Fifty years after the first humans stepped on the Moon, space faring nations have entered a new era of space exploration. NASA's reference mission to Mars is expected to comprise 1100 days. Deep space exploratory class missions could even span decades. They will be the most challenging and dangerous expeditions in the history of human spaceflight and will expose crew members to unprecedented health and performance risks. The development of adverse cognitive or behavioral conditions and psychiatric disorders during those missions is considered a critical and unmitigated risk factor. Here, we argue that spatial cognition, i.e., the ability to encode representations about self-to-object relations and integrate this information into a spatial map of the environment, and their neural bases will be highly vulnerable during those expeditions. Empirical evidence from animal studies shows that social isolation, immobilization, and altered gravity can have profound effects on brain plasticity associated with spatial navigation. We provide examples from historic spaceflight missions, spaceflight analogs, and extreme environments suggesting that spatial cognition and its neural circuitry could be impaired during long-duration spaceflight, and identify recommendations and future steps to mitigate these risks.
