The adult brain has a remarkable capacity to produce new neurons and glia which offers a lot promise for cell replacement therapies to treat devastating neurodegenerative diseases and brain trauma. Adult Neural Stem Cells (NSCs) are located in a specialized micro-environment and integrate multiple signals that maintain them in a quiescent state or that activate them to induce their proliferation.
Using live imaging approaches in freely behaving mice, we have recently shown that adult NSCs activation is regulated by day/night cycle and that NSCs quiescent and proliferative states are defined by different Ca2+ signatures. In vivo optogenetic manipulation of Ca2+ fluxes to mimic NSCs quiescent state, reversed their transition into proliferative state induced by constant daylight conditions (Gengathran al., 2021).
The drawing on the theme of “Beautiful day and night” shows that NSCs, (represented as leaves) are more likely to divide during the daylight period.The color of leaves during the night (blue) and day (orange) represents low and high intracellular Ca2+ levels, respectively, that are observed in active and quiescent NSCs. The mountains in the image background further illustrate the functional differences between active and quiescent NSCs, the latest presenting a higher Ca2+ event frequency and amplitude, as shown by the presence or higher and more numerous mountain peaks in the night part of the image. For more information see Gengathran al., 2021. Image by Mireille Massouh based on the proposal of Archana Gengatharan.
We are studying the molecular and cellular pathways that regulate long-ranging neuronal migration.We have previously shown that neuronal precursors use blood vessels for their faithful migration towards olfactory bulb. Not only neuroblasts use blood vessels as a physical scaffold, but they also receive molecular cues from the endothelial cells, such as BDNF, that foster their migration under physiological conditions (Snapyan et al., 2009) and following ischemia (Grade et al., 2013). Astrocytes control vasculature development in the developing migratory stream via VEGF signalling (Bozoyan et al., 2012). We have also shown that extracellular matrix molecule, tenascin-R regulates radial migration in the adult, but not perinatal olfactory bulb (David et al., 2013) and that dynamic interplay between autophagy and energy consumption is reguired for cell migration (Bressan et al., 2020; Bressan and Saghatelyan, 2020).
Video by Inessa Stanishevskaya
Once arrived into the olfactory bulb, neuronal precursors mature and integrate into the bulbar neuronal network. We are interested in the role of principal cells activity, as well as other bulbar cells, in the maturation and integration of adult-born neurons. We have found that principal cells' activity modulates early stages of maturation of adult-born interneurons, via activation of NMDA receptors (Breton-Provencher et al., 2014).
Using in vivo two-photon imaging, we have also uncovered a completely new form of structural plasticity in the adult olfactory bulb. We showed that mature spines of adult-born, but not pre-existing, neurons relocate over a few microns in the bulbar network in an activity-dependent manner. Spine relocation of adult-born neurons allows a fast reorganization of the bulbar network to odor-induced activity with functional consequences for odor information processing (Breton-Provencher et al., 2016).
Activity-dependent spine relocation is shown by the relocation of a spine from one mitral cell dendrite (green) to another. The activity-dependent release of glutamate and BDNF is indicated by the yellow cloud. For more information see Breton-Provencher et al., 2016. Image by Mireille Massouh at Massouh BioMedia.
Functional role of adult-born neurons
We combine morphological, electrophysiological and behavioral studies to understand the role of adult-born neurons in the bulbar network functioning and odor behavior. We have shown that ablation of adult-born neurons (Breton-Provencher et al., 2009) or modulation in the number of new cells in the olfactory bulb (David et al., 2013) affects bulbar network functioning and specific types of odor behavior.
We also aim at understanding what are specific properties that different subtypes of interneurons (Malvaut et al., 2017) and new neurons (Hardy et al., 2018) bring to the olfactory network and what is their role in the OB functioning and execution of selected olfactory behaviors.
Artistic representation of functionally distinct subtypes of granule cells in the adult olfactory bulb defined by the expression of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα). In Malvaut et al., 2017, we demonstrate that CaMKIIα-expressing neurons (green) receive weaker inhibitory input and are preferentially activated by olfactory stimulation as compared to their CaMKIIα–immunonegative counterparts (yellow). CaMKIIα-expressing granule cells are essential for discrimination of structurally similar odors represented on the image by lemons (yellow) and limes (green) on the dendritic tree of granule cells. Image by Frederic Cantin