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

Abstract

Astronauts during interplanetary missions will be exposed to galactic cosmic radiation, including charged particles like 56Fe. Most preclinical studies with mature, “astronaut-aged” rodents suggest space radiation diminishes performance in classical hippocampal- and prefrontal cortex-dependent tasks. However, a rodent cognitive touchscreen battery unexpectedly revealed 56Fe radiation improves the performance of C57BL/6J male mice in a hippocampal-dependent task (discrimination learning) without changing performance in a striatal-dependent task (rule-based learning). As there are conflicting results on whether the female rodent brain is preferentially injured by or resistant to charged particle exposure, and as the proportion of female vs. male astronauts is increasing, further study on how charged particles influence the touchscreen cognitive performance of female mice is warranted. We hypothesized that, similar to mature male mice, mature female C57BL/6J mice exposed to fractionated whole-body 56Fe irradiation (3 × 6.7cGy 56Fe over 5 days, 600 MeV/n) would improve performance vs. Sham conditions in touchscreen tasks relevant to hippocampal and prefrontal cortical function [e.g., location discrimination reversal (LDR) and extinction, respectively]. In LDR, 56Fe female mice more accurately discriminated two discrete conditioned stimuli relative to Sham mice, suggesting improved hippocampal function. However, 56Fe and Sham female mice acquired a new simple stimulus-response behavior and extinguished this acquired behavior at similar rates, suggesting similar prefrontal cortical function. Based on prior work on multiple memory systems, we next tested whether improved hippocampal-dependent function (discrimination learning) came at the expense of striatal stimulus-response rule-based habit learning (visuomotor conditional learning). Interestingly, 56Fe female mice took more days to reach criteria in this striatal-dependent rule-based test relative to Sham mice. Together, our data support the idea of competition between memory systems, as an 56Fe-induced decrease in striatal-based learning is associated with enhanced hippocampal-based learning. These data emphasize the power of using a touchscreen-based battery to advance our understanding of the effects of space radiation on mission critical cognitive function in females, and underscore the importance of preclinical space radiation risk studies measuring multiple cognitive processes, thereby preventing NASA’s risk assessments from being based on a single cognitive domain.

Long-Term Sex- and Genotype-Specific Effects of 56Fe Irradiation on Wild-Type and APPswe/PS1dE9 Transgenic Mice

“…However, in a different study, we found that 0.10 Gy 56 Fe irradiation did not impair fear memory in male APP/PS1 mice 6 months after irradiation, though both males and females showed impairment on the novel object recognition test [20]. Of note, one recent study found that fractionated 56 Fe improved hippocampal-dependent memory but impaired striatal-dependent memory in female WT mice [41]. 56 Fe is one of many heavy ions that astronauts will encounter in space, and sex differences have been reported with other ion species as well.…”

Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity

“…1A ) underwent touchscreen behavioral testing 1 week post-surgery. Touchscreen experiments were performed between 08:00 to 14:00 during weekdays (Soler et al, 2021). As is standard in most rodent touchscreen experiments, mice were food restricted during touchscreen experiments.…”

“…General Touchscreen Training (prior to LDR) or "General TS Train" (Fig. 1A), consists of five stages (Whoolery et al, 2020;Soler et al, 2021): Habituation, Initial Touch, Must Touch, Must Initiate, and Punish Incorrect (PI). Methods for each stage are described in turn below.…”

“…Location Discrimination Reversal (LDR; program LD1 choice reversal v3; ABET II software, Cat #89546-6) tests the ability to discriminate 2 conditioned stimuli that are separated either by a large or small separation. The reversal component of LDR is used here and, as in classic LDR studies (Clelland et al, 2009;Oomen et al, 2013;Swan et al, 2014;Soler et al, 2021), is used to test cognitive flexibility. Taken together, LDR is a hippocampal-dependent task which allows assessment of both discrimination ability as well as cognitive flexibility.…”

Quantitative proteomic analytic approaches to identify metabolic changes in the medial prefrontal cortex of rats exposed to space radiation

“…Creative problem solving utilizes several executive functions involved in planning, organization, decision making, judgment, task monitoring, attention, hypothesis generation, abstract thinking, and cognitive flexibility (Stuss and Levine, 2002;Cato et al, 2004;Sue Baron, 2004;Spinella, 2005). Regrettably, ground-based rodent experiments suggest that exposure to ≤25 cGy of several SR ions (i.e., protons, 4 He, 16 O, 28 Si, 48 Ti and 56 Fe) impairs various aspects of executive function but primarily cognitive flexibility tasks (Britten et al, 2014;Davis et al, 2014;Parihar et al, 2015;Britten et al, 2018;Jewell et al, 2018;Parihar et al, 2018;Acharya et al, 2019;Britten et al, 2020a;Britten et al, 2020b;Whoolery et al, 2020;Britten et al, 2021a;Burket et al, 2021;Soler et al, 2021;Britten et al, 2022).…”