Mechanisms underlying activation of neural stem cells in the adult central nervous system

At the end of the 19th century, Dr. Ramón y Cajal, a scientific pioneer, discovered that the nervous system was composed of individual cellular elements, later called neurons. He also noticed the complexity of this system and mentioned the impossibility of new neurons to be integrated into the adult nervous system. One of his famous quotes: “In adult centers the nerve paths are something fixed, ended, immutable. Everything may die, nothing may be regenerated” is representative of the prevalent dogma at the time (Ramón y Cajal 1928). Key studies conducted in the 1960-1970s suggested a different point of view. It was demonstrated that new neurons could be born during adulthood, but this discovery created an omnipresent skepticism in the scientific community. It took 30 years for the concept of adult neurogenesis to become widely accepted. This discovery, along with more advanced techniques, opened doors to potential therapeutic avenues for neurodegenerative diseases. Adult neural stem cells (NSCs) reside mainly in two niches in the brain: the subventricular zone of the lateral ventricles and the dentate gyrus of the hippocampus. Under normal conditions, neurogenesis level is relatively high in the SVZ whereas some steps are rate-limiting in the hippocampus. In contrast, the spinal cord is rather defined as a quiescent environment. One of the main questions that arose from these discoveries is: how do you activate adult NSCs in order to increase neurogenesis levels? In the hippocampus, environmental enrichment (including cognitive stimulation, exercise and social interactions) has been shown to promote hippocampal neurogenesis. The plasticity potential of this region is important as it could play a crucial role in rescuing learning and memory deficits. In the spinal cord, studies conducted in vitro demonstrated that ependymal cells found around the central canal have self-renewal and multipotency capacities (neurons, astrocytes, oligodendrocytes). Interestingly, it turns out that in vivo, following a spinal cord lesion, ependymal cells become activated, can self-replicate, but can only give rise to glia cell fate (astrocytes and oligodendrocytes). This new post-injury function shows that plasticity can still occur in a quiescent environment and could be exploited to develop endogenous spinal cord repair strategies. v As mentioned above, NSCs play important roles in normal brain function and neural repair following injury. However, little information is known about how a quiescent NSC becomes activated in order to perform these functions. The general objective of this project was to investigate the mechanisms underlying activation of neural stem cells in the adult central nervous system. My specific aims were to address this question using adult mice in two complementary models: 1) activation of hippocampal NSCs by environmental enrichment, and 2) activation of spinal cord NSCs by injury-induced neuroinflammation. Moreover, 3) to gain new insights into the molecular mechanisms of these models, we will perform transcriptomics studies to open new lines of investigation. The first project is expected to provide us with new insights into the basic cellular and molecular mechanisms through which environmental enrichment modulates adult brain plasticity. We first evaluated the contribution of individual environmental enrichment components to hippocampal neurogenesis (Chapter II). Voluntary exercise promotes neurogenesis, whereas a social context increases neuronal activation. We then determined the effect of these components on behavioural performances and transcriptome using an eight-arm radial maze to assess spatial memory, novel object recognition, and RNA-Seq, respectively (Chapter III). Runners show stronger spatial short-term memory recall, whereas mice exposed to social interactions had a better cognitive flexibility to abandon old memory. Surprisingly, RNA-Seq analysis indicated clear differences in the expression of modified transcripts between low runners and high runners, as well as for social interacting mice (within the complex environment). The second project consists of discovering how ependymal cells acquire NSC properties in vitro or multipotentiality following lesions in vivo. A RNA-Seq analysis revealed that the transforming growth factor-β1 (TGF-β1) acts as an upstream regulator of significant changes following spinal cord injury (Chapter IV). We therefore confirmed the presence of this cytokine after lesion and investigated its role on proliferation, differentiation, and survival of neurosphere-initiating cells from the spinal cord. Our results suggest that TGF-β1 regulates the acquisition and expression of stem cell properties of spinal cord-derived ependymal cells.

Keyphrases: neuroinflammation, transforming growth factor-beta1, neural stem cells, adult neurogenesis, hippocampus, spinal cord, environmental enrichment, exercise, behaviour, neurosphere-initiating cells