Late Effects of 1H + 16O on Short-Term and Object Memory, Hippocampal Dendritic Morphology and Mutagenesis

Abstract

The space extending beyond Earth's magnetosphere is subject to a complex field of high-energy charged nuclei, which are capable of traversing spacecraft shielding and human tissues, inducing dense ionization events. The central nervous system is a major area of concern for astronauts who will be exposed to the deep-space radiation environment on a mission to Mars, as charged-particle radiation has been shown to elicit changes to the dendritic arbor within the hippocampus of rodents, and related cognitive-behavioral deficits. We exposed 6-month-old male mice to whole-body 1 H (0.5 Gy; 150 MeV/n; 18-19 cGy/minute) and an hour later to 16 O (0.1Gy; 600 MeV/n; 18-33 Gy/min) at NASA's Space Radiation Laboratory as a galactic cosmic ray-relevant model. Animals were housed with bedding which provides cognitive enrichment. Mice were tested for cognitive behavior 9 months after exposure to elucidate late radiation effects. Radiation induced significant deficits in novel object recognition and short-term spatial memory (Y-maze). Additionally, we observed opposing morphological differences between the mature granular and pyramidal neurons throughout the hippocampus, with increased dendritic length in the dorsal dentate gyrus and reduced length and complexity in the CA1 subregion of the hippocampus. Dendritic spine analyses revealed a severe reduction in mushroom spine density throughout the hippocampus of irradiated animals. Finally, we detected no general effect of radiation on single-nucleotide polymorphisms in immediate early genes, and genes involved in inflammation but found a higher variant allele frequency in the antioxidants thioredoxin reductase 2 and 3 loci.

Life-long brain compensatory responses to galactic cosmic radiation exposure

“…Taken together, these results confirm that the proliferative niche of neural stem cells in the dentate gyrus of the hippocampus is highly susceptible to HZE-induced damage. Consistent with these findings, HZE-exposure also impairs hippocampus-dependent spatial learning and memory in rodents measured in the Morris Water Maze 14 , 15 , Barnes Maze 16 , 17 , novel object recognition test 18 , 19 , and contextual fear conditioning 10 , 20 up to three months post irradiation. Limoli and colleagues have shown that memory impairments in the novel object recognition task and fear conditioning in mice persist for 24 weeks after exposure to 48 Ti or 16 O ions 21 , and that the impairments in recognition memory persisted for a year after exposure to charge particles of 4 He 22 .…”

Effects of a 33-ion sequential beam galactic cosmic ray analog on male mouse behavior and evaluation of CDDO-EA as a radiation countermeasure

“…Whole-body exposure to 50cGy of monoenergetic protons decreased open field activity when assessed in males 9 months later (Kiffer et al, 2018b). However, a sequential 50cGy exposure to protons and 10cGy 16 O did not change open field behavior in male mice 9 months later (Kiffer et al, 2020). A 50cGy proton exposure has also been reported to decrease spatial memory and disrupt hippocampal signaling in male mice (Bellone et al, 2015; Lee et al, 2017; Rudobeck et al, 2017).…”

“…This may reflect the abundance of literature on object recognition testing, the higher radiosensitivity of the hippocampus (the brain region often linked to object recognition ability), or a combination of these (Kwak et al, 2016;Kiffer et al, 2019b). Prior work assessing hippocampus-dependent behavior following irradiation paradigms most similar to the 33-GCR we used here (50cGy of protons, 1hr break, 10cGy of 16 O) found radiation decreased object-dependent short-term spatial memory in male mice 3 and 9 months later, and decreased object memory 9 months later (Kiffer et al, 2018a(Kiffer et al, , 2020. It is therefore notable that here, we report no 33-GCR-induced changes in object recognition.…”

“…O did not change open field behavior in male mice 9 months later (Kiffer et al, 2020). A 50cGy proton exposure has also been reported to decrease spatial memory and disrupt hippocampal signaling in male mice (Bellone et al, 2015;Lee et al, 2017;Rudobeck et al, 2017).…”

Acute, Low-Dose Neutron Exposures Adversely Impact Central Nervous System Function

“…Past studies have well established that cognitive deficits arise following acute irradiation at mission-relevant doses (<0.5 Gy) [1] with protons [6][7][8] and 4 He [9][10][11], the most prevalent GCR components. Cognition also becomes negatively impacted by less abundant high atomic number, high energy (HZE), fully ionized nuclei GCR components including 16 O [12][13][14], 28 Si [15,16], 56 Fe [17][18][19] and some combined 2-3 ion exposures [8,[20][21][22][23]. Furthermore, we have previously demonstrated that low dose irradiation is sufficient to perturb neuronal intrinsic, synaptic and network properties, whether in response to protons [24,25], 4 He [9] or some of the most advanced GCR simulation yet with 5 combined ions [26].…”