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Relationship: 2836

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

Increase, Neural Remodeling leads to Impairment, Learning and memory

Upstream event

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

Increase, Neural Remodeling

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	adjacent	Moderate	Low	Vinita Chauhan (send email)	Open for citation & comment

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
mouse	Mus musculus	Moderate	NCBI
rat	Rattus norvegicus	Moderate	NCBI

Sex Applicability

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

Sex	Evidence
Male	Moderate
Female	Low

Life Stage Applicability

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

Term	Evidence
Adult	Moderate
Not Otherwise Specified	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

Neural stem cells (NSCs) come from different sources, such as the subgranular zone (SGZ) located in the dentate gyrus (DG) of the hippocampal formation, and the subventricular zone (SVZ) region of the brain. NSCs give rise to mature neurons that are then able to receive signals from other neurons (Bálentová & Adamkov, 2020; Hladik & Tapio, 2016; Monje & Palmer, 2003; Romanella et al., 2020; Tomé et al., 2015). Changes in neuronal architecture can lead to altered synaptic activity, necrosis, demyelination, neurogenesis, neurodegeneration, and dendrite morphology, all of which encompass neural remodeling (Hladik & Tapio, 2016; Monje & Palmer, 2003; Tomé et al., 2015). These alterations can then cause cognitive deficits in the form of impaired learning and memory (Barker & Warburton, 2011; Hladik & Tapio, 2016; Monje & Palmer, 2003; Tomé et al., 2015). Impaired learning consists reduced ability to create new associative or non-associative relationships, whereas impaired memory consists of decreased ability to establish sensory, short-term or long-term memories (Desai et al., 2022; Kiffer et al., 2019). Multiple brain areas are involved these processes, such as the hippocampal region, amygdala, prefrontal cortex, basal ganglia, and other areas of the neocortex (Cucinotta et al., 2014; Desai et al., 2022; NCRP Commentary, 2016).

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

Several reviews provide support for the biological plausibility of the link between neural remodeling and impaired learning and memory. It is generally accepted that neural remodeling can disrupt learning and memory through changes to neurogenesis, neurodegeneration, neuronal excitability and synaptic plasticity, demyelination and dendritic spine density (Hladik & Tapio, 2016; Bálentová & Adamkov, 2020; Tomé et al., 2015; Monje & Palmer, 2003; Romanella et al., 2020).

Neurogenesis in the DG creates new neurons in the hippocampus that can make connections to Cornu Ammonis (CA) neurons involved in learning and memory (Monje & Palmer, 2003; Tomé et al., 2015). Accordingly, learning and memory can be impaired through reduced neurogenesis in the neurogenic SGZ of the DG (Bálentová & Adamkov, 2020; Monje & Palmer, 2003). Many studies also associate decreased neurogenesis to impaired hippocampal-dependent cognitive function, indicating that it is a common mechanism for the relationship (Tomé et al., 2015). Similarly, apoptosis and neurodegeneration impair cognitive function (Bálentová & Adamkov, 2020; Hladik & Tapio, 2016). In the hippocampus, the degree of atrophy corresponds to the degree of impaired learning and memory (Tomé et al., 2015).

Synaptic strength and neuronal excitability are important components of learning and memory. Decreased hippocampal excitability and disrupted long-term potentiation (LTP), a form of long-term synaptic plasticity, are associated with reduced learning and memory (Romanella et al., 2020). Changes in the expression of synaptic receptors and other synaptic proteins may also result in impaired learning and memory (Hladik & Tapio, 2016).

Demyelination correlates with decreased long-term memory formation (Tomé et al., 2015) and along with white matter necrosis, these lead to impaired learning and memory (Bálentová & Adamkov, 2020). Although demyelination is a factor in learning and memory, sub-threshold demyelination may still cause impaired learning and memory (Monje & Palmer, 2003).

Reduced dendritic complexity and spine density are also associated with impaired learning and memory (Bálentová & Adamkov, 2020; Hladik & Tapio, 2016; Romanella et al., 2020). The complexity of signal processing in the hippocampus can be reduced by a loss in dendritic spines, which results in impaired learning and memory (Romanella et al., 2020). In addition, various studies show reduced dendritic branching, length and area in hippocampal neurons associated with learning and memory (Hladik & Tapio, 2016).

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

The empirical evidence surrounding this KER stems from research using in vivo models. When compared to the control, irradiated subjects demonstrated significant changes in neuronal integrity and cognitive deficits (Achanta, Fuss & Martinez, 2009; Acharya et al., 2019; Akiyama et al., 2001; Hodges et al., 1998; Howe et al., 2019; Krukowski et al., 2018; Madsen et al., 2003; Miry et al., 2021; Parihar et al., 2015, 2016; Raber et al., 2004; Rola et al., 2004; Simmons et al., 2019; Sorokina et al., 2021; Whoolery et al., 2017; Winocur et al., 2006).

Dose Concordance

There is strong evidence suggesting dose-concordance between neural remodeling and impaired learning and memory. Dose-dependent changes in dendritic complexity are correlated with behavioral deficits at doses from 0.05 to 30 Gy (Bálentová & Adamkov, 2020; Howe et al., 2019; Parihar et al., 2015, 2016; Simmons et al., 2019; Whoolery et al., 2017). Mice exposed to 0.05 and 0.3 Gy of 48Ti showed dose-dependent decreases in total dendritic length and number of dendritic branch points. When subjected to cognitive testing, mice exposed to 0.3 Gy demonstrated greater impairment in the novel object recognition (NOR) and object in place (OiP) tests compared to 0.05 Gy exposed mice (Parihar et al., 2016). These results for OiP were correlated positively to the number of dendritic spines and negatively to the number of postsynaptic density protein 95, also a marker for neural remodeling. Similarly, another study identified a correlation between the total number of dendritic spines and the performance of mice in the OiP task (Parihar et al., 2015). This study also demonstrated dose-dependent decreases in the total number of spines, total dendritic length, number of branch points, number of dendritic branches, and DI in both the NOR and OiP tasks when exposed to 0.05 and 0.3 Gy of 16O and 48Ti.

Changes in the levels of neurogenesis also exhibit dose-concordance with cognitive deficits. Whoolery et al. (2017) identified a 0.8- and 0.4-fold decrease in the number of Ki-67+ cells in male mice exposed to 0.2 and 1 Gy of 28Si particles, respectively. The mice also demonstrated a decrease in percentage freezing by 0.4-fold in contextual FC, indicative of impaired learning and memory, when exposed to 0.2 Gy, although no significant changes in learning and memory were seen at 1 Gy. Another study identified dose-dependent decreases in the numbers of Ki67+ and BrdU+ cells in three age groups (postnatal day (PD) 21, PD 50, and PD 70) in rats exposed to 0.3, 3, and 10 Gy of ionizing radiation (Achanta, Fuss & Martinez, 2009). In PD 21 rats, dose-dependent decreases in freezing response were observed at doses of 0.3 and 10 Gy during the trace fear conditioning/testing. These results show that higher doses of irradiation lead to greater alterations in neuronal integrity, correlated with greater cognitive impairments. Many other studies showed decreased neurogenesis or increased neurodegeneration and impaired learning and memory at doses from 0.3 to 25 Gy, with stressors like X-rays, gamma rays, carbon ions and iron ions (Achanta, Fuss & Martinez, 2009; Akiyama et al., 2001; Hodges et al., 1998; Madsen et al., 2003; Miry et al., 2021; Raber et al., 2004; Rola et al., 2004; Sorokina et al., 2021; Winocur et al., 2006).

Neuron excitation has also been measured to assess neuron integrity. After 0.18 Gy of 252Cf neutron, with an activity of 1.6 GBq, excitatory signaling in CA1 neurons of mice was reduced and both NOR and OiP showed decreased learning and memory (Acharya et al., 2019).

Synaptic composition in hippocampal neurons was assessed as well to determine neuron integrity. GluR1, involved in hippocampal-dependent working memory, and recognition memory were both reduced after 0.5 Gy of simulated galactic cosmic radiation (GCR) (Krukowski et al., 2018).

Time Concordance

Evidence supporting time concordance between neural remodeling and impaired learning and memory come from several studies. Whoolery et al. (2017) found that the number of Ki-67+ cells decreased 24 hours after 0.2 Gy of 28Si radiation of mice, while contextual FC 3 months after radiation showed impaired memory. Similarly, after 10 Gy X-rays, cell proliferation and the number of immature neurons decreased by 95% in mice after 3 months, and a Barnes maze showed impaired hippocampal-dependent spatial learning and memory measured after proliferation at 3 months as well (Raber et al., 2004). After mice were irradiated with 16O and 48Ti particles at 0.05 and 0.30 Gy, dendritic complexity and spine density were reduced and synaptic spine puncta were increased 15 weeks post-irradiation while learning and memory was impaired 15 and 24 weeks post-irradiation (Parihar et al., 2016). Neurogenesis was reduced immediately after 3 Gy 300 kVp X-ray radiation in rats and remained low 2 and 6 weeks later, and memory was impaired 1, 3 and non-significantly at 7 weeks post-irradiation (Madsen et al., 2003). Rats irradiated with gamma rays showed decreased neurogenesis and impaired performance during FC both 4 weeks post-irradiation (Winocur et al., 2006). In a longer-term study, neurogenesis was impaired 1 and 3 months after 5 Gy X-ray radiation in mice, while the Morris Water Maze (MWM) demonstrated impaired learning and memory also at 3 months (Rola et al., 2004). This trend continued after 9 months where both learning and memory through NOR testing and neural remodeling through mushroom and thin spine density were reduced after mice were irradiated with 0.05 Gy 16O particles (Howe et al., 2019). Hodges et al. (1998) showed neural remodeling at 41 weeks after 250 kVp X-ray irradiation and impaired learning and memory from 35 to 44 weeks post-irradiation.

Incidence Concordance

No available data.

Essentiality

No identified studies applied countermeasures to support the causal relationship between neural remodeling and impaired learning and memory.

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

One study observed cognitive deficits in the one- and two-way avoidance, press-lever avoidance, and water maze tests, but through pathological examination, no abnormalities were seen in the brains (white matter and axons were normal with no inflammation or glial response) (Lamproglou et al., 1995). This is indicative of impaired cognition without any changes in neuron integrity.
At 25 Gy of X-irradiation, Hodges et al. (1998) observed both neural remodeling and impaired learning and memory. However, at 20 Gy in the same study, neural remodeling was not observed.
Whoolery et al. (2017) found that neural remodeling was high at 1 Gy and low and 0.2 Gy but found impaired learning and memory at 0.2 Gy and not at 1 Gy.
Miry et al. (2021) found that 1 Gy of 56Fe particles led to increased learning and memory 20 months after exposure, although this is part of the compensatory or repair mechanisms following early suppressive changes.

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
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

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 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.

Time Concordance

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.

Response-response Relationship

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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

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Domain of Applicability

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Evidence for this relationship comes from rat and mouse models. There is in vivo evidence in both male and female animals, with more evidence in males. Animal age is occasionally not indicated in studies, but most evidence is in adult rodent models.

References

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

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