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Relationship: 2836


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
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 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). 

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  


Effects on the KER  



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 



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 


Ramipril (Angiotensin converting enzyme inhibitor) 

Mitigated neurodegeneration and prevented cognitive impairment 

Hladik & Tapio, 2016 


Memantine (NMDA receptor antagonist) 

Reduced rate of memory decline after radiotherapy 

Bálentová & Adamkov, 2020 


Systemic hypoxia 

Systemic hypoxia reversed the effects of radiation on learning and memory 

Bálentová & Adamkov, 2020; Hladik & Tapio, 2016 

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

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. 


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

Achanta, P., M. Fuss and J. L. Martinez. (2009), "Ionizing Radiation Impairs the Formation of Trace Fear Memories and Reduces Hippocampal Neurogenesis", Behavioral Neuroscience, Vol. 123/5, 

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, 

Akiyama, K. et al. (2001), "Cognitive Dysfunction and Histological Findings in Adult Rats One Year After Whole Brain Irradiation.", Neurologia medico-chirurgica, Vol. 41/12, Japan Neurological Society, 

Bálentová, S. and M. Adamkov. (2020), "Pathological changes in the central nervous system following exposure to ionizing radiation", Physiological Research, Czech Academy of Sciences, 

Burgess, N. (2002), "The hippocampus, space, and viewpoints in episodic memory", The Quarterly Journal of Experimental Psychology, Vol. 55/4, Experimental Psychology Society, 

Cucinotta, F. A. et al. (2014), "Space radiation risks to the central nervous system", Life Sciences in Space Research, Vol. 2, Elsevier Ltd, Amsterdam, 

Desai, R. I. et al. (2022), "Impact of spaceflight stressors on behavior and cognition: A molecular, neurochemical, and neurobiological perspective", Neuroscience & Biobehavioral Reviews, Vol. 138, Elsevier, Amsterdam,

D’Hooge, R. and P. P. De Deyn. (2001), "Applications of the Morris water maze in the study of learning and memory", Brain Research Reviews, Vol. 36/1, Elsevier B.V.,

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., 

Hodges, H. et al. (1998), "Late behavioural and neuropathological effects of local brain irradiation in the rat", Behavioural Brain Research, Vol. 91/1–2, Elsevier, 

Howe, A. et al. (2019), "Long-term changes in cognition and physiology after low-dose 16 O irradiation", International Journal of Molecular Sciences, Vol. 20/1, MDPI AG, 

Kiffer, F., M. Boerma and A. Allen. (2019b), "Behavioral effects of space radiation: A comprehensive review of animal studies", Life Sciences in Space Research, Vol. 21, Elsevier, Amsterdam, 

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

Lamproglou, I. et al. (1995), "Radiation-induced cognitive dysfunction: An experimental model in the old rat", International Journal of Radiation Oncology, Biology, Physics, Vol. 31/1, Elsevier, 

Madsen, T. M. et al. (2003), "Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat", Neuroscience, Vol. 119/3, Elsevier Ltd, 

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

Monje, M. L. and T. Palmer. (2003), "Radiation injury and neurogenesis", Current Opinion in Neurology, Vol. 16/2, Ovid Technologies (Wolters Kluwer Health), 

National Council on Radiation Protection and Measures (NCRP). (2016). Commentary No. 25 – Potential for central nervous system effects from radiation exposure during space activities phase I: Overview.   

Parihar, V. K. et al. (2016), "Cosmic radiation exposure and persistent cognitive dysfunction", Scientific Reports, Vol. 6/1, Nature Publishing Group,

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, 

Raber, J. et al. (2004), "Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis", Radiation Research, Vol. 162/1, Allen Press, 

Rola, R. et al. (2004), "Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice", Experimental Neurology, Vol. 188/2, Academic Press Inc., 

Romanella, S. M. et al. (2020), "Noninvasive Brain Stimulation & Space Exploration: Opportunities and Challenges", Neuroscience & Biobehavioral Reviews, Vol. 119, 

Simmons, D. A. et al. (2019), "Reduced cognitive deficits after FLASH irradiation of whole mouse brain are associated with less hippocampal dendritic spine loss and neuroinflammation", Radiotherapy and Oncology, Vol. 139, 

Sorokina, S. S. et al. (2021), "Low dose of carbon ion irradiation induces early delayed cognitive impairments in mice", Radiation and Environmental Biophysics, Vol. 60, Nature, 

Tomé, W. A. et al. (2015), "Hippocampal-dependent neurocognitive impairment following cranial irradiation observed in pre-clinical models: current knowledge and possible future directions", The British Journal of Radiobiology, Vol. 89/1057, British Institute of Radiology, 

Vorhees, C. V. and M. T. Williams. (2014), "Assessing Spatial Learning and Memory in Rodents", ILAR Journal, Vol. 55/2, Oxford University Press, Oxford, 

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, 

Winocur, G. et al. (2006), "Inhibition of neurogenesis interferes with hippocampus-dependent memory function", Hippocampus, Vol. 16/3,