Physical exercise restores adult neurogenesis deficits induced by simulated microgravity

Cognitive impairments are reported in astronauts during spaceflight and observed in ground-based SMG models. The neuronal mechanisms underlying these effects are largely unknown. Adult neurogenesis, crucial for memory, is a potential target. Previous research has shown SMG's impact on neurotransmission, monoamine distribution, hippocampal neuron morphology/electrophysiology, and hippocampal/cortical protein/gene expression, all potentially contributing to cognitive deficits. This study uses the hindlimb unloading (HU) model of SMG in rats to investigate the impact on adult neurogenesis in the DG and SVZ/OB, and evaluates physical exercise as a countermeasure, given its known beneficial effects on neurogenesis and mitigating microgravity's effects.

Studies using rodent models of simulated microgravity (SMG), primarily the hindlimb unloading (HU) model, have demonstrated various neurobiological and behavioral changes. These changes include modifications in neurotransmission, monoamine distribution, morphological and electrophysiological alterations in hippocampal neurons, and changes in protein and gene expression in the hippocampus and cerebral cortex. These alterations have been linked to cognitive deficits. While irradiation, social isolation, and impoverished environments are known to affect adult neurogenesis, the direct impact of microgravity remains understudied. In vitro studies show reduced proliferation, altered cell cycle, and incomplete differentiation/maturation in neural stem cells from HU mice. In vivo studies demonstrate reduced proliferating cells in the SVZ and DG after HU, but these were limited to proliferation and lacked investigation into survival and maturation.

Adult male Long-Evans rats were subjected to the HU model of SMG for varying durations (6 h, 24 h, 7 days, 21 days). EdU and/or BrdU were injected to label newborn cells. Proliferation and survival of newborn cells were assessed in the DG, SVZ, and OB using immunohistochemistry. Gene expression was analyzed using RT-qPCR and RNA-seq. A separate group of rats underwent a 3-week physical exercise regimen (treadmill) before and during 7-day SMG exposure to assess the countermeasure's effect. Physiological parameters (body weight, temperature, food/water intake, corticosterone levels) were monitored daily. Statistical analyses included unpaired t-tests, Mann-Whitney tests, ANOVA, and post-hoc tests as appropriate.

Seven days of SMG significantly reduced newborn cell proliferation in the DG, but not the SVZ. This effect was transient, not observed after 21 days of SMG. Short-term (7 days) but not long-term (21 days) survival of newborn cells was decreased in both the SVZ/OB and DG after SMG exposure. Physical exercise reversed the SMG-induced decrease in newborn cell survival in the SVZ and DG. RT-qPCR showed 25 genes downregulated after 7 days of SMG and 3 upregulated after 21 days in the hippocampus. RNA-seq analysis identified 20 genes involved in neurogenesis with altered expression in SMG rats. Physical exercise modulated gene expression in both CTL and SMG rats, but did not fully reverse the effects of SMG on gene expression. Physical exercise also improved weight recovery in control rats after EdU injections.

The study demonstrates a transient impairment of adult neurogenesis, primarily in the hippocampus, after SMG exposure. The findings suggest a period of adaptation of physiological systems to the new environment. The beneficial effect of physical exercise on adult neurogenesis supports its role as an effective countermeasure to mitigate the detrimental effects of SMG. The transient nature of the SMG effects on neurogenesis suggests potential compensatory mechanisms are activated after a prolonged period of microgravity. Further research is needed to explore the relationship between neurogenesis impairments and specific cognitive functions affected by microgravity.

Simulated microgravity transiently impairs adult neurogenesis, particularly in the hippocampus. Physical exercise serves as a promising countermeasure, restoring newborn cell survival. Future research should investigate the impact of SMG on neurogenesis during behavioral challenges and explore other contributing factors such as radiation and sex differences.

The study focused on male rats, limiting the generalizability to females. The HU model, while widely used, is not a perfect replica of actual microgravity. The transcriptomic analysis was limited to specific genes involved in neurogenesis, potentially missing broader effects of SMG on the brain. The sample size for some analyses could be considered relatively small, which might affect the statistical power.