Several neurological diseases are associated with, or are the cause of, movement impairments; among them, spinal cord injury, multiple sclerosis, and spinal muscular atrophy are examples with analogous effects on anti-gravity muscles. Similarly, it is well known that prolonged space missions and extended bed-rest induce functional alterations in many organs of the human body, including modifications of skeletal neuromuscular function (Kakurin et al., 1972) due to anti-gravity muscle reduced activity.

While the relationship between physical activity and cognitive ability has been known for centuries, recent studies demonstrate the significant impact that voluntary physical activity exerts on neurogenesis (van Praag et al., 1999; Adami and Bottai, 2016). Voluntary physical activity can both produce a significant increase in the levels of proliferative progenitor cells and restore neurogenesis artificially altered in rodent models of muscle disuse/inactivity (Farioli-Vecchioli et al., 2014). Voluntary physical activity has also been shown to overcome the age-dependent depletion of hippocampal neurogenesis (van Praag et al., 2005). In contrast, there is relatively little information available about the effect of prolonged muscle disuse on neurogenesis per se; previous studies describe in vivo changes with little focus on the differentiation process (Yasuhara et al., 2007). Thus we currently lack a detailed in vitro study of the influence of muscle reduced activity on neural stem cells (NSCs) characteristics.

Adult neurogenesis is restricted to few areas of the mammalian brain: the sub-ventricular zone of the lateral ventricles (SVZ), where it can be detected by evaluating the proliferation capability (for instance using marker associated to the cell cycle progression such as Ki67) (Shen et al., 2008; Liu and Crews, 2017), the sub-granular zone of the dentate gyrus of the hippocampus and the spinal cord (Bottai et al., 2003).

The synergistic action of extrinsic and intrinsic factors in the microenvironment of neurogenic areas controls the fate of the NSCs and is able to adjust the balance between undifferentiated progenitor cells and newly differentiated cells (Bottai et al., 2003).

The knowledge of the determinants affecting neurogenesis in individuals with movement restrictions is of pivotal interest in the attempt to develop new strategies to reduce the negative central and peripheral impact of motor deprivation in immobile patients and in astronauts. The effects of prolonged motor restraint on neurogenesis and the role of trophic determinants involved in this phenomenon can be studied using a recognized rodent model of severe motor deprivation: the so-called hindlimb unloading (HU) mouse model (Morey et al., 1979; Desaphy et al., 2005) which reproduces the absence of weight support on hindlimbs. In the literature, only a few studies have shown alterations in the levels of nerve growth factor (NGF) mRNA and of the brain-derived neurotrophic factor (BDNF) in the somatosensory cortex, supporting the hypothesis that disuse regulates neurotrophic factor expression (Dupont et al., 2005). A change has also been demonstrated in learning ability and memory in rats subjected to anti-gravity (Sun et al., 2009). The central effects of HU condition include a significant decrease in hindlimb representation on the motor cortex of the rat (Langlet et al., 2012). By contrast, physical exercise such as running leads to cell cycle shortening in some progenitors, and the S-phase shortening represents a major intrinsic regulator of the proneurogenic effect in the hippocampus exerted by running (Farioli-Vecchioli et al., 2014).

Low levels of exercise are thought to represent a major risk factor of developing metabolic alteration (Laaksonen et al., 2002) that could affect the central nervous system and in particular some neurogenic areas (Bottai and Adami, 2013; Adami and Bottai, 2016). L-lactate is a common metabolite in mammals, its production occurs in all cells including neurons and glia, and lactate is used actively by brain cells in culture (Medina and Tabernero, 2005). Pyruvate is formed during glycolysis and part of it is converted into L-lactate by lactate dehydrogenase (LDH). This prompted us to study lactate production as a marker of the metabolic activity of NSCs.

Our studies provide a new line of experimental investigation that can complement previous works on the role of exercise in neurogenesis. Overall, our analysis indicates the importance of the role of movement on NSCs properties in vitro.

Our study adds more information for a better understanding of the role of movement reduction in NSCs features. It is known that physical inactivity is a risk factor for Alzheimer's disease (AD) (Hashimoto et al., 2017) since hippocampal atrophy was associated with the AD. In a recent meta-analysis, Guure and collaborators found that physical activity is more protective against AD than all the other forms of dementia (Guure et al., 2017).

Physical activity induces an increase in the hippocampal volume and ameliorates the neurogenesis (Bednarczyk et al., 2009) most likely via the augmentation of the blood flow (Cass, 2017). Consistently with this, the level of VEGF in the plasma of suspended rats decreases after 14 days of treatment, whereas it remains unaltered in the brain (Yasuhara et al., 2007) and in the soleus muscle (Wagatsuma, 2008). Long suspension (4 weeks) induced an inflammatory response in the common carotid artery of rats exposed to simulated microgravity, indicating that the inflammatory response may be a cellular mechanism that is responsible for the arterial remodeling during exposure to simulated microgravity (Liu et al., 2014). Prospective studies indicate that physical inactivity is one of the most frequent avoidable risk factors for developing AD. Moreover, elevated physical activity levels are associated with a lower risk of AD. The AD patient who undertook exercise training showed decreased neuropsychiatric symptoms, improvement in cognitive function, and a slower decline in the activities of daily life (Cass, 2017). After exercise AD patients regained some of their brain capabilities following appropriate and controlled physical training (Okonkwo et al., 2014).


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