Life-long brain compensatory responses to galactic cosmic radiation exposure

Abstract

Galactic cosmic radiation (GCR) composed of high-energy, heavy particles (HZE) poses potentially serious hazards to long-duration crewed missions in deep space beyond earth’s magnetosphere, including planned missions to Mars. Chronic effects of GCR exposure on brain structure and cognitive function are poorly understood, thereby limiting risk reduction and mitigation strategies to protect against sequelae from exposure during and after deep-space travel. Given the selective vulnerability of the hippocampus to neurotoxic insult and the importance of this brain region to learning and memory, we hypothesized that GCR-relevant HZE exposure may induce long-term alterations in adult hippocampal neurogenesis, synaptic plasticity, and hippocampal-dependent learning and memory. To test this hypothesis, we irradiated 3-month-old male and female mice with a single, whole-body dose of 10, 50, or 100 cGy 56Fe ions (600 MeV, 181 keV/μm) at Brookhaven National Laboratory. Our data reveal complex, dynamic, time-dependent effects of HZE exposure on the hippocampus. Two months post exposure, neurogenesis, synaptic plasticity and learning were impaired compared to sham-irradiated, age-matched controls. By six months post-exposure, deficits in spatial learning were absent in irradiated mice, and synaptic potentiation was enhanced. Enhanced performance in spatial learning and facilitation of synaptic plasticity in irradiated mice persisted 12 months post-exposure, concomitant with a dramatic rebound in adult-born neurons. Synaptic plasticity and spatial learning remained enhanced 20 months post-exposure, indicating a life-long influence on plasticity and cognition from a single exposure to HZE in young adulthood. These findings suggest that GCR-exposure can persistently alter brain health and cognitive function during and after long-duration travel in deep space.

Multi-Domain Touchscreen-Based Cognitive Assessment of C57BL/6J Female Mice Shows Whole-Body Exposure to 56Fe Particle Space Radiation in Maturity Improves Discrimination Learning Yet Impairs Stimulus-Response Rule-Based Habit Learning

“…Two even more recent studies highlight that 56 Fe particle exposure can have seemingly beneficial effects on the mouse hippocampus, a brain region critical for memory and mood regulation. One study showed exposure to whole-body 56 Fe particle irradiation (IRR) improves hippocampal-dependent spatial learning 12 and 20 months (mon) post-IRR in male and female mice ( Miry et al, 2021 ). Another study exposed 6-mon-old (“astronaut-age”) male mice to whole-body 56 Fe particles ( Whoolery et al, 2020 ) and used a rodent touchscreen platform to probe the functional integrity of brain circuits ( Oomen et al, 2013 ; Hvoslef-Eide et al, 2016 ; Kangas and Bergman, 2017 ), drawing similarity to the way astronauts undergo touchscreen testing ( Basner et al, 2017 ; Moore et al, 2017 ).…”

Multi-domain touchscreen-based cognitive assessment of C57BL/6J female mice shows whole body exposure to 56Fe particle space radiation in maturity improves discrimination learning yet impairs stimulus-response habit learning

“…With these studies in mind, it is notable that touchscreen analysis of both female and male mice (of “astronaut age” at time of exposure) show 56 Fe IRR improves LDR (present results) or LD (Whoolery et al, 2020), respectively, vs. Sham exposure without influencing other cognitive domains (exceptions in female mice are discussed below). A third perspective on these data with 56 Fe IRR improving LDR in female mice is highlighted in recent work showing that the rodent brain has a compensatory, dynamic, time-dependent response to 56 Fe IRR (Miry et al, 2021). More longitudinal studies are needed to clarify the time course of the LDR “improvement” reported here in 56 Fe IRR female mice.…”

“…The mechanism underlying 56 Fe IRR-induced improvement in discrimination learning and decrement in rule-based learning is unknown, although the hippocampus and striatum, respectively, are linked to these functions (Clelland et al, 2009; McTighe et al, 2009; Horner et al, 2013; Oomen et al, 2013; Delotterie et al, 2015). Interestingly, a recent study reports 56 Fe IRR induced hippocampal cellular, synaptic, and behavioral plasticity 2-mon post-IRR normalizes 6-mon post-IRR, and is actually enhanced 12-mon post-IRR (Miry et al, 2021). Thus, we hypothesize that the improved hippocampal-dependent discrimination learning and decreased striatal-based habit learning shown here are due to dynamic and compensatory processes post-IRR that are brain-region specific.…”

“…Two even more recent studies highlight that 56 Fe particle exposure can have seemingly beneficial effects on the mouse hippocampus, a brain region intimately involved with memory and mood regulation. One study showed exposure to whole body 56 Fe particle irradiation (IRR) improves hippocampal-dependent spatial learning 12 and 20 mon post-radiation in male and female mice (Miry et al, 2021). Another study exposed 6-mon old (“astronaut-age”) male mice to whole body 56 Fe particles (Whoolery et al, 2020) and used a rodent touchscreen platform to probe the functional integrity of brain circuits (Oomen et al, 2013; Hvoslef-Eide et al, 2016; Kangas and Bergman, 2017), drawing similarity to the way astronauts undergo touchscreen testing (Basner et al, 2017; Moore et al, 2017).…”

“…Taken together, these studies suggest caution in concluding that HZE particle exposure decreases rodent cognition; the reality is likely that there are time-, task-, species-dose-, energy-, etc. dependent effects (Miry et al, 2021). In addition, these studies point out the importance - recently underscored for the space radiation field (Britten et al, 2021) - of measuring multiple cognitive processes in rodents, thereby preventing NASA’s risk assessments from being based on a single cognitive domain.…”