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Relationship: 2838

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Energy Deposition leads to Impairment, Learning and memory

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Energy Deposition

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Impairment, Learning and memory

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Deposition of Energy Leading to Learning and Memory Impairment	non-adjacent	Moderate	Low	Vinita Chauhan (send email)	Open for citation & comment	WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	Low	NCBI
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	High
Female	Low

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Adult	High
Old Age	Low
Juvenile	Low

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Deposition of energy from ionizing radiation (IR) can induce biological changes within living systems (UNSCEAR, 1982). The amount of IR absorbed and consequently the amount of damage ensued is quantified by the linear energy transfer (LET) of the radiation. Low-LET radiation consists of electromagnetic ionizing radiation such as X- and gamma rays, as well as protons that deposit smaller amounts of energy, whereas high-LET radiation deposits large amounts of energy and includes heavy ions, alpha particles and high-energy and neutrons. Therefore, high-LET radiation produces dense ionization while low-LET radiation induces sparse ionization events where energy is exponentially absorbed by tissues.

Deposition of energy can lead to reduced cognitive function related to learning and memory. Impaired learning can be seen as diminished ability to create new associative or non-associative relationships, whereas impaired memory consists of reduced ability to establish sensory, short-term or long-term memories (Desai et al., 2022; Kiffer et al., 2019b). Multiple brain areas are involved in learning and memory processes, with the most well-known occurring in the hippocampal region, as well as the amygdala, the prefrontal cortex, the basal ganglia, and other areas of the neocortex. These regions of the brain have been shown to be affected by deposition of energy (Cucinotta et al., 2014; Desai et al., 2022; NCRP Commentary, 2016).

Following deposition of energy, the process begins at the macromolecular level from direct damage to neurons and glial cells and via the generation of oxidative stress and promotion of neuroinflammatory environments in the central nervous system (CNS) (Mhatre et al., 2022; Lalkovičová et al., 2022). The altered cellular environment caused by a deposition of energy can impact the functions of both neurons and glial cells, which can promote a persistent pro-inflammatory response, reduced neurogenesis, reduced dendritic spine lengths and density, and the inhibition of neuronal connectivity and synaptic activity (Hladik & Tapio, 2016; Cekanaviciute et al., 2018). In vivo studies link structural and functional changes in neurons and glial cells to a decreased ability to complete cognitive assessments that test various domains of learning and memory.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

The strategy for collating the evidence to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Overall Weight of Evidence: Moderate

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The biological rationale linking deposition of energy to impaired learning and memory is strongly supported in the literature, as reported by several review articles published on the subject (Desai et al., 2022; Kiffer et al., 2019b; Pasqual et al., 2021; NCRP, 2016; Collett et al., 2020; Cucinotta et al., 2014; Hladik & Tapio, 2016; Cekanaviciute et al., 2018; Mhatre et al., 2022; Lalkovičová et al., 2022; Greene-Schloesser et al., 2012; Turnquist et al., 2020; Katsura et al., 2021). It is well established that radiation exposure leads to both acute and chronic elevation in reactive oxygen species (ROS), and this subsequently mediates cell signaling within mature neurons, neural stem cells and glial cells (NCRP, 2016; Mhatre et al., 2022). ROS acts as a second messenger to activate microglia and astrocytes via redox-responsive transcription factor-mediated molecular signaling pathways, and once these glial cells are activated, they can adopt a pro-inflammatory morphology and thus release pro-inflammatory mediators (Hladik & Tapio, 2016; Cucinotta et al., 2014; Collett et al., 2020). Pro-inflammatory mediators such as cytokines mediate the immune response through ligand binding to cell surface receptors that can activate signaling cascades such as JAK-STAT or MAPK pathways to produce or recruit more cytokines (Mousa & Bakhiet, 2013; Prieto & Cotman, 2018).

Once these inflammatory reactions are initiated, the radiation-activated microglia can alter the functions of neurons. Structurally, the neuron is comprised of the cell body, dendrites, axon, and axon terminals (Lodish et al., 2000). Neurons communicate by electrical and chemical signaling via synapses, where axons from the presynaptic neuron interface with the dendritic arms of the postsynaptic neuron. Deposition of energy inhibits neuronal connectivity and synaptic activity through the loss of dendritic spines as well as dendrite length and branching (Cekanaviciute et al., 2018; Jandial et al., 2018). Overexpression of pro-inflammatory mediators disrupts the integrity of neurons through increased necrosis and demyelination, decreased neurogenesis, decreased neural stem cell proliferation and decreased synaptic complexity (Hladik & Tapio, 2016; Cekanaviciute et al., 2018; Lalkovičová et al., 2022). Together, these radiation-induced neuronal damage and persistent neuroinflammation alter learning and memory capabilities as evidenced by behavioral changes from in vivo studies.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

There is strong evidence supporting the connection between the deposition of energy leading to impaired learning and memory. The evidence was gathered from studies using in vivo rodent models and human studies. The applied stressors ranged from 0.5 cGy to 40 Gy and included heavy ions (e.g.,28Si, 16O, 56Fe, 48Ti), X-rays, gamma rays, protons, and alpha particles. Impaired learning and memory in rodents were measured through various behavioral tests that assessed several cognitive aspects such as short-term memory, long-term memory, recognition memory, spatial memory, working memory, declarative memory, associative learning, discrimination, and reversal learning (Britten et al., 2018; Rabin et al., 2014; Lonart et al., 2012; Britten et al., 2012; Bellone et al., 2015; Parihar et al., 2016; Rabin et al., 2012; Krukowski et al., 2018a; Forbes et al., 2014; Gan et al., 2019; Manda et al., 2007a; Acharya et al., 2016; Impey et al., 2016; Parihar et al., 2018; Belarbi et al., 2013; Krukowski et al., 2018b; Jewell et al., 2018; Rabin et al., 2015; Parihar et al., 2015; Kiffer et al., 2019a ; Hodges et al., 1998). Additionally in humans, cognitive test scores from the Swedish military enlistment exam of 18-year-old men, which evaluates general instruction, concept discrimination, technical comprehension, and spatial recognition, were used to evaluate the potential impact of beta ray, gamma ray, or X-ray exposures from radiotherapy treatment for cutaneous haemangioma when they were infants (18 months old or earlier) (Hall et al., 2004).

Dose Concordance

Many studies demonstrate dose concordance relating to deposition of emerging and impaired learning and memory. NOR is a behavioral assay that is used to evaluate recognition memory by measuring the time spent with a novel object instead of a familiar one after habituation and training with the familiar object (Cekanaviciute et al., 2018Mice irradiated with 9 Gy X-rays showed a DI (discrimination index; tendency to explore novel instead of familiar objects/locations) of -13 compared to the control of 23, demonstrating impaired memory after irradiation (Acharya et al., 2016). Another study in rats reported a reduction in the discrimination ratio (DR) from 0.5 to 0.2 after 40 Gy X-rays, also suggesting reduced learning and memory after radiation exposure (Forbes et al., 2014). However, this was only observed in 3-month-old rats. Mice irradiated with 0.05 or 0.3 Gy of either 16O and 48Ti particles showed a dose- and particle size-dependent decrease in the DI for NOR (Parihar et al., 2015; Parihar et al., 2016). Another study with heavy ions also reported impairments in novel object recognition after 0.1 Gy and 0.4 Gy of 56Fe ion irradiation, but not after 0.2 Gy of 56Fe ion irradiation (Impey et al., 2016). Memory was also inhibited in mice after 4He particle irradiation at 0.5 Gy, but not after 4He particle irradiation at 0.15 Gy or 1 Gy after being tested using NOR (Krukowski et al., 2018b). In a mixed ion beam study using the galactic cosmic ray (GCR) simulator, NOR was impaired after 0.15 Gy and 0.5 Gy of irradiation in males only, with no reduction in performance reported in female mice (Krukowski et al., 2018a). In contrast, results from a separate study suggest that there is an impact on female mice, as female mice irradiated with 16O particles showed dose-dependent decreases in the DR from 22 (control) to -2 (0.1 Gy) and -5 (0.25 Gy) for NOR (Kiffer et al., 2019a). Memory assessed with NOR was also impaired in rats exposed to various particles (protons, carbon, oxygen, silicon, titanium and iron ions) with doses from 0.1 to 2 Gy (Rabin et al., 2014). Rats irradiated with 0.25 Gy 56Fe or 0.05 Gy 16O particles showed attenuated memory, but not learning, measured with NOR (Rabin et al., 2015).

Object in Place (OiP), a similar test to NOR where the same objects are used but the locations of one or more of the objects is changed, is also used to assess memory (Cekanaviciute et al., 2018). Mice irradiated with 9 Gy X-rays showed a DI of -3 compared to the control of 38 suggesting impaired memory (Acharya et al., 2016). Mice irradiated with 16O particles showed a dose-dependent decrease in the DI for NOR at 0.05 or 0.3 Gy, while 48Ti irradiation also resulted in significantly decreased DI at both 0.05 and 0.3 Gy (Parihar et al., 2015; Parihar et al., 2016). After 0.05 and 0.3 Gy 4He irradiation, mice also showed reduced performance in the OiP test suggesting impaired memory (Parihar et al., 2018).

A few studies used the multistage attentional set shifting (ATSET) test, which measures the ability to relearn cues over various schedules of reinforcement (Heisler et al., 2015). During ATSET, simple discrimination (SD) was inhibited by 0.05, 0.15 and 0.2 Gy of 28Si particles in rats, shown by increased latency to complete the task and a 20 to 30 percentage point decrease in completion of various stages (Britten et al., 2018). Of rats irradiated with 0.2 Gy 56Fe particles, 2 of 11 completed all stages, while 8 of 11 control rats completed all stages (Lonart et al., 2012). In addition, the same study (Lonart et al., (2012) demonstrated that irradiated rats required significantly more attempts to complete the SD stage. The number of attempts for compound discrimination (CD) was increased about 2-fold from 0.01 to 0.15 Gy in rats irradiated with 56Fe particles (Jewell et al., 2018). There was also a dose-dependent decrease in the percent of rats that failed at least 1 stage. Similarly, rats took more trial (2X) to complete the CD stage after 5 cGy of 48Ti (Parihar et al., 2016).

Fear conditioning (FC) and fear extinction (FE) are used to assess learning and memory. FC measures the learned fear response to an adverse event, while FE measures the dissociation of this response to the adverse event (Parihar et al., 2016). Mice tested with fear conditioning after 9 Gy X-rays spent 19% of the time frozen, while control mice spent 43% of the time frozen during the context test (Acharya et al., 2016). Mice irradiated with 0.3 Gy 48Ti showed similar levels of FC to controls, but FE was inhibited in irradiated mice as they were unable to abolish fear memory (Parihar et al., 2016). This also occurred for 0.05 Gy 4He particles (Parihar et al., 2018).

Various maze tests were performed to assess learning and memory. During an MWM test, control mice took 246 cm to reach the hidden platform, while 10 Gy-irradiated mice took 392 cm (Belarbi et al., 2013). A water maze did not show initial differences in learning and memory after 0.5 Gy protons, but reversal learning, where mice had to forget what they had previously learned, showed 1.6-fold increased swim distance to the hidden platform in irradiated mice (Bellone et al., 2015). Rats irradiated with X-rays (13 Gy) and 56Fe particles (0.2, 0.4 and 0.6 Gy) showed increased escape latency compared to controls (Britten et al., 2012). A Hebb-Williams maze after rats were irradiated with 6 Gy gamma rays showed significant decreases in learning and memory as well (Manda et al., 2007a). After irradiation, rats exposed to 25 Gy had significant impairments in both the T-maze, a measure of spatial working memory, and water maze tests, while rats exposed to lower dose of 20 Gy, had significant impairment of working memory in the T-maze (Hodges et al., 1998).

A Swedish cohort study by Hall et al. (2004) showed that exposure to β-rays, gamma rays and X-ray doses of 1 to 250 mGy for treatment of cutaneous hemangioma during infancy was related to reduced test scores approximately 18 years later, including tests of concept discrimination (P=0.03), general instruction (P=0.03) and technical comprehension (P=0.003). In mice, reduced performance on temporal order (TO) tasks, where short-term memory is assessed through the animals’ preference to two sets of objects, was reported after 0.05 and 0.3 Gy of 16O, 48Ti and 4He particle irradiation (Parihar et al., 2016; Parihar et al., 2018). A three-chamber social approach task, which assesses social memory, was impaired in male mice after 0.5 Gy of exposure to the GCR simulator compared with animals exposed to 0.15 Gy of GCR simulator. However, there were no significant differences in TO in the exposed animals compared to unexposed controls (Krukowski et al., 2018a). Performance on operant responding, which reflects the cortex’ ability to organize processes was assessed in rats. Performance on this test was reduced after 0.25, 0.5, 1 and 2 Gy 56Fe ion exposure, suggesting alterations in learning and memory (Rabin et al., 2012). However, there was no consistent trend across doses (Rabin et al., 2012).

Furthermore, a meta-analysis identified several studies that showed a risk of developing central nervous diseases such as Alzheimer’s and dementia after exposure to low-to-moderate doses of ionizing radiation in adulthood. The various studies investigated CNS diseases in relation to occupational exposure, environmental exposure, those exposed for medical purposes, Chernobyl cleanup workers and Japanese Atomic Bomb Survivors with dose ranges <1 Gy. Results from the meta-analysis suggest that there is no increase in standardized mortality ratio (SMR) from diseases of the nervous system when comparing the radiation exposed cohorts to the general population. However, there was a positive and significant excess relative risk from ionizing radiation for Parkinson’s disease (Azizova et al., 2020; Lopes et al., 2022).

Time Concordance

Novel object recognition (NOR) was used in multiple studies to assess recognition memory at varying time points following energy deposition. In many cases, the deposition of energy by radiation led to impaired recognition memory in the animal models studied. A decrease in DI indicates a reduction in recognition memory. At 5 to 6 weeks after 9 Gy irradiation, mice had decreased DI for NOR (Acharya et al., 2016). Similarly, at 6 weeks after 48Ti (0.05 and 0.30 Gy) and 16O (0.30 Gy) irradiation, the DI for NOR decreased significantly in male mice (Parihar et al., 2015). After exposure to 5 and 30 cGy of 48Ti, cognitive impairment was greater after 24 weeks than 12 weeks as evidenced by reduced NOR DI for both doses of 48Ti (Parihar et al., 2016). Mice at 90 days post helium exposure or 45 days post GCR simulator radiation (0.15 or 0.50 Gy) both demonstrated memory impairments as mice were unable to distinguish novel and familiar objects (Krukowski et al., 2018a; Krukowski et al., 2018b). After 2 weeks of exploring, mice previously irradiated with 0.1 or 0.4 Gy showed impaired object recognition; however, at the 20-week time-point, no impairment was indicated following 0.1, 0.2 or 0.4 Gy of 56Fe (Impey et al., 2016). NOR performance was impaired in mice at 2- and 4-months post 16O irradiation, 11 months post 12C irradiation, at 3- and 12-months post 56Fe exposure and at 7- and 17-months post 48Ti irradiation. As well, NOR was impaired 4, 5, 9, 10 and 13 months after 28Si exposure, with the lowest performance occurring at 9 months (Rabin et al., 2014). Mice demonstrated impaired memory 270 days after 16O radiation at 0.01 Gy or 0.25 Gy (Kiffer et al., 2019a). Four and 13 months after proton exposure, NOR was impaired in rats (Rabin et al., 2014). Also in rats, memory ability decreased 18 h after 56Fe and 16O exposure but no significant changes in learning ability by NOR were found after 48 h (Rabin et al., 2015). Months after 40 Gy X-ray irradiation, rats showed differences in NOR results by age. Rats that were 3 months old at the time of irradiation, showed a decrease in NOR 3 months post irradiation, while no changes were observed in older ages and later timepoints (Forbes et al., 2014). No changes in novel object location (NOL) were observed for rats between 6 and 15 months of age (Forbes et al., 2014).

To study spatial learning and memory, mice and rat models were subjected to various maze tests. Proton-irradiated mice tested with Barnes maze and water maze did not show impairment 3 months after irradiation (Bellone et al., 2015). However, 3 months after exposure to 13 Gy of X-rays, rats became less capable of escaping the Barnes maze and demonstrated increased escape latency (Britten et al., 2012). After 6 months, mice reached the platform with a longer distance during the reversal learning test (Bellone et al., 2015). Rats exposed to 0, 8 and 10 Gy of X-rays experienced no impairments in spatial memory, while those exposed to 0.2, 0.4 and 0.6 Gy 56Fe demonstrated increased relative escape latency over the 3-day testing periods (Britten et al., 2012). Cognitive changes in spatial learning or memory were observed in the water maze after 2 weeks, but not at 20 weeks (Impey et al., 2016). Mice studied in a water maze 1 year following 4He irradiation (0.05 and 0.30 Gy) showed impaired cognitive flexibility and memory retrieval (Parihar et al., 2018). Mice previously irradiated with 6 Gy gamma rays needed a 1.7-fold increase in time to reach the goal of the Hebb-William maze by day 30 post-irradiation, while in the control, the time required decreased 0.2-fold by day 30 (Manda et al., 2007a). Irradiated mice 9 months after 16O irradiation at 0.1 and 0.25 Gy had no difference in positive discrimination ratio during a Y-maze test, a measure spatial working memory, compared with control mice, indicating that radiation had no effect on memory 9 months post-irradiation (Kiffer et al., 2019a). Rats irradiated at 20 Gy and 25 Gy experienced deficits in T-maze testing 35 weeks post irradiation and at 44 weeks, rats exposed to 25 Gy reflected working memory deficits assessed by the water maze test (Hodges et al., 1998).

OiP used in multiple studies showed impairment in discrimination of objects after irradiation. Mice 5 to 6 weeks after 9 Gy irradiation showed decreased OiP DI (Acharya et al., 2016). Similarly, 6 weeks after charged particle exposure, the DI for OiP in male mice decreased to a greater extent following 48Ti irradiation compared to 16O irradiation (Parihar et al., 2015). As well, a greater change was observed after 0.30 Gy of 16O irradiation compared with 0.05 Gy of 16O irradiation after 6 weeks, indicating higher impairment at the higher dose (Parihar et al., 2015). In a similar experiment to Parihar et al. (2015), the OiP DI decreased after 0.30 Gy of 48Ti irradiation at week 12, in addition to DI decrease at 24 weeks after 0.30 Gy of 16O irradiation and 0.05 Gy of 48Ti irradiation. Hence, cognitive impairment was greater after 24 weeks than 12 weeks (Parihar et al., 2016). 4He particle irradiation of mice led to long-term recognition memory impairments at 6, 15 and 52 weeks post-radiation (Parihar et al., 2018).

Fear conditioning and fear extinction of previously irradiated mice were studied at different timepoints after irradiation. Mice irradiated with 0.3 Gy and 0.05 Gy spent more time freezing their motion than the control mice at 24 weeks and 1 year, respectively, following irradiation (Parihar et al., 2016; Parihar et al., 2018). Mice irradiated with 9 Gy X-rays spent less time frozen during FC, measured after 5-6 weeks (Acharya et al., 2016). FE was attenuated in mice after 0.3 Gy of 48Ti irradiation after 24 weeks post-irradiation (Parihar et al., 2016). The same was found after 0.05 Gy of 4He exposure 1-year post-irradiation (Parihar et al., 2018).

ATSET was used to assess simple and compound discrimination, reversal learning and set shifting, among others. Only 2 out of 11 of the irradiated rats (0.20 Gy of 56Fe) completed all the paradigms 90 days after radiation compared to 8 out 11 unirradiated rats that completed all paradigms (Lonart et al., 2012). At 90-days post-irradiation, irradiated rats required more trial attempts to complete the simple discrimination stage compared to the control rats (Lonart et al., 2012). Rats took 2-fold more tries to complete the CD stage 12 weeks after radiation (Parihar et al., 2016).

In irradiated mice, temporal order DI decreased at 12 and 24 weeks for all tested doses (0.05 or 0.30 Gy of 16O or 48Ti), demonstrating cognitive impairment (Parihar et al., 2016). Meanwhile, Parihar et al. (2018) found impaired TO memory for 6-, 15- and 52-weeks post 4He particle irradiation (Parihar et al., 2018). Male mice had significantly impaired social memory in the three-chamber social approach task at day 45 following exposure to 0.50 Gy of the GCR simulator (Krukowski et al., 2018a). Operant responding as a cognitive function test was used on 56Fe irradiated rats who showed decreased cognitive function at 2, 4-8, 10-, and 15-months post-irradiation (Rabin et al., 2012). Swedish men who were irradiated under 18 months of age were found to have cognitive impairments following reduced test scores for technical comprehension, concept discrimination and general instruction at 18 and 19 years old (Hall et al., 2004).

Incidence Concordance

No available data.

Essentiality

As deposition of energy is a physical stressor, it cannot be blocked by chemicals although it can be shielded. Further research is required to determine the effect of shielding radiation on learning and memory. Since deposited energy initiates events immediately, the removal of deposited energy also supports the essentiality of the key event. Studies that do not deposit energy are observed to have no downstream effects. However, impaired learning and memory can occur in response to ionizing radiation, although in the absence of this energy deposition, compromised cognitive abilities would occur with aging, or if predisposed to neurodegenerative diseases such as Alzheimer’s (Lindsay et al., 2002).

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Most of the evidence for this KER is supported using in vivo rodent models; therefore, there is still a knowledge gap on how radiation exposure realistically alters the brains of other species, such as humans, to lead to impaired learning and memory (Desai et al., 2022). Additionally, further research is needed to gain a better understanding on the sex differences in behavioral effects after radiation exposure (Kiffer et al., 2019b).
Belarbi et al. (2013) did not find any changes in NOR performance after 10 Gy gamma rays.
Forbes et al. (2014) showed impaired ability during NOR tests, but not during NOL tests after 40 Gy X-rays.

Kiffer et al. (2019a) showed impaired ability during NOR tests, but not during Y-maze tests after 0.1 and 0.25 Gy 16O particles.
Miry et al. (2021) showed impaired hippocampal-dependent learning and memory 2 months after 10, 50 and 100 cGy 56Fe exposure, but by 6 months post-exposure, deficits in spatial learning were no longer observed in irradiated mice. Instead, enhanced spatial learning was observed at 12- and 20-months post-exposure.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

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
Stress	Psychological Stress	Psychological stress related to perceived risk of radiation exposure can also impact learning and memory.	Collett et al., 2020

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

The table below provides some representative examples of quantitative linkages between the two key events. It was difficult to identify a general trend across all the studies due to differences in experimental design and reporting of the data. All data is statistically significant unless otherwise stated.

Dose Concordance

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 min). 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.

Time Concordance

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 behavioral 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 min). 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.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

TNF is a key cytokine that can initiate and promote inflammation through the activation of the NFκB pathway in glia cells. In uncontrolled conditions, TNF can lead to the development of neurodegenerative diseases as it can increase the production of pro-inflammatory cytokines and can also lead to elevated levels of iNOS, COX-2, and NOX subunits. These can then activate NADPH oxidases to produce ROS, which can activate the NFκB pathway to amplify the overall TNF/ROS/NFκB responses to promote neuroinflammation. This process ultimately results in a feed-forward loop of chronic neurodegeneration and consequently, impaired learning and memory (Fischer and Maier, 2015).

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Evidence for this relationship comes from human, rat, and mouse models, with a large amount of evidence in mice and rats. There is in vivo evidence in both male and female animals, with a lot of evidence in males. This relationship has been shown in adult animals in many studies.

References

List of the literature that was cited for this KER description. More help

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