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Relationship: 2839


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, Pro-Inflammatory Mediators 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 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
human Homo sapiens Low NCBI
mouse Mus musculus Moderate NCBI
rat Rattus norvegicus Low NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages Moderate

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

Inflammatory mediators such as IL-1β, TNF-α, and IL-6, can influence the normal behavior of neuronal cells and their functional connection. Overexpression of pro-inflammatory mediators disrupts the integrity and function of the neuronal network through decreased neurogenesis, synaptic complexity and increased necrosis and demyelination, ultimately impairing learning and memory (Cekanaviciute, Rosi, & Costes, 2018; Fan & Pang, 2017). Impaired short-term and long-term memory, as well as associative learning are consequences of the dysregulated expression of pro-inflammatory cytokines as reported in behavioural paradigms (Donzis & Tronson, 2014).  

Under physiological conditions, cytokine levels are low but greatly increased in response to various insults. Cytokines mediate immune response through ligand binding to cell surface receptors, which activate signaling cascades such as the JAK-STAT or MAPK pathways to produce or recruit more cytokines. Once organs initiate inflammatory reactions, the cytokines can modulate different metabolic and molecular pathways that have direct effects on neurons or indirect effects mediated by microglia, astrocytes or vascular endothelial cells (Mousa & Bakhiet, 2013; Prieto & Cotman, 2018). Modulation of these pathways ultimately affects crucial neuronal networks such as that within the hippocampus, which is one of the main brain regions responsible for learning and memory (Barrientos et al., 2015; Bourgognon & Cavanagh, 2020). 

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 of biological plausibility between increase in pro-inflammatory mediators and impaired learning and memory. In the central nervous system, cytokines and their receptors are constitutively expressed and affect brain plasticity, which is the ability to modify its activity and connections in response to intrinsic or extrinsic stimuli. In a pathological state, pro-inflammatory, or Th-1 type cytokines become particularly relevant in the brain and these cytokines bind to their receptors to induce a conformational change and activate intracellular signaling pathways (Mousa & Bakhiet, 2013). The main cytokines presenting detrimental effects are IL-1β, TNF-α and IL-6, as these are the most studied.  

The mechanism by which these cytokines modify learning and memory processes are not clearly understood due to the complexity of inflammatory signaling, although it involves alterations in the neural circuits that regulate these processes (Bourgognon & Cavanagh, 2020; Pugh et al., 2001). Multiple studies have demonstrated that IL-1β presents a critical role in the formation of hippocampal dependent memory, as IL-1β and its receptor are highly expressed in the hippocampus. Experimentally elevated levels of IL-1β in the hippocampus lead to impaired performance in behavioral paradigms such as spatial memory, contextual learning, and passive avoidance tasks (Donzis & Tronson, 2014; Pugh et al. 2001; Yirmiya & Goshen, 2011).  

There are several possible mechanisms for this detrimental effect. One proposed mechanism is through reduced N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor functions, both of which are involved in long-term potentiation, a process that strengthens synaptic connections between neurons. Other potential mechanisms for the effects of IL-1β on brain plasticity and memory can involve the activation of several pathways such as p38 mitogen-activated protein kinase (MAPK), c-jun NH2-terminal kinase (JNK), caspase 1, nuclear factor kappa B (NF-kB), and brain-derived neurotrophic factor (BDNF). These complex pathways have roles in neuronal health, long-term potentiation, brain plasticity and ultimately learning and memory (Patterson, 2015). The mechanisms of IL-6 and TNF-α in terms of impaired cognition also remain unclear, although the pathways that these cytokines activate are similar to those of IL-1β due to the network of cytokine interactions (Donzis & Tronson, 2014). 

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
  • Due to the indirect linkage between the two key events, there is no clear understanding of how increases in pro-inflammatory mediators cause impaired learning and memory. (Donzis & Tronson, 2014). 

  • A previous prospective population-based cohort study found an association between antihistamine use and increased risk of dementia, which is the loss of cognitive functioning. Therefore, anti-inflammatory medications such as antihistamines could modulate the progression to impaired learning and memory (Gray et al., 2015). 

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  



NSPP (anti-inflammatory drug) 

There was a 0.35-fold decrease in IL-6 levels compared to controls when 10 Gy irradiated mice were treated with NSPP. Mice that were exposed to whole brain irradiation (10 Gy) and treated with NSPP (5 mg/kg) exhibited significantly improved performance in novel object recognition and object in place. 

Bhat et al., 2020 


α-MSH (modulator of action of pro-inflammatory cytokines) 

α-MSH injected into the hippocampus prevented the IL-1β-induced decrease in contextual fear memory. 

Gonzalez et al., 2009 


MW-151 (inhibitor of pro-inflammatory microglial cytokine production) 

Treatment decreased the OX-6+ cell density and restored memory. 

Jenrow et al., 2013 


Lidocaine (an anti-inflammatory local anesthetic) 

Lidocaine treatment restored IL-6 levels and improved memory. 

Tan et al., 2014 


Young age 

Rats aged 3 months showed increased IL-1β levels in the hippocampus for less time than in mice aged 24 months. Hippocampal-dependent memory was impaired in the old mice. The inflammatory response is shorter and less severe in young individuals, leading to reduced cognitive impairment. 

Barrientos et al., 2009; Barrientos et al., 2012 


E-EPA (known to improve cognitive function through reducing inflammation) 

E-EPA reduced the increase in IL-6 expression and improved memory to control levels. 

Taepavarapruk & Song, 2010 

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

Not identified.  

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 most of the evidence in mice. The relationship is not sex or life stage specific. 


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

Alley, D. E. et al. (2008), "Inflammation and Rate of Cognitive Change in High-Functioning Older Adults", The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, Vol. 63/1, Oxford University Press, Oxford, 

Alley, D. E. et al. (2008), "Inflammation and Rate of Cognitive Change in High-Functioning Older Adults", The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, Vol. 63/1, 

Barrientos, R. M. et al. (2015), "Neuroinflammation in the normal aging hippocampus", Neuroscience, Vol. 309, Elsevier, Amsterdam,

Barrientos, R. M. et al. (2009), "Time course of hippocampal IL-1 β and memory consolidation impairments in aging rats following peripheral infection", Brain, Behavior, and Immunity, Vol. 23/1, Elsevier, Amsterdam, 

Barrientos, R. M. et al. (2012), "Aging-related changes in neuroimmune-endocrine function: Implications for hippocampal-dependent cognition", Hormones and Behavior, Vol. 62/3, Elsevier, Amsterdam, 

Bhat, K. et al. (2020), "1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine treatment after brain irradiation preserves cognitive function in mice", Neuro-Oncology, Vol. 22/10, Oxford University Press, Oxford, 

Bourgognon, J.-M. and J. Cavanagh. (2020), "The role of cytokines in modulating learning and memory and brain plasticity", Brain and Neuroscience Advances, Vol. 4, 

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

Donzis, E. J. and N. C. Tronson. (2014), "Modulation of learning and memory by cytokines: Signaling mechanisms and long term consequences", Neurobiology of Learning and Memory, Vol. 115, Elsevier, Amsterdam, 

Fan, L. W. and Y. Pang. (2017), "Dysregulation of neurogenesis by neuroinflammation: key differences in neurodevelopmental and neurological disorders", Neural Regeneration Research, Vol. 12/3, Wolters Kluwer, 

Gonzalez, P. V. et al. (2009), "Memory impairment induced by IL-1β is reversed by α-MSH through central melanocortin-4 receptors", Brain, Behavior, and Immunity, Vol. 23/6, Elsevier, Amsterdam, 

Goshen, I. et al. (2007), "A dual role for interleukin-1 in hippocampal-dependent memory processes", Psychoneuroendocrinology, Vol. 32/8–10, Elsevier, Amsterdam, 

Gray, S. L. et al. (2015), "Cumulative Use of Strong Anticholinergics and Incident Dementia", JAMA Internal Medicine, Vol. 175/3, 

Hein, A. M. et al. (2010), "Sustained hippocampal IL-1β overexpression impairs contextual and spatial memory in transgenic mice", Brain, Behavior, and Immunity, Vol. 24/2, Elsevier, Amsterdam, 

Heyser, C. J. et al. (1997), "Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain", Proceedings of the National Academy of Sciences, Vol. 94/4, National Academy of Sciences, Washington, 

Holmes, C. et al. (2009), "Systemic inflammation and disease progression in Alzheimer disease", Neurology, Vol. 73/10, Wolters Kluwer, 

Jenrow, K. A. et al. (2013), "Selective Inhibition of Microglia-Mediated Neuroinflammation Mitigates Radiation-Induced Cognitive Impairment", Radiation Research, Vol. 179/5, BioOne, 

Moore, A. H. et al. (2009), "Sustained expression of interleukin-1β in mouse hippocampus impairs spatial memory", Neuroscience, Vol. 164/4, Elsevier, Amsterdam, 

Mousa, A. and M. Bakhiet. (2013), "Role of Cytokine Signaling during Nervous System Development", International Journal of Molecular Sciences, Vol. 14/7, MDPI, Basel, 

Patterson, S. L. (2015), "Immune dysregulation and cognitive vulnerability in the aging brain: Interactions of microglia, IL-1β, BDNF and synaptic plasticity", Neuropharmacology, Vol. 96, Elsevier, Amsterdam, 

Prieto, G. A. and C. W. Cotman. (2017), "Cytokines and cytokine networks target neurons to modulate long-term potentiation", Cytokine & Growth Factor Reviews, Vol. 34, Elsevier, Amsterdam, 

Pugh, C. R. et al. (2001), "The immune system and memory consolidation: a role for the cytokine IL-1β", Neuroscience & Biobehavioral Reviews, Vol. 25/1, Elsevier, Amsterdam, 

Schram, M. T. et al. (2007), "Systemic Markers of Inflammation and Cognitive Decline in Old Age", Journal of the American Geriatrics Society, Vol. 55/5, Wiley, 

Sparkman, N. L. et al. (2006), "Interleukin-6 Facilitates Lipopolysaccharide-Induced Disruption in Working Memory and Expression of Other Proinflammatory Cytokines in Hippocampal Neuronal Cell Layers", Journal of Neuroscience, Vol. 26/42, Society for Neuroscience, 

Taepavarapruk, P. and C. Song. (2010), "Reductions of acetylcholine release and nerve growth factor expression are correlated with memory impairment induced by interleukin-1β administrations: effects of omega-3 fatty acid EPA treatment", Journal of Neurochemistry, Vol. 112/4, Wiley 

Tan, H. et al. (2014), "Critical role of inflammatory cytokines in impairing biochemical processes for learning and memory after surgery in rats", Journal of Neuroinflammation, Vol. 11/1, Springer Nature, 

Yirmiya, R. and I. Goshen. (2011), "Immune modulation of learning, memory, neural plasticity and neurogenesis", Brain, Behavior, and Immunity, Vol. 25/2, Elsevier, Amsterdam,