Effects of motor deprivation on neurogenesis

Neurogenesis, that takes place during adulthood, allows, under physiological conditions, tissue homeostasis adapted to maintain a proper number of neurones, oligodendrocytes and astrocytes in specific areas of the Central Nervous System (CNS). The dentate gyrus (DG) of the hippocampus and the sub ventricular zone (SVZ) represent two neurogenic niches in rodents, and in pathological situations, they could have a reparative role, although somewhat limited. Numerous therapeutic efforts are aimed to strengthen and enhance their self- repair ability of these niches. It is well known that neurogenesis is stimulated by physical activity, which also restraints the decline that occurs with age or due to neurodegenerative diseases such as Alzheimer’s disease. On the contrary, there are indications that the absence or reduction of physical activity can have a negative role on neurogenesis. Severe motor activity limitation is a condition that characterises the patients bedridden for long periods of time, or suffering from neurodegenerative diseases determining muscle inactivity such as spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, spinal muscular atrophy, and is present even in the absence or reduction of gravity to which they are subjects, for example, the astronauts. In these situations, studies conducted so far mainly focused on the hippocampus. The purpose of this work is to study how marked muscular inactivity affects neurogenesis in SVZ and depict the factors that are involved in the interaction between the muscle and the neurogenic area. With this idea in mind we isolated neural stem cells from SVZ of animals subjected to a severe limitation on movement of the hind limbs (hindlimb unloaded, HU) and from animal control free in their movements (CTR) and studied stem cell characteristics such as proliferation, multipotency, self-renewal, cell cycle progression and gene expression. Parallel analysis of NSCs properties indicates that HU cells are differently responsive to growth factors stimulation resulting in a reduced proliferative capacity compared to CTR. Cell cycle progression shows an altered cell phase distribution and the increase in the fraction of apoptotic cells in HU NSCs. Even the capacity to differentiate into neurones and oligodendrocytes is different resulting, with a HU NSCs limited ability to generate differentiated cells. These results might reflect a profound and lasting change in growth factor and neurotrophins signalling in in vitro HU NSCs. Our attention is committed to study the mechanisms underlying these changes, as well as to determine inducing factors, analysing the expression of genes, that may constitute a trait d’union between muscle activity and NSC neurogenesis.