Energy Deposition leads to Impairment, Learning and memory

Modulating Factor 

Details 

Effects on the KER 

References 

 Drug 

PLX5622-1200ppm (PLX) diet that contains a CSF1-R (colony stimulating factor 1 receptor) inhibitor that induces depletion of microglia within 3 days. 

The PLX diet was able to rescue the short and long-term memory impairments due to radiation exposure. 

Krukowski et al., 2018b; Acharya et al., 2016 

Drug 

Fluoxetine treatment – an antidepressant that belongs to the selective serotonin reuptake inhibitor (SSRI) class. 

Fluoxetine was able to attenuate the learning and memory defects in mice that were subjected to radiation. 

Gan et al., 2019 

Genotype 

CCR2 (chemokine C-C motif receptor 2) knockout. CCR2 is involved in peripheral macrophage infiltration at the sites of injury in the CNS. 

CCR2 deficiency was able to prevent the cognitive impairments induced by cranial radiation as shown by improvements in the MWM test. 

Belarbi et al., 2013 

Drug 

Treatment with α-lipoic acid (LA) as it has antioxidant properties. 

LA-treated mice did not show any significant decline in spatial memory post-irradiation.  

Manda et al., 2007b 

Sex 

Male and female mice responded differently to NOR, three chamber social approach and open field task following irradiation. 

Male animals generally demonstrated memory impairment after irradiation. 

Krukowski et al., 2018a 

Drug 

Treatment with melatonin as it is involved in many physiological processes and has antioxidant properties.  

Pre-treatment with melatonin showed significant protection against impairment in learning ability. Melatonin was found to reduce the time taken to reach the goal in a Hebb-Williams maze compared to irradiation. 

Manda et al., 2007a 

Various modulating factors  

Commonly applied countermeasures include: 

• Those targeting the reduction of oxidative stress (ie. Pharmaceutical antioxidants, nutritional antioxidants) 

• Decreasing DNA damage (ie. Overexpression of BMI1 gene to accelerate DNA repair) 

• Enhancing cell survival (ie. Inhibition of p53-induced apoptosis) 

• Reducing inflammation (ie. Pharmaceutically blocking pro-inflammatory cytokine/chemokine signaling) 

• Limiting tissue damage and increasing repair (ie. Cell transplants) 

Various approaches to CNS radioprotection have been utilized as either primarily protective (administered prior to irradiation) or mitigative (administered after irradiation). These countermeasures have been found to limit the harmful effects of radiation exposure. 

Pariset et al., 2021 

Reference 

Experiment Description 

Result 

Hodges et al., 1998 

In vivo. Male Sprague-Dawley Rats were irradiated with X-rays at 0, 20 Gy or 25 Gy at 1.4 Gy/min. Rats were tested from 26 weeks to 44 weeks after irradiation using the T maze and water maze to assess working memory and brain damage induced by radiation. 

 Rats irradiated with 25 Gy, showed impairments in all tests and rats irradiated with 20 Gy were not as impaired in the water maze learning and had no impairment in water maze working memory. Rats irradiated with 20 Gy had significant impairment of working memory in the T-maze. 

Hall et al., 2004 

In vivo. A Swedish cohort study that analyzed military tests of learning ability, logical reasoning and spatial recognition of 2211 men 17-18 years after β-ray, 26Ra gamma ray or X-ray radiation for cutaneous hemangioma before the age of 18 months from 1930-1959. 

Test scores for concept discrimination and general instruction as well as technical comprehension decreased in a dose-dependent manner from 0 to 250 mGy. Spatial recognition did not significantly change. 

Acharya et al., 2016 

In vivo. C57Bl/6J mice were irradiated with 9 Gy X-rays and novel object recognition (NOR), OiP and FC were measured. The DI was calculated from exploration times in familiar and novel locations. Percent of time spent freezing was used to determine FC. 

The DI for NOR was 23 without irradiation and -13 with 9 Gy. The DI for OiP was 38 without irradiation and -3 with 9 Gy. Mice without irradiation spent 43% of the time frozen and mice with 9 Gy spent 19% of the time frozen during the context test. 

Belarbi et al., 2013 

In vivo. C57Bl/6J mice were irradiated with 10 Gy 137Cs gamma rays. NOR and MWM were used to determine learning and memory impairment. 

NOR did not show any significant differences between control and 10 Gy irradiated groups. In MWM, control mice traveled 246 cm to the hidden platform, while 10 Gy irradiated mice traveled 392 cm to the hidden platform. 

Bellone et al., 2015 

In vivo. Male B6C3F1/J mice were irradiated with 150 MeV protons at 0.5 Gy (1.5-2.5 Gy/min). A water maze was used to assess learning and memory. 

No changes were found initially during the water maze test, but irradiated mice took a 1.6-fold longer swim distance to reach the platform during the reversal learning phase. 

Britten et al., 2012 

In vivo. Wistar rats were irradiated with 125 kVp X-rays or 1 GeV/u 56Fe ions to study the effect of low dose exposure in the spatial learning ability of rats. Rats were tested 3 months after irradiation using the Barnes maze. 

13 Gy X-ray irradiated rats and rats exposed to all doses of 56Fe ions studied (0.2, 0.4 and 0.6 Gy)  demonstrated a higher relative escape latency of 1.8-fold and ~2.5-fold, respectively, compared to the control group. 

Britten et al., 2018 

In vivo. Wistar rats were exposed to heavy ions, 600 MeV/n 28Si. Attentional set shifting (ATSET) was used to assess various cognitive processes. 

28Si irradiation of rats significantly reduced their ability to complete simple discrimination. Rats exposed to 0.05 Gy, 0.15 Gy and 0.20 Gy had a lower percentage stage completion of simple discrimination compared to 0 Gy rats (60-70% completion compared to 90%). 0.15 Gy irradiated rats also had a lower completion rate of compound discrimination compared to 0 Gy rats. 

Lonart et al., 2012 

In vivo. Male Wistar rats were irradiated with 56Fe ions. ATSET test was used to assess simple and compound discrimination, reversal learning and set-shifting, among others. 

8 of 11 unirradiated rats completed all the paradigms, while only 2 of 11 irradiated rats (0.20 Gy) completed all the paradigms. Irradiated rats required more trial attempts to complete the simple discrimination stage compared to unirradiated rats. 

Forbes et al., 2014 

In vivo. Male FxBN rats were irradiated with X-rays at 40 Gy from 2 fractions of 5 Gy per week over 4 weeks (each fraction at 1.25 Gy/min). Learning and memory were assessed using NOR and NOL. 

40 Gy significantly reduced the DR of 3-month-old rats during NOR from 0.5 to 0.2. No changes in NOL were observed, and no changes at other ages were observed. 

Parihar et al., 2015 

In vivo. Male Thy1-EGFP transgenic mice were irradiated with charged particles (16O and 48Ti) at 600 MeV/amu (0.5 to 1.0 Gy/min). NOR and OiP tests were done to assess learning and memory. 

NOR: 

The control group DI was 39. The DI was 25 after 5 cGy 16O, 10 after 30 cGy 16O, 2 after 5 cGy 48Ti and -4 after 30 cGy 48Ti. 

OiP: 

The control group DI was 32. The DI was 29 after 5 cGy 16O, -4 after 30 cGy 16O, -8 after 5 cGy 48Ti and -3 after 30 cGy 48Ti. 

Parihar et al., 2016 

In vivo. Male Thy1-EGFP transgenic mice were irradiated with charged particles (16O and 48Ti) at 600 MeV/amu (0.05 to 0.25 Gy/min). NOR, OiP, TO and FE tests were done to assess learning and memory. Wistar rats were used in the ATSET test. 

Impairment in cognitive ability was observed at both 5 and 30 cGy. The impairment was typically greater in 48Ti than 16O. The DI was between 20 and 40 for all controls and was reduced to less than 0 after many of the different radiation treatments. 

Parihar et al., 2018 

In vivo. Male C57BL/6J mice were irradiated with 4He particles (400 MeV/n) at 5 cGy/min. Learning and memory were assessed using OiP, TO and FE. 

Cognitive tests showed impaired learning and memory at both 5 and 30 cGy (except FE which was only tested at 5 cGy). For example, control mice spent 2-fold more time exploring novel objects than familiar objects, while irradiated rats did not spend significantly different time exploring novel objects. Impairment at 30 cGy was not significantly different than at 5 cGy. 

Impey et al., 2016 

In vivo. Male C57BL/6J mice were irradiated with 600 MeV 56Fe ions at 0.1, 0.2 or 0.4 Gy and various dose rates from 0.25 to 0.36 Gy/min. NOR and a water maze were used to determine learning and memory ability. 

Transiently, mice with 0.1 and 0.4 Gy spent more time exploring the familiar object and less exploring the novel object. No differences were observed in the water maze test. 

Jewell et al., 2018 

In vivo. Male Wistar rats were irradiated with 56Fe particles (600 MeV/n) at 1 and 3 cGy (2 cGy/min), or 5, 10 and 15 cGy (5 cGy/min). ATSET was performed to assess various cognitive processes. 

At every dose, the number of attempts for CD was significantly increased, with a maximum of 2-fold. Various doses were also able to significantly increase the number of attempts for SD, CD reversal  and intra-dimensional shifting (IDS). Significant increases in time to complete the test were sparse. However, doses of 3 cGy and above showed nonsignificant increases in latency in almost all tests. 

Krukowski et al., 2018b 

In vivo. C57BL/6J wild type mice were exposed to alpha particles at 0, 15, 50 or 100 cGy (16.37 cGy/min). NOR was used as an assay for behavioral analysis at 90 days post-irradiation. 

After 50 cGy exposure, animals spent  similar time exploring the familiar and novel object, indicating memory impairment. 

Krukowski et al., 2018a 

In vivo. Male and female C57BL/6J wild type mice were exposed to 0, 15 or 50 cGy of GCR simulator (2.54 cGy/min). NOR assay was used to study recognition memory. A three-chamber social approach task determined social behavior and social memory. 

NOR: 

Male mice demonstrated memory impairment when exposed to 15 or 50 cGy. 

Three-chamber social approach task: 

Male mice exposed to 50 cGy showed impairments in social memory compared to the 15 cGy group.  

Kiffer et al., 2019a 

In vivo. Female C57BL/6 mice were irradiated with 16O particles (600 MeV/n) at 0.1 or 0.25 Gy (18 to 33 cGy/min). A Y-maze was performed to measure spatial memory and NOR was performed to measure non-spatial declarative memory. 

Y-maze: 

No changes were observed in irradiated mice. 

NOR: 

The DR was 22 for the control, -2 for 0.1 Gy and -5 for 0.25 Gy. Both changes were significant. 

Manda et al., 2007a 

In vivo. Male Swiss albino mice were irradiated with 6 Gy 60Co gamma rays. Hebb-Williams maze was used to measure learning ability and spatial working memory continuously for 30 days after radiation exposure. 

Irradiated mice took approximately 8 times longer to reach their goals and their learning ability declined after radiation exposure compared to controls and mice pre-treated with melatonin. 

Rabin et al., 2012 

In vivo. Male Fischer 344 rats were irradiated with various doses (50 to 100 cGy/min) of 56Fe particles (1000 MeV/n). Operant responding was used to test cognitive function. Rats were trained to press a lever to receive food at various reinforcement schedules. 

Doses of 25, 50, 150 and 200 cGy influenced cognitive function. However, there was no significant trend related to dose. 

Rabin et al., 2014 

In vivo. Male Sprague-Dawley rats were irradiated with various types of ionizing radiation (5 to 100 cGy/min so the time did not exceed 3 to 4 mins). LET ranged from 0.22 (protons) to 181 (56Fe) keV/µM. The dose ranged from 0.1 to 200 cGy. The radiation types used were 16O (600 and 1000 MeV/n), 12C (290 MeV/n), 28Si (380, 600 and 1000 MeV/n), 48Ti (1100 MeV/n), 56Fe (600 MeV/n) and protons (1000 MeV/n). NOR was performed to assess learning and memory. 

In most particles studied, a lower or equal dose to that of younger rats was needed to disrupt NOR and cognitive performance in older rat subjects. Recognition memory performance was disrupted by a dose 10% - 50% less in older rats than younger rats. Older rats irradiated with 380 MeV/n 28Si particles showed a recognition memory disruption at a lower dose (0.005 Gy in older rats compared to 0.1 Gy in younger rats). Whereas higher dose was necessary to disrupt recognition memory in older rats exposed to 1000 MeV/n 28Si particles compared to the younger rats (0.5 Gy in older rats compared to 0.25 Gy in younger rats). Following 28Si radiation, memory was impaired at every dose from 0.1 to 2 Gy. 

Rabin et al., 2015 

In vivo. Male Sprague-Dawley rats were irradiated with 56Fe particles (600 MeV/n, 12 keV/µm) at 25 cGy (25 cGy/min) or 16O particles (600 MeV/n, 189 keV/µm) at 5 cGy (5 cGy/min). NOR was performed to determine recognition learning and memory. 

56Fe and 16O both resulted in an equal time spent with the novel object during the memory NOR test. The NOR test did not show significant changes in learning ability. 

Reference 

Experiment Description 

Result 

Hall et al., 2004 

In vivo. A Swedish cohort study that analyzed military tests of learning ability, logical reasoning and spatial recognition of 2211 men 17- 18 years after β-ray, 6Ra gamma ray or X-ray radiation for cutaneous hemangioma before the age of 18 months from 1930-1959. 

Irradiation at 18 months old or less resulted in significantly reduced concept discrimination and general instruction as well as technical comprehension test scores at 18 and 19 years of age. 

Hodges et al., 1998 

In vivo. Male Sprague-Dawley Rats were irradiated with X-rays at 0, 20 Gy or 25 Gy at 1.4 Gy/min. Rats were tested from 26 weeks to 44 weeks after irradiation using the T maze and water maze to assess working memory and brain damage induced by radiation. 

At 29 weeks post irradiation, no learning impairments were observed in the irradiated groups during the T-maze forced alteration task. At 35 weeks post irradiation, the mean percentage of correct responses changed from 80% to 65% in both groups during the T-maze testing. At 44 weeks after irradiation, rats exposed to 25 Gy showed working memory deficits assessed by the water maze test.  

Bellone et al., 2015 

In vivo. Male B6C3F1/J mice were irradiated with 150 MeV protons at 0.5 Gy (1.5-2.5 Gy/min). A water maze was used to assess learning and memory 3 and 6 months post-irradiation. 

No changes were observed in either test after 3 months. After 6 months, mice took a 1.6-fold longer distance to reach the platform. 

Britten et al., 2012 

In vivo. Wistar rats were irradiated with 125 kVp X-rays or 1 GeV/u 56Fe ions to study the effect of low dose exposure in the spatial learning ability of rats. Rats were tested for 3 days 3 months after irradiation using the Barnes maze. 

3 months after exposure to 13 Gy of X-rays, rats demonstrated increased escape latency. Rats exposed to 8 and 10 Gy of X-rays experienced similar escape latency as the 0 Gy group over 3 days. 

Rats exposed to 56Fe ion irradiation demonstrated increased relative escape latency throughout the 3-day testing periods at all doses (0.2, 0.4 and 0.6 Gy). 

Acharya et al., 2016 

In vivo. C57Bl/6J mice were irradiated with 9 Gy of X-rays and NOR, OiP and FC were measured 5 and 6 weeks post-irradiation. The discrimination index (DI) was calculated from exploration times in familiar and novel locations. Percent of time spent freezing was used to determine FC. 

5 to 6 weeks after irradiation, the DI for NOR and OiP were significantly reduced, and mice spent significantly less time frozen. 

Forbes et al., 2014 

In vivo. Male FxBN rats were irradiated with X-rays at 40 Gy from 2 fractions of 5 Gy per week over 4 weeks (each fraction at 1.25 Gy/min). Learning and memory were assessed using NOR and NOL at 3 and 18 months post-irradiation. 

Irradiation significantly reduced the DR of 3-month-old rats during NOR, from 0.5 to 0.2, 3 months after irradiation. No changes in NOL were observed, and no changes at other ages and timepoints were observed. 

Parihar et al., 2015 

In vivo. Male Thy1-EGFP transgenic mice were irradiated with charged particles (16O and 48Ti) at 600 MeV/amu (0.5 to 1.0 Gy/min). NOR and OiP tests were done to assess learning and memory 6 weeks after irradiation. 

After 6 weeks, impairment in cognitive ability was observed. The impairment was greater in 48Ti than 16O and greater in 30 cGy than 5 cGy. 

Parihar et al., 2016 

In vivo. Male Thy1-EGFP transgenic mice were irradiated with charged particles (16O and 48Ti) at 600 MeV/amu (0.05 to 0.25 Gy/min). NOR, OiP, TO and FE tests were done to assess learning and memory after 12 and 24 weeks. Wistar rats were used in the ATSET test. 

Cognitive ability was lower after 24 weeks than 12 weeks in mice, but radiation was able to reduce the DI in tests at both time points. 

Parihar et al., 2018 

In vivo. Male C57BL/6 J mice were irradiated with 4He particles (400 MeV/n) at 5 cGy/min. Learning and memory were assessed using OiP and TO 6, 15 and 52 weeks after irradiation. FE was assessed 1 year after irradiation. Water maze was performed 1 year following radiation. 

Learning and memory were significantly attenuated at all time points tested using all tests. 

Impey et al., 2016 

In vivo. Male C57BL/6J mice were irradiated with 600 MeV 56Fe at 0.1, 0.2 and 0.4 Gy and various dose rates from 0.25 to 0.36 Gy/min. NOR and a water maze were used to determine learning and memory ability 2 and 20 weeks post-irradiation. 

Some mice at 2 weeks spent more time exploring the familiar object and less exploring the novel object. No differences were observed after 20 weeks in NOR or in the water maze test after either time point. 

Krukowski et al., 2018b 

In vivo. C57BL/6J wild type mice were exposed to alpha particles at 0, 15, 50 or 100 cGy (16.37 cGy/min). NOR was used as an assay for behavioural analysis at 90 days post-irradiation. 

At late time points (90 + days post alpha exposure) mice exposed to either 15 or 50 cGy of alpha particles exhibited deficits in recognition memory as they were unable to distinguish the novel and familiar objects. 

Krukowski et al., 2018a 

In vivo. Male and female C57BL/6J wild type mice were exposed to 0, 15 or 50 cGy of GCR simulator (2.54 cGy/min). NOR assay was used to study recognition memory. A three-chamber social approach task determined social behavior and social memory. 

At 45 days post-exposure, male mice exposed to 50 cGy of GCR showed significant impairments in social memory in the three-chamber social approach task compared to the 15 cGy group. NOR test revealed that radiation-induced recognition memory impairments in male cohorts only at 15 and 50 cGy. 

Kiffer et al., 2019a 

In vivo. Female C57BL/6 mice were irradiated with 16O particles (600 MeV/n) at 0.1 or 0.25 Gy (18 to 33 cGy/min). A Y-maze was performed to measure spatial memory and NOR was performed to measure non-spatial declarative memory. 

After 270 days, NOR showed impaired memory. 

Irradiated mice at 0.1 and 0.25 Gy spent significantly more time exploring the novel object in the Y-maze, indicating no radiation-induced memory impairment. 

Lonart et al., 2012 

In vivo. Male Wistar rats were irradiated with 56Fe particles. ATSET test was used to assess simple and compound discrimination, reversal learning and set-shifting among others. 

8 of 11 unirradiated rats completed all the paradigms, while only 2 of 11 irradiated rats (0.2 Gy) completed all the paradigms 90 days post-irradiation. Irradiated rats required more trial attempts to complete the simple discrimination stage compared to unirradiated rats 90 days post-irradiation. 

Manda et al., 2007a 

In vivo. Male Swiss albino mice were irradiated with 6 Gy 60Co gamma rays. Hebb-Williams maze was used to measure learning ability and spatial working memory continuously for 30 days after radiation exposure. 

Time needed to reach the goal increased by 1.7-fold by day 30 after radiation, while in sham-irradiated control mice it decreased 0.2-fold in this time. 

Rabin et al., 2012 

In vivo. Male Fischer 344 rats were irradiated with various doses (50 to 100 cGy/min) of 56Fe particles (1000 MeV/n). Operant responding was used to test cognitive function. Rats were trained to press a lever to receive food at various reinforcement schedules. 

Tests done 2, 4, 5, 6, 7, 8, 10 and 15 months after irradiation showed decreased cognitive function compared to controls. However, no consistent changes across time points were shown.  

Rabin et al., 2014 

In vivo. Male Sprague-Dawley rats were irradiated with various types of ionizing radiation (5 to 100 cGy/min so the time did not exceed 3 to 4 mins). LET ranged from 0.22 (protons) to 181 (56Fe) keV/µM. The dose ranged from 0.1 to 200 cGy. The radiation types used were 16O (600 and 1000 MeV/n), 12C (290 MeV/n), 28Si (380, 600 and 1000 MeV/n), 48Ti (1100 MeV/n), 56Fe (600 MeV/n) and protons (1000 MeV/n). NOR was performed to assess learning and memory at various times. 

16O impaired NOR performance after 2 and 4 months, but not after 10 and 12 months. 12C showed impaired NOR performance after 11 months but not 1 month. 28Si radiation showed significantly impaired NOR performance at a few doses after 4, 5, 9, 10 and 13 months, with the lowest performance occurring at 9 months. 48Ti showed impairment at 7 and 17 months. 56Fe showed impairment at 3 and 12 months. Protons showed impairment at 4 and 13 months. 

Rabin et al., 2015 

In vivo. Male Sprague-Dawley rats were irradiated with 56Fe particles (600 MeV/n, 12 keV/µm) at 25 cGy (25 cGy/min) or 16O particles (600 MeV/n, 189 keV/µm) at 5 cGy (5 cGy/min). NOR was performed within 48 h to determine recognition learning and memory. 

56Fe and 16O both resulted in a 0.8-fold decrease in memory ability about 18 h after radiation. The NOR test did not show significant changes in learning ability measured about 48 h after radiation.