimensional imaging techniques to analyze the morphology of these adult born cells, describing new subtypes of CalR+ interneurons based on their dendritic arborizations and projections, as well as their localization in the GCL or GL. We also show that the migration and morphology of these newly generated neurons can be altered by misexpressing the transcription factor Tbr1 in the OB core. Therefore, the morphology acquired by neurons located in a specific OB layer is the result of a combination of both extrinsic (e.g., layer allocation) and intrinsic mechanisms (e.g., transcription factors). Defining the cellular processes and molecular mechanisms that govern adult neurogenesis might help better understand brain circuit formation and plasticity, as well as eventually opening the way to develop strategies for brain repair.

Cell type- and layer-specific plasticity of olfactory bulb interneurons following olfactory sensory neuron ablation

“…However, it seems unlikely that we labeled less than 0.8 % of the newly generated CR+ neurons that reached the GL by 7 days post-MMZ. Furthermore, OB core neurogenesis generates similar proportions of CR+ PGCs and GCs 36,37 , but GCL CR+ neuron density was not increased at 7 days post-MMZ. Hence, we concluded that enhanced neurogenesis could not account for the rapid increase in CR+ density in the GL and EPL following MMZ treatment.…”

“…The first possibility is enhanced integration of CR+ neurons in the GL and EPL. While 7 days is very short for new SVZ-derived neurons to reach the GL, with 90 % of newborn juxtaglomerular neurons retrovirally labeled in the RMS arriving after 7 days post-injection 64 , CR+ neurons are also generated in the OB core 36,37 , enabling them to reach the GL within 7 days. Indeed, we found a 2-fold increase in the density of newborn EdU+CR+ neurons in the GL and EPL at 7 days post-MMZ, suggesting that OB core neurogenesis may be upregulated.…”

“…PV+ neurons form dense reciprocal connections with mitral and tufted cell dendrites [30][31][32][33][34] and are thought to modulate OB output gain 32 ; hence, changes in their density could have an important impact on OB output. Finally, CR+ neurons were selected because they are the most abundant subtype of adult-born OB neurons 28,35 , comprise both PGC and granule cell (GC) populations, and are generated not only in the SVZ but also in the core of the OB itself and possibly the rostral migratory stream [36][37][38][39][40][41] .…”