Increase, Neural Remodeling leads to Impairment, Learning and memory

Modulating factor  

Details  

Effects on the KER  

References  

Sex 

Female mice 

Female mice were protected from the GCR-induced deficits in learning and memory and did not show changes in synapse levels 

Krukowski et al., 2018 

Antioxidant 

α-tocopherol 

Improved global cognitive ability, memory and executive function 

Hladik & Tapio, 2016 

Stem cells 

Human neural stem cell treatment 

Increased neurogenesis in the brain after radiation and improved learning and memory 

Hladik & Tapio, 2016 

Drug 

Ramipril (Angiotensin converting enzyme inhibitor) 

Mitigated neurodegeneration and prevented cognitive impairment 

Hladik & Tapio, 2016 

Drug 

Memantine (NMDA receptor antagonist) 

Reduced rate of memory decline after radiotherapy 

Bálentová & Adamkov, 2020 

Hypoxia 

Systemic hypoxia 

Systemic hypoxia reversed the effects of radiation on learning and memory 

Bálentová & Adamkov, 2020; Hladik & Tapio, 2016 

Reference 

Experiment Design 

Summary 

Acharya et al., 2019 

In vivo. Mice were irradiated with neutrons from a 252Cf source over 180 days at 1 mGy/day. Electrophysiological measurements were taken from CA1 pyramidal neurons to assess neuron integrity. NOR, OiP and FE were used to assess learning and memory. 

Spontaneous excitatory postsynaptic current (sEPSC) frequency decreased with a mean difference of approximately –0.81 Hz. Field excitatory postsynaptic potential (fEPSP) slopes also decreased in the dorsal hippocampus and cortical layer. 

Avoidance behavior was increased by 20 sec, time spent interacting was decreased by 10 sec, and the discrimination index in both NOR and object in place OiP were decreased by 19.  

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). In the medial prefrontal cortex, neuron integrity was measured through spine density, dendritic complexity and postsynaptic density protein 95 synaptic puncta, while NOR, OiP, TO and FE tests were done to assess learning and memory. Wistar rats were used in an attentional set-shifting (ATSET) test. 

Dendritic complexity and spine density were both decreased about 0.7-fold, while synaptic puncta were increased about 1.5-fold after both types of radiation at 0.05 and 0.3 Gy. Impairment in cognitive ability was observed at both 0.05 and 0.3 Gy. The impairment was typically greater in 48Ti than 16O. The correlation between the OiP DI and number of synaptic puncta was significant at 0.05 Gy 48Ti and 0.3 Gy 48Ti and 16O. The correlation between the OiP DI and number of dendritic spines was significant at 0.05 Gy 48Ti and 16O and 0.3 Gy 48Ti. 

Parihar et al., 2015 

In vivo. Thy1- EGFP transgenic mice were irradiated with 600 MeV/amu 16O and 48Ti particles (0.5-1 Gy/min). In the medial prefrontal cortex, neuron integrity was measured through spine density, dendritic complexity and postsynaptic density protein 95 synaptic puncta, while learning and memory was assessed with NOR and OiP. 

Dendritic complexity was decreased 0.6-fold, spine density decreased 0.5-fold and synaptic puncta increased 1.4-fold for both radiation types at 0.05 and 0.3 Gy. The DI for NOR and OiP was reduced dose- and particle size-dependently, decreasing from a control DI of 30-40 to DI < 0 after 0.3 Gy of 48Ti. The correlation between OiP DI and number of dendritic spines was significant with 0.3 Gy 48Ti.   

Krukowski et al., 2018 

In vivo. Male and female C57Bl/6J mice were irradiated with GCR (60% 252 MeV/n protons, 20% 249.3 MeV/n helium and 20% 594.4 MeV/n oxygen) at various doses. Neuronal integrity was measured through synaptic composition and number of synaptosomes. Memory was assessed through NOR. 

No changes were observed in female mice. Male mice showed a 0.9-fold decrease in the number of synaptosomes after 0.5 Gy. GluR1 (associated with hippocampal-dependent 

working memory) levels were decreased 0.8-fold. No changes in synapsin 1 and postsynaptic density protein 95 were observed. Recognition memory was reduced after 0.15 and 0.5 Gy irradiation in male mice, as irradiated mice did not spend significantly more time with the novel object. 

Raber et al., 2004 

In vivo. Male C57BL/6J mice were irradiated with 10 Gy of X-rays. Ki-67 positive (proliferating) and DCx positive (immature) cells were measured to assess neuron integrity. NOR, MWM and Barnes maze were used to assess learning and memory. 

Before cognitive testing, the number of Ki-67 and DCx positive cells each decreased by 95% after irradiation. In the Barnes maze, irradiated mice took a longer path to reach the escape tunnel and also made more errors than control mice. Irradiated mice showed no impairment during NOR and the MWM. 

Madsen et al., 2003 

In vivo. Adult male Wistar rats were irradiated with 3 Gy of 300 kVp X-rays (4.58 Gy/min). Neuron integrity was assessed using BrdU (thymidine analog) staining to show neurogenesis in the DG. Learning and memory was assessed using NOR, novel location recognition (NLR) and a water maze. 

At a dose of 3 Gy, BrdU-positive cells decreased from approximately 1750 to values too small to be observed when injected during the second block of irradiation. The place recognition test showed reduced time spent in the novel location to almost 50% in irradiated rats. NOR and the water maze did not show any changes in cognitive function.  

Akiyama et al., 2001 

In vivo. Male Fischer 344 rats were irradiated with 25 Gy of 10 MeV X-rays. Bodian and neurofilament (NF) staining were used to identify axons in the corpus callosum. MWM and a passive avoidance test were used to assess learning and memory. 

Rats irradiated with 25 Gy had fewer axons and took longer in each trial to reach the platform in the MWM, although not significantly. When the platform was removed, irradiated rats crossed the area where the platform was 0.6-fold fewer times than control rats. During passive avoidance, the retention time after a shock was also decreased 0.6-fold in irradiated rats.  

Hodges et al., 1998 

In vivo. Male Sprague–Dawley rats were irradiated with 250 kVp X-rays at 1.4 Gy/min. Histological analysis was performed to measure damage and necrosis in the fimbria-fornix, hippocampus and corpus callosum. Learning and memory were measured through a T-maze and water maze. 

At 20 Gy, there was no histological evidence of neural remodeling, while learning and memory were impaired. At 25 Gy, various necrotic areas were observed in the brain, while learning and memory were impaired. For example, irradiated rats at both 20 and 25 Gy showed 2-fold more errors in the T-maze. 

Rola et al., 2004 

In vivo. Male C57BL/6J mice were irradiated with X-rays at 1.75 Gy/min). Ki-67 positive (proliferating) and DCx positive (immature) cells were measured along with BrdU staining to assess neuron integrity in the subgranular zone. NOR, NLR, MWM, Barnes maze and passive avoidance learning were used to assess learning and memory. 

The number of Ki-67-positive and DCx-positive cells decreased linearly at 0, 2 and 5 Gy, then leveled off at 10 Gy, reaching reductions of 0.1-fold for Ki-67 and 0.3-fold for DCx. The number of BrdU-positive cells decreased by 70% after 5 Gy. Also, after 5 Gy in the MWM, irradiated mice spent 30% less time in the target quadrant compared to control mice, indicative of reduced memory retention. No changes were observed in NOR, NLR, Barnes maze and passive avoidance tests. 

Whoolery et al., 2017 

In vivo. Nestin-GFP male and female mice (C57BL/6J background) were irradiated with 300 MeV/n 28Si particles (linear energy transfer = 67 keV/µm) at 1 Gy/min. Stereological immunopositive cell counts were determined for BrdU, Ki-67 and DCx in the DG granule cell layer. FC was used to assess learning and memory. 

Ki-67-positive cells decreased 0.8-fold at 0.2 Gy and 0.4-fold at 1 Gy, which occurred in both males and females. BrdU-positive cells decreased by 0.8- and 0.7-fold at 1 Gy in males and females, respectively. DCx-positive cells decreased by 0.5-fold at 1 Gy in both sex groups. Small and nonsignificant decreases in BrdU- and DCx-positive cells occurred at 0.2 Gy. Mice exhibited a decrease in percentage freezing of 0.4-fold at 0.2 Gy in contextual FC. No changes in learning and memory were observed at 1 Gy. 

Howe et al., 2019 

In vivo. C57BL/6 mice were irradiated with heavy ions 16O (600 MeV/n) at 0.05 Gy. NOR was used to assess non-spatial declarative memory. Y-maze assessed short-term spatial memory of mice. Sholl analysis was performed to quantify the neurons in the hippocampus. The morphology and density of dendritic spines from the DG and dorsal CA1 and CA3 pyramidal neurons. Behaviour was evaluated 9 months after irradiation. 

Overall dendritic complexity in the DG decreased 0.59-fold, while overall dendrite density in the DG decreased 0.94-fold. 

Irradiated animals exhibited a 0.11-fold change in the discrimination ratio in NOR, as the irradiated group was unable to discriminate between the familiar and novel object, indicating cognitive impairment. 

Irradiated mice spent more time exploring the novel object than the familiar object in the Y-maze, indicating no impairment on short-term spatial memory.  

Achanta, Fuss & Martinez, 2009 

In vivo. Male Sprague Dawley rats were irradiated with 0.3, 3 or 10 Gy of X-rays. BrdU staining was used to assess neuronal proliferation. Changes in cognitive behavior was evaluated by FC/testing. Fear testing was performed at 90 days post-irradiation. 

At 3-months post-irradiation, total number of Ki67+ cells (proliferative marker for cells) decreased by 0.8-, 0.7-, and 0.3-fold in the PD 21 group; 0.8-, 0.7-, and 0.3-fold in the PD 50 group; and 0.9-, 0.083-, and 0.3-fold in the PD 70 group, at 0.3, 3, and 10 Gy, respectively.  

Total number of BrdU+ cells decreased by 0.7-, 0.4-, and 0.1-fold in the PD 21 group; 0.6-, 0.48-, and 0.03-fold in the PD 50 group; and 0.9-, 0.6-, and 0.04-fold in the PD 70 group, at 0.3, 3, and 10 Gy, respectively. 

% mean freezing in the PD 21 group in response to a conditioned stimulus (CS) decreased by 0.7- and 0.6-fold in the trace fear conditioning after 3 Gy and 10 Gy, respectively, and 0.7- and 0.6-fold with an intertrial interval (ITI) after 3 Gy and 10 Gy, respectively.  

% mean freezing in the PD 50 group in response to a CS decreased by 0.6-fold in trace fear conditioning after 10 Gy, and 0.6-fold with an ITI after both 0.3 and 10 Gy.  

% mean freezing in the PD 70 group in response to a CS decreased by 0.6-fold in trace fear conditioning and 0.6-fold with an ITI after 10 Gy. 

Winocur et al., 2006 

In vivo. Long-Evans rats were irradiated with 7.5 or 10 Gy of 60Co gamma rays. BrdU staining was used to label the DNA of proliferating cells. DCX as an immature neuron marker and NeuN for mature neuron staining were used. Cognitive impairment was identified by contextual FC in the studied rats 4 weeks after irradiation. 

Numbers of BrdU+ cells decreased by 0.2- and 0.2-fold after 10 and 7.5 Gy, respectively. Total number of DCX+ cells decreased by 0.03- and 0.10-fold, for 10 and 7.5 Gy, respectively. 

Times spent freezing in the irradiated context-only group were decreased by 0.1- and 0.4-fold at the short and long delays, respectively.  

Simmons et al., 2019 

In vivo. C57BL/6J mice were irradiated with 30 Gy electrons (16 and 20 MeV). Spatial and non-spatial object recognition was studied by object location and NOR 10 weeks after irradiation. Spine density was measured by Golgi-stained hippocampal neuron tracing using Neurolucida neuron tracing software and Neurolucida Explorer software (MBF Bioscience). 

Apical dendritic spine density decreased 0.8-fold in 30 Gy conventional irradiated (given over 240 s) mice. The discrimination index for NOR decreased from 23% to 8% after 30 Gy given conventionally. The discrimination index for NOL decreased from 12% to -8% after 30 Gy given conventionally. Conventionally irradiated mice spent significantly less time with the object in a new location, indicating impairment to hippocampus learning and memory. Irradiated mice spent less time exploring a novel object than control mice. No significant changes were observed when the 30 Gy was given over 0.1-0.16 s. 

Sorokina et al., 2021 

In vivo. Male mice were irradiated with accelerated carbon ions at 0.7 Gy (450 MeV/n). Spatial learning, short-term and long-term hippocampus-dependent memory were studied using Barnes Maze and NOR 2 months after irradiation. Nissl staining was performed 1 month after cognitive evaluations to quantify neuronal cells. 

Neuronal quantification revealed a decrease in the number of cells in irradiated mice by 0.9-fold in the DG. The length of the CA3c field of the dorsal hippocampus decreased by 0.89-fold. 

In the Barnes maze, the latency to the goal box was 3.1-fold higher in the irradiated mice than control on the 9th day after learning, indicating long-term decreased learning. NOR did not show any changes to learning and memory, shown through the 0.7 Gy irradiated mice spending significantly longer with the novel object.  

Miry et al., 2021 

In vivo. C57BL/6J mice were irradiated with 0.1, 0.5 and 1 Gy 56Fe. Active avoidance was used to study spatial learning and discrimination. Immunohistological analysis of proliferating neural cells were performed using DCX, an immature neural marker. Other tests performed included the Barnes Maze for spatial learning. Mice were studied at multiple time-points (2, 6, 12, and 20 months) post-exposure. 

2 months post-exposure, levels of DCX+ cells decreased by 0.7- (0.1 Gy), 0.4- (0.5 Gy) and 0.6-fold (1 Gy) in male mice, and 0.7- (0.1 Gy), 0.6- (0.5 Gy) and 0.4-fold (1 Gy) in female mice. 12 months post-exposure, levels of DCX+ cells increased by 2.6- (0.1 Gy), 2.4- (0.5 Gy), and 2.3-fold (1 Gy) in male mice, and 2.2- (0.1 Gy), 1.1- (0.5 Gy), and 2-fold (1 Gy) in female mice. 

In the active avoidance task, the normalized error entries significantly increased in both male and female 0.5 Gy irradiated mice compared to the 0 Gy group.  

In Barnes maze, male mice 20 months post-exposure to 1 Gy 56Fe showed a significant decrease in latency to escape. The most profound change was measured on day 2 with a 0.6-fold decrease in latency to escape, as the irradiated mice learned the location of the escape box faster than the control group over the 5-day training period. 

Reference 

Experiment Design 

Summary 

Parihar et al., 2016 

In vivo. Male Thy1-EGFP transgenic mice were irradiated with 600 MeV/amu charged particles (16O and 48Ti) (0.05 to 0.25 Gy/min) at 0.05 and 0.3 Gy. In the medial prefrontal cortex, neuron integrity was measured through spine density, dendritic complexity and postsynaptic density protein 95 synaptic puncta, while NOR, OiP, TO and fear extinction (FE) tests were done to assess learning and memory. Wistar rats were used in an ATSET test. 

Dendritic complexity and spine density were reduced 0.7-fold 15 weeks post-irradiation, while synaptic puncta were increased 1.3-fold 15 weeks post-irradiation and 1.5-fold 27 weeks post-irradiation. Learning and memory were impaired 15 weeks post-irradiation, and even further impaired 24 weeks post-irradiation. 

Raber et al., 2004 

In vivo. Male C57BL/6J mice were irradiated with 10 Gy of X-rays. Ki-67 positive (proliferating) and DCx positive (immature) cells were measured to assess neuron integrity. NOR, MWM and Barnes maze were used to assess learning and memory. 

Before cognitive testing (3 months post-irradiation), the number of Ki-67 and DCx positive cells each decreased by 95% after irradiation. In the Barnes maze, irradiated mice took a longer path to reach the escape tunnel and also made more errors than control mice 3 months after irradiation. Irradiated mice showed no impairment during NOR and the MWM. 

Madsen et al., 2003 

In vivo. Adult male Wistar rats were irradiated with 3 Gy of 300 kVp X-rays (4.58 Gy/min). Neuron integrity was assessed using BrdU (thymidine analog) staining to show neurogenesis in the DG. Learning and memory was assessed using NOR, NLR and a water maze. 

At a dose of 3 Gy, numbers of BrdU-positive cells (neurogenesis) decreased from approximately 1750 to values too low to be observed when injected during the second block of irradiation. BrdU-positive cells decreased from 1300 to 300 when injected 2 weeks after end of irradiation. BrdU-positive cells decreased from 1300 to 250 when injected 6 weeks after end of irradiation. The place recognition test showed impairments in irradiated animals as time in the new arm decreased from 72% to 62% at 1 week post-irradiation; and 67% to 54% at 3 weeks post-irradiation. After 7 weeks, rats showed impaired location memory but not significantly. 

Hodges et al., 1998 

In vivo. Male Sprague–Dawley rats were irradiated with 250 kVp X-rays at 1.4 Gy/min and 20 or 25 Gy. Histological analysis was performed to measure damage and necrosis in the fimbria-fornix, hippocampus and corpus callosum. Learning and memory were measured through a T-maze and water maze. 

Neural remodeling, only measured at 41 weeks after radiation, was observed. Impaired learning and memory wereobserved from 35 to 44 weeks after radiation. 

Rola et al., 2004 

In vivo. Male C57BL/6J mice were irradiated with X-rays at 1.75 Gy/min). Ki-67 positive and DCx positive cells were measured along with BrdU staining to assess neuron integrity in the subgranular zone. NOR, NLR, MWM, Barnes maze and passive avoidance learning were used to assess learning and memory. 

The number of Ki-67-positive and DCx-positive cells decreased 0.1-fold and 0.3-fold, respectively, 48h after 5 Gy. The number of BrdU-positive cells decreased by 70% at both 1 and 3 months after 5 Gy. Also, after 3 months, in the MWM, irradiated mice spent 30% less time in the target quadrant after 5 Gy compared to control mice. No changes were observed in NOR, NLR, Barnes maze and passive avoidance tests. 

Whoolery et al., 2017 

In vivo. Nestin-GFP male and female mice (C57BL/6J background) were irradiated with 300 MeV/n 28Si particles (linear energy transfer = 67 keV/µm) at 1 Gy/min. Stereological immunopositive cell counts were determined for BrdU, Ki-67 and DCx in the DG granule cell layer. FC was used to assess learning and memory. 

24 h post-irradiation, BrdU-positive cells decreased by 0.75- and 0.65-fold at 1 Gy in the male and female groups, respectively, DCx-positive cells decreased by 0.5-fold at 1 Gy in both sex groups and Ki-67-positive cells decreased by 0.8-fold at 0.2 Gy and 0.4-fold at 1 Gy in both males and females. At 3 months post-irradiation, BrdU-positive cells decreased by 0.83- and 0.31-fold in male mice only at 0.2 and 1 Gy, respectively, Ki-67 was not significantly changed and DCx was reduced at 1 Gy but only when both sexes were combined. 3 months post-irradiation, male mice exhibited a decrease in percentage freezing of 0.43-fold at 0.2 Gy in contextual FC. 

Howe et al., 2019 

In vivo. C57BL/6 mice were irradiated with heavy ions 16O (600 MeV/n) at 0.05 Gy. NOR was used to assess non-spatial declarative memory. Y-maze assessed short-term spatial memory of mice. Sholl analysis was performed to quantify the neurons in the hippocampus. The morphology and density of dendritic spines from the DG and dorsal CA1 and CA3 pyramidal neurons. Behavior was evaluated 9 months after irradiation. 

9 months after irradiation, mice exhibited a 0.1-fold change in discrimination ratio in NOR indicating cognitive impairment. Dendritic spine density at 9 months post-irradiation was found to be reduced in the DG. 

Achanta, Fuss & Martinez, 2009 

In vivo. Male Sprague Dawley rats were irradiated with 0.3, 3 or 10 Gy. BrdU staining was used to assess neuronal proliferation.  Changes in cognitive behavior were evaluated by FC/testing. Fear testing was performed at 90 days post-irradiation. 

Total number of BrdU+ cells and total number of Ki67+ cells (proliferative marker for cells) 3-months post-irradiation decreased in PD 21, PD50 and PD 70 groups.  

Fear conditioning/testing at 90 days post-irradiation showed a decrease in % mean freezing in response to a CS in PD21, PD50 and PD 70. As well, ITI decreased in the studied groups. 

Winocur et al., 2006 

In vivo. Long-Evans rats were irradiated with 7.5 or 10 Gy of 60Co gamma rays. BrdU staining was used to label the DNA of proliferating cells. DCX as an immature neuron marker and NeuN for mature neuron staining were used. Cognitive impairment was identified by contextual fear conditioning in the studied rats 4 weeks after irradiation. 

Numbers of BrdU+ cells decreased by 0.22- and 0.23-fold 4 weeks after irradiation. 

Fear conditioning took place 4 weeks post-irradiation. The time spent freezing in the irradiated context-only group was decreased by 0.1- and 0.4-fold at the short and long delays, respectively.  

Sorokina et al., 2021 

In vivo. Male mice were irradiated with accelerated carbon ions at 0.7 Gy (450 meV/n). Spatial learning, short-term and long-term hippocampus-dependent memory were studied using Barnes Maze and NOR 2 months after irradiation. Nissl staining was performed 1 month after cognitive evaluations to quantify neuronal cells. 

1 month after cognitive evaluations, neuronal quantification revealed a decrease in the number of cells by 0.9-fold in the DG. The length of the CA3c field of the dorsal hippocampus decreased by 0.5-fold. 

In the Barnes maze 2 months after irradiation, the latency to the goal box was 3.1-fold higher in the irradiated mice than control on the 9th day after learning. Meanwhile no significant changes in latency to the goal box were observed on the second day of learning. NOR did not show any changes to memory. 

Miry et al., 2021 

In vivo. C57BL/6J mice were irradiated with 0.1, 0.5 and 1 Gy of 56Fe ions. Active avoidance was used to study spatial learning and discrimination. Immunohistological analysis of proliferating neural cells were performed using DCX, an immature neural marker. Other tests performed included the Barnes maze for spatial learning. Mice were studied at multiple time-points (2, 6, 12, and 20 months) post-exposure. 

2 months post-exposure, levels of DCX+ cells decreased by 0.4- to 0.7- fold in both male and female mice. 12 months post-exposure, DCX+ cells were increased in irradiated mice compared to control mice and levels of DCX+ cells increased by 1.1- to 2.6-fold in male and female mice. 

20 months after exposure, learning was found to be improved.