Exposures of brain tissue to ionizing radiation can lead to persistent deficits in cognitive functions and behaviors. However, little is known about the quantitative relationships between exposure dose and neurological risks, especially for lower doses and among genetically diverse individuals. We investigated the dose relationship for spatial memory learning among genetically outbred male Wistar rats exposed to graded doses of (56) Fe particles (sham, 5, 10, 15, and 20 cGy; 1 GeV/n). Spatial memory learning was assessed on a Barnes maze using REL3 ratios measured at three months after exposure. Irradiated animals showed dose-dependent declines in spatial memory learning that were fit by a linear regression (P for slope <0.0002). The irradiated animals showed significantly impaired learning at 10 cGy exposures, no detectable learning between 10 and 15 cGy, and worsened performances between 15 and 20 cGy. The proportions of poor learners and the magnitude of their impairment were fit by linear regressions with doubling doses of ∼10 cGy. In contrast, there were no detectable deficits in learning among the good learners in this dose range. Our findings suggest that genetically diverse individuals can vary substantially in their spatial memory learning, and that exposures at low doses appear to preferentially impact poor learners. This hypothesis invites future investigations of the genetic and physiological mechanisms of inter-individual variations in brain function related to spatial memory learning after low-dose HZE radiation exposures and to determine whether it also applies to physical trauma to brain tissue and exposures to chemical neurotoxicants. Environ. Mol. Mutagen. 57:331-340, 2016. © 2016 Wiley Periodicals, Inc.

Traditionally, the brain has been regarded as a relatively insensitive late-reacting tissue, with radiologically detectable damage not being reported at doses < 60 Gy. When NASA proposed interplanetary exploration missions, it was required to conduct an intensive health and safety evaluation of cancer, cardiovascular, and cognitive risks associated with exposure to deep space radiation (SR). The SR dose that astronauts on a mission to Mars are predicted to receive is ~300 mGy. Even after correcting for the higher RBE of the SR particles, the biologically effective SR dose (<1 Gy) would still be 60-fold lower than the threshold dose for clinically detectable neurological damage. Unexpectedly, the NASA-funded research program has consistently reported that low (<250 mGy) doses of SR induce deficits in multiple cognitive functions. This review will discuss these findings and the radical paradigm shifts in radiobiological principles for the brain that were required in light of these findings. These included a shift from cell killing to loss of function models, an expansion of the critical brain regions for radiation-induced cognitive impediments, and the concept that the neuron may not be the sole critical target for neurocognitive impairment. The accrued information on how SR exposure impacts neurocognitive performance may provide new opportunities to reduce neurocognitive impairment in brain cancer patients.

Prolonged deep space missions to planets and asteroids will expose astronauts to galactic cosmic radiation, comprised of low-linear energy transfer (LET) ionizing radiations, high-energy protons and high-Z and energy (HZE) particles, such as (56)Fe nuclei. In prior studies with rodents exposed to HZE particle radiation at doses likely to be encountered during deep space missions (<20 cGy) investigators reported impaired hippocampal-dependent neurocognitive performance and further observed substantial variation among the irradiated animals in neurocognitive impairment, ranging from no observable effects to severe impairment. These findings point to the importance of incorporating quantitative measures of interindividual variations into next generation risk assessment models of radiation risks on neurocognition. In this study, 269 male proven breeder Wistar rats were exposed to 1 GeV/n (56)Fe at doses of 0, 5, 10, 15 and 20 cGy, and tested for spatial memory performance on the Barnes maze at three months after exposure. The radiation response data were compared using changes in mean cohort performance and by the proportion of poor responders using the performance benchmark of two standard deviations below the mean value among the sham-irradiated cohort. Acute exposures to mission-relevant doses of 1 GeV/n (56)Fe reduced the mean spatial memory performance at three months after exposure (P < 0.002) and increased the proportions of poor performers, 2- to 3-fold. However, a substantial fraction of animals in all exposure cohorts showed no detectable change in performance, compared to the distribution of sham-irradiated animals. Our findings suggest that individualized metrics of susceptibility or resistance to radiation-induce changes in neurocognitive performance will be advantageous to the development of probabilistic risk assessment models for HZE-induced neurocognitive impairment.

Prolonged deep space missions to planets and asteroids will expose astronauts to galactic cosmic radiation (GCR), a mixture of low-LET ionizing radiations, high-energy protons and high-Z and energy (HZE) particles. Ground-based experiments are used to determine whether this radiation environment will have an effect on the long-term health of astronauts and their ability to complete various tasks during their mission. Emerging data suggest that mission-relevant HZE doses impair several hippocampus-dependent neurocognitive processes in rodents, but that there is substantial interindividual variation in the severity of neurocognitive impairment, ranging from no observable effects to severe impairment. While the majority of studies have established the effect that the most abundant HZE species (⁵⁶Fe) has on neurocognition, some studies suggest that the lighter ⁴⁸Ti HZE particles may be equally, if not more, potent at impairing neurocognition. In this study, we assessed the effect that exposure to 5-20 cGy 1 GeV/n ⁴⁸Ti had on the spatial memory performance of socially mature male Wistar rats. Acute exposures to mission-relevant doses (≤5 cGy) of 1 GeV/n ⁴⁸Ti significantly (P < 0.05) reduced the mean spatial memory performance of the rats at three months after exposure, and significantly (P < 0.015) increased the percentage of rats that have severe (Z score ≥ 2) impairment, i.e., poor performers. Collectively, these data further support the notion that the LET dependency of neurocognitive impairment may differ from that of cell killing.

The proposed deep space exploration to the moon and later to Mars will result in astronauts receiving significant chronic exposures to space radiation (SR). SR exposure results in multiple neurocognitive impairments. Recently, our cross-species (mouse/rat) studies reported impaired associative memory formation in both species following a chronic 6-month low dose exposure to a mixed field of neutrons (1 mGy/day for a total dose pf 18 cGy). In the present study, we report neutron exposure induced synaptic plasticity in the medial prefrontal cortex, accompanied by microglial activation and significant synaptic loss in the hippocampus. In a parallel study, neutron exposure was also found to alter fluorescence assisted single synaptosome LTP (FASS-LTP) in the hippocampus of rats, that may be related to a reduced ability to insert AMPAR into the post-synaptic membrane, which may arise from increased phosphorylation of the serine 845 residue of the GluA1 subunit. Thus, we demonstrate for the first time, that low dose chronic neutron irradiation impacts homeostatic synaptic plasticity in the hippocampal-cortical circuit in two rodent species, and that the ability to successfully encode associative recognition memory is a dynamic, multicircuit process, possibly involving compensatory changes in AMPAR density on the synaptic surface.

The Mars mission will result in an inevitable exposure to cosmic radiation that has been shown to cause cognitive impairments in rodent models, and possibly in astronauts engaged in deep space travel. Of particular concern is the potential for cosmic radiation exposure to compromise critical decision making during normal operations or under emergency conditions in deep space. Rodents exposed to cosmic radiation exhibit persistent hippocampal and cortical based performance decrements using six independent behavioral tasks administered between separate cohorts 12 and 24 weeks after irradiation. Radiation-induced impairments in spatial, episodic and recognition memory were temporally coincident with deficits in executive function and reduced rates of fear extinction and elevated anxiety. Irradiation caused significant reductions in dendritic complexity, spine density and altered spine morphology along medial prefrontal cortical neurons known to mediate neurotransmission interrogated by our behavioral tasks. Cosmic radiation also disrupted synaptic integrity and increased neuroinflammation that persisted more than 6 months after exposure. Behavioral deficits for individual animals correlated significantly with reduced spine density and increased synaptic puncta, providing quantitative measures of risk for developing cognitive impairment. Our data provide additional evidence that deep space travel poses a real and unique threat to the integrity of neural circuits in the brain.

This article summarizes a Symposium on Radiation risks of the central nervous system held virtually at the 67th Annual Meeting of the Radiation Research Society, 3-6 October 2021. Repeated low-dose radiation exposure over a certain period could lead to reduced neuronal proliferation, altered neurogenesis, neuroinflammation and various neurological complications, including psychological consequences, necessitating further research in these areas. Four speakers from radiation biology, genetics and epidemiology presented the latest data from their studies seeking insights into this important topic. This symposium highlighted new and important directions for further research on mental health disorders, neurodegenerative conditions and cognitive impairment. Future studies will examine risks of mental and behavioral disorders and neurodegenerative diseases following protracted radiation exposures to better understand risks of occupational exposures as well as provide insights into risks from exposures to galactic cosmic rays.

For missions beyond low Earth orbit to the moon or Mars, space explorers will encounter a complex radiation field composed of various ion species with a broad range of energies. Such missions pose significant radiation protection challenges that need to be solved in order to minimize exposures and associated health risks. An innovative galactic cosmic ray simulator (GCRsim) was recently developed at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL). The GCRsim technology is intended to represent major components of the space radiation environment in a ground analog laboratory setting where it can be used to improve understanding of biological risks and serve as a testbed for countermeasure development and validation. The current GCRsim consists of 33 energetic ion beams that collectively simulate the primary and secondary GCR field encountered by humans in space over the broad range of particle types, energies, and linear energy transfer (LET) of interest to health effects. A virtual workshop was held in December 2020 to assess the status of the NASA baseline GCRsim. Workshop attendees examined various aspects of simulator design, with a particular emphasis on beam selection strategies. Experimental results, modeling approaches, areas of consensus, and questions of concern were also discussed in detail. This report includes a summary of the GCRsim workshop and a description of the current status of the GCRsim. This information is important for future advancements and applications in space radiobiology.