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Space travel presents a number of environmental challenges to the central nervous system, including changes in gravitational acceleration that alter the terrestrial synergies between perception and action, galactic cosmic radiation that can damage sensitive neurons and structures, and multiple factors (isolation, confinement, altered atmosphere, and mission parameters, including distance from Earth) that can affect cognition and behavior. Travelers to Mars will be exposed to these environmental challenges for up to 3 years, and space-faring nations continue to direct vigorous research investments to help elucidate and mitigate the consequences of these long-duration exposures. This article reviews the findings of more than 50 years of space-related neuroscience research on humans and animals exposed to spaceflight or analogs of spaceflight environments, and projects the implications and the forward work necessary to ensure successful Mars missions. It also reviews fundamental neurophysiology responses that will help us understand and maintain human health and performance on Earth. [ABSTRACT FROM AUTHOR]