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Relationship: 2837


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 Abnormal Neural Remodeling

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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

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 High NCBI
rat Rattus norvegicus Low NCBI
dog Canis lupus familiaris Low NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male High
Female Low
Unspecific 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

Energy deposition through ionizing radiation can lead to chemical changes including bond breakages and the generation of by-products, such as free radicals from water hydrolysis, which can change cellular homeostasis (Einor et al., 2016; Martinez-López & Hande, 2020; Reisz et al., 2014). This energy can come in many forms (i.e., gamma rays, X-rays, alpha particles, heavy ions, protons), to produce a range in complexity of damage (Drobny, 2013). When deposited onto neurons, oxidative stress can affect neuronal signaling through the induction of alterations to the neuronal architecture and synaptic activity. The energy can further cause necrosis and demyelination, and decrease neurogenesis and synaptic complexity; these together are important to maintain the integrity of the neurons (Cekanaviciute et al., 2018; J. R. Fike et al., 1984; Hladik & Tapio, 2016). Furthermore, there can also be disruptions in neuronal signaling, as well as changes to drebrin cluster and postsynaptic density proteins (PSD), which are known to regulate dendritic spine morphogenesis. Together these can lead to neural remodeling (Takahashi et al., 2003). 

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

Multiple reviews provide support of biological plausibility between deposition of energy and neuron remodeling. Numerous studies examine the effects of multiple radiation sources including gamma rays, X-rays, protons, heavy ions, alpha particles, and neutrons, on both in vivo and in vitro model systems. The collected data demonstrate changes in the physical and electrophysiological properties of neurons in response to ionizing radiation exposure (Cekanaviciute et al., 2018; Hladik & Tapio, 2016). Irradiation of the brain induces oxidative stress and inflammation, which is linked to the occurrence of neuronal alterations within the hippocampus, an important structure in the process of learning and memory (Jarrard, 1993; Monje et al., 2003; Rola et al., 2007: Lalkovičová et al., 2022). There is no clear understanding on how deposited energy directly affects neuron integrity; however, immature neurons are found to be more radiosensitive and exhibit significant changes in spine density, dendritic spine length, protein clustering, and decreased cell proliferation, leading to reduced dendritic complexity (Manda et al., 2008a ; Mizumatsu et al., 2003; Okamoto et al., 2009; Rola et al., 2005; Shirai et al., 2013). Many neurodegenerative conditions are related to changes in synaptic plasticity, including changes in neuronal connectivity, action potential, and synaptic protein levels (Vipan Kumar Parihar & Limoli, 2013). These alterations occur primarily within the hippocampus and dentate gyrus, two regions of the mammalian brain where adult neurogenesis can occur (Ming & Song, 2011) following ionizing radiation exposure. 

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 shows that at a high dose of 90 Gy (X-rays), hippocampal dendritic spine length is increased compared to the control (Shirai et al., 2013). Kiffer et al. found a decrease in spine length in the CA1 subregion of the hippocampus; however, there was an increase in spine length and dendritic complexity in the dorsal dentate gyrus after exposure to 0.5 Gy 1H and 0.1 Gy 16O (Kiffer et al., 2020). Further research involving different regions of the brain is required to identify the effects of deposition of energy on the dentate gyrus. 

  • The study by Krukowski et al. (2018a), as highlighted in a review by Cekanaviciute et al. (2018), found a lack of cellular changes in hippocampal synapse loss and microgliosis in females subjected to low dose ionizing radiation. Another study highlighted in this review showed greater reduction in new neuronal survival in male than female mice in response to 28Si irradiation (Whoolery et al., 2017). Additional data is required to determine if these differences are sex-related or due to other factors. There is a lack of studies performed on female subjects to identify specific sex-related effects of deposited energy on neuron integrity. 

  • Previous studies have found transient changes in neurogenesis after exposure to 56Fe ions at varying doses ranging from 10 cGy to 1 Gy (DeCarolis et al., 2014; Miry et al., 2021 These studies found early decreases in neurogenesis, although DeCarolis et al. reported that this reduction returned to normal as early as 7 days post-irradiation. In a separate study, Miry et al. (2021) found that at 12 months post-exposure, neurogenesis levels significantly exceeded controls. Other inconsistent studies include Acharya et al. (2019) and Bellone et al. (2015); the former reported decreases in CA1 pyramidal neuron excitability after exposure to 18 cGy of neutron radiation, whereas the latter study reported increases in post-synaptic excitability within CA1 neurons after 0.5 Gy of proton irradiation. 

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 


Effects on the KER 



SB415286 – a potent and selective cell-permeable, ATP-competitive GSK-3β inhibitor, as GSK-3β induces apoptosis in response to various conditions 

Treatment with SB415286 provided significant neuroprotection against radiation necrosis within the brain at 45 Gy.  

Jiang et al., 2014 


N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) – a melatonin metabolite which has antioxidant properties.   

AMFK treatment ameliorated levels of reactive oxygen species, and increased number of immature neurons and proliferating cells post-irradiation in vivo. Without the treatment, exposure to radiation led to a significant decrease in DCX positive cells by 81% and Ki-67 positive cells by 86%. (AMFK) treatment provided protection to immature neurons by 45.38% and proliferating cells by 52.35%. 

Manda et al., 2008b 


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

The PLX diet was able to significantly increase the levels of the presynaptic protein, synapsin 1 after exposure to helium irradiation.  

Krukowski et al., 2018b 

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


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

Most evidence is derived from in vivo studies, predominately using rodent models, whereas evidence from dog models is low. The relationship is applicable in both sexes; however, adult males are used more often in animal studies. Limited studies demonstrate the relationship in preadolescent animals.


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

Acharya, M. M. et al. (2019), "New concerns for neurocognitive function during deep space exposures to chronic, low dose-rate, neutron radiation", eNeuro, Vol. 6/4, Society for Neuroscience, Washington, 

Allen, A. R. et al. (2015), "56Fe Irradiation Alters Spine Density and Dendritic Complexity in the Mouse Hippocampus", Radiation Research, Vol. 184/6, BioOne, Washington, 

Al Zaman, M. A. and Q. M. R. Nizam. (2022), "Study on Shielding Effectiveness of a Combined Radiation Shield for Manned Long Termed Interplanetary Expeditions", Journal of Space Safety Engineering, Vol. 9/1, Elsevier, Amsterdam, 

Bellone, J. A. et al. (2015), "A single low dose of proton radiation induces long-term behavioral and electrophysiological changes in mice", Radiation Research, Vol. 184/2, BioOne, Washington, 

Cekanaviciute, E., S. Rosi and S. V. Costes. (2018), "Central Nervous System Responses to Simulated Galactic Cosmic Rays", International Journal of Molecular Sciences, Vol. 19/11, Multidisciplinary Digital Publishing Institute (MDPI), Basel, 

Chakraborti, A. et al. (2012), "Cranial Irradiation Alters Dendritic Spine Density and Morphology in the Hippocampus", PLOS ONE, Vol. 7/7, Public Library of Science, San Francisco, 

Chiang, C. S., W. H. McBride and H. Rodney Withers. (1993), "Myelin-associated changes in mouse brain following irradiation", Radiotherapy and Oncology, Vol. 27/3, Elsevier, Amsterdam, 

DeCarolis, N. A. et al. (2014), "56Fe particle exposure results in a long-lasting increase in a cellular index of genomic instability and transiently suppresses adult hippocampal neurogenesis in vivo", Life Sciences in Space Research, Vol. 2, 

Dhikav, V. and K. Anand. (2012), "Hippocampus in health and disease: An overview", Annals of Indian Academy of Neurology, Vol. 15/4, Wolters Kluwer, Alphen aan den Rijn, 

Drobny, J. G. (2013), "Introduction", Ionizing Radiation and Polymers (pp. 1–10), Elsevier, Amsterdam, 

Einor, D. et al. (2016), "Ionizing radiation, antioxidant response and oxidative damage: A meta-analysis", Science of The Total Environment, Vols. 548–549, Elsevier, Amsterdam, 

Fike, J. R. et al. (1984), "Computed Tomography Analysis of the Canine Brain: Effects of Hemibrain X Irradiation", Radiation Research, Vol. 99/2, Allen Press, Lawrence, 

Hainmueller, T. and M. Bartos. (2020), "Dentate gyrus circuits for encoding, retrieval and discrimination of episodic memories", Nature Reviews Neuroscience, Vol. 21/3, Springer Nature, Berlin, 

Harris, K. M. and J. K. Stevens. (1989), "Dendritic spines of CA 1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics", Journal of Neuroscience, Vol. 9/8, Society for Neuroscience, Washington, 

Hladik, D. and S. Tapio. (2016), "Effects of ionizing radiation on the mammalian brain", Mutation Research - Reviews in Mutation Research, Vol. 770, Elsevier B.V., Amsterdam, 

HR, C. C. M. W. W. (1993), "Radiation-induced astrocytic and microglial response in mouse brain", papers3://publication/uuid/729C572E-9A43-4EF4-A184-8A9DAD8CBC38. 

Jarrard, L. E. (1993), "On the role of the hippocampus in learning and memory in the rat", Behavioral and Neural Biology, Vol. 60/1, Academic Press, Cambridge, 

Jiang, X. et al. (2014), "A GSK-3β Inhibitor Protects Against Radiation Necrosis in Mouse Brain", International Journal of Radiation Oncology*Biology*Physics, Vol. 89/4, Elsevier, Amsterdam, 

Kiffer, F. et al. (2020), "Late Effects of 1H + 16O on Short-Term and Object Memory, Hippocampal Dendritic Morphology and Mutagenesis", Frontiers in Behavioral Neuroscience, Vol. 14, Frontiers Media S.A., 

Klein, P. M. et al. (2021), "Detrimental impacts of mixed-ion radiation on nervous system function", Neurobiology of Disease, Vol. 151, Elsevier, 

Krukowski, K. et al. (2018a), "Female mice are protected from space radiation-induced maladaptive responses", Brain, Behavior, and Immunity, Vol. 74, Academic Press Inc., 

Krukowski, K. et al. (2018b), "Temporary microglia-depletion after cosmic radiation modifies phagocytic activity and prevents cognitive deficits", Scientific Reports 2018 8:1, Vol. 8/1, Nature Publishing Group, Berlin, 

Lalkovičová, M. (2022), "Neuroprotective agents effective against radiation damage of central nervous system", Neural Regeneration Research, Vol. 17/9, 

Manda, K., M. Ueno and K. Anzai. (2008a), "Memory impairment, oxidative damage and apoptosis induced by space radiation: Ameliorative potential of α-lipoic acid", Behavioural Brain Research, Vol. 187/2, Elsevier, Amsterdam, 

Manda, K., M. Ueno and K. Anzai. (2008b), "Space radiation-induced inhibition of neurogenesis in the hippocampal dentate gyrus and memory impairment in mice: ameliorative potential of the melatonin metabolite, AFMK", Journal of Pineal Research, Vol. 45/4, John Wiley & Sons, Inc., Hoboken, 

Martinez-López, W. and M. P. Hande. (2020), "Health effects of exposure to ionizing radiation", Advanced Security and Safeguarding in the Nuclear Power Industry (pp. 81–97), Elsevier, Amsterdam, 

Ming, G. and H. Song. (2011), "Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions", Neuron, Vol. 70/4, NIH Public Access, 

Miry, O. et al. (2021), "Life-long brain compensatory responses to galactic cosmic radiation exposure", Scientific Reports, Vol. 11/1, 

Mizumatsu, S. et al. (2003), "Extreme sensitivity of adult neurogenesis to low doses of X-irradiation", Cancer Research, Vol. 63/14. 

Monje, M. L., H. Toda and T. D. Palmer. (2003), "Inflammatory Blockade Restores Adult Hippocampal Neurogenesis", Science, Vol. 302/5651, American Association for the Advancement of Science, Washington, 

Okamoto, M. et al. (2009), "Effect of radiation on the development of immature hippocampal neurons in vitro", Radiation Research, Vol. 172/6, BioOne, Washington, 

Panagiotakos, G. et al. (2007), "Long-Term Impact of Radiation on the Stem Cell and Oligodendrocyte Precursors in the Brain", (S. Akbarian, Ed.)PLoS ONE, Vol. 2/7, 

Parihar, V. K. et al. (2016), "Cosmic radiation exposure and persistent cognitive dysfunction", Scientific Reports, Vol. 6/June, Nature Publishing Group, Berlin,

Parihar, V. K. et al. (2015), "What happens to your brain on the way to Mars", Science Advances, Vol. 1/4, American Association for the Advancement of Science, Washington, 

Parihar, V. K. et al. (2014), "Persistent changes in neuronal structure and synaptic plasticity caused by proton irradiation", Brain Structure and Function 2014 220:2, Vol. 220/2, Springer Nature, Berlin, 

Parihar, V. K. and C. L. Limoli. (2013), "Cranial irradiation compromises neuronal architecture in the hippocampus", Proceedings of the National Academy of Sciences of the United States of America, Vol. 110/31, National Academy of Sciences, Washington 

Reisz, J. A. et al. (2014), "Effects of Ionizing Radiation on Biological Molecules—Mechanisms of Damage and Emerging Methods of Detection", Antioxidants & Redox Signaling, Vol. 21/2, Mary Ann Liebert, Inc., New Rochelle, 

Rola, R. et al. (2005), "High-LET radiation induces inflammation and persistent changes in markers of hippocampal neurogenesis", Radiation Research (Volume 164, pp. 556–560), BioOne, Washington, 

Rola, R. et al. (2007), "Lack of extracellular superoxide dismutase (EC-SOD) in the microenvironment impacts radiation-induced changes in neurogenesis", Free Radical Biology and Medicine, Vol. 42/8, Pergamon, Bergama, 

Shirai, K. et al. (2006), "Differential effects of x-irradiation on immature and mature hippocampal neurons in vitro", Neuroscience Letters, Vol. 399/1–2, Elsevier, Amsterdam, 

Shirai, K. et al. (2013), "X Irradiation Changes Dendritic Spine Morphology and Density through Reduction of Cytoskeletal Proteins in Mature Neurons", Radiation Research, Vol. 179/6, Allen Press, Lawrence, 

Takahashi, H. et al. (2003), "Drebrin-Dependent Actin Clustering in Dendritic Filopodia Governs Synaptic Targeting of Postsynaptic Density-95 and Dendritic Spine Morphogenesis", The Journal of Neuroscience, Vol. 23/16, Society for Neuroscience, Washington, 

Tiller-Borcich, J. K. et al. (1987), "Pathology of Delayed Radiation Brain Damage: An Experimental Canine Model", Radiation Research, Vol. 110/2, Allen Press, Lawrence, 

Whoolery, C. W. et al. (2017), "Whole-body exposure to 28Si-radiation dose-dependently disrupts dentate gyrus neurogenesis and proliferation in the short term and new neuron survival and contextual fear conditioning in the long term", Radiation Research, Vol. 188/5, Radiation Research Society,