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Relationship: 2412


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

Increased Cholinergic Signaling leads to Cognitive Function, Decreased

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
Organo-Phosphate Chemicals induced inhibition of AChE leading to impaired cognitive function non-adjacent Moderate Moderate Brendan Ferreri-Hanberry (send email) Under development: Not open for comment. Do not cite

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

Sex Applicability

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

Life Stage Applicability

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

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

Acetylcholine signaling underlies the specific aspect of cognitive function including learning and memory, simultaneously acetylcholine is regulated by disperse group of cholinergic neurons (Luchicchi A et al., 2014). Cholinergic signaling refers to the activation of receptors bound with acetylcholine and here receptors defines as acetylcholine or cholinergic receptors which classify into Muscarinic and Nicotinic receptors ( Precious work documented that Acetylcholine (Ach) released from cholinergic input of basal forebrain play important role in supporting neurocognitive function (Berman JA et al., 2007). The loss of basal forebrain cholinergic neuron is directly linked to decrease in Ach release in hippocampus and cortex areas and to Alzheimer related cognitive dysfunction (Bekdash, R.A et al., 2021; Ballinger EC et al., 2016).  Thus cholinergic signaling is a key player in mediating cognitive performance.  Simultaneously previous worked showed that failure of cholinergic circuit of basal forebrain is accountable for cognitive impairment. Cholinergic signaling from medial septal (MS) and diagonal band (DB) to the hippocampus is certainly important for formation of spatial memories.  (Ballinger EC et al., 2016). Thus the role of cholinergic signaling in cognitive function is preserve. Prior work has also shown that stimulation of cholinergic neurons in the MS controlled via cholinergic basal forebrain - hippocampal projection and cholinergic to GABAergic basal forebrain to hippocampal pathway (Ballinger EC et al., 2016). Thus this two pathways worked synergistically to maximize hippocampal-firing (Dannenberg et al., 2015).

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

Evidence Supporting this KER

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

The weight of evidence supporting the relationship between decrease cognitive functions is induced by increased cholinergic signaling is 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

Cholinergic signaling is determined by the capacity of Ach to bind to respective Ach receptors on target neurons to modulate their excitability (Bekdash, R.A et al., 2021).  Previous study tested the hypothesis that failures of cholinergic circuitry of the basal forebrain are responsible for the cognitive impairments associated with neurodegenerative disorders (Ballinger EC et al., 2016; Bartus et al., 1982). Study have further connect alterations in cholinergic signaling in disorders of attention and cognitive control (Ballinger EC et al., 2016; Higley and Picciotto, 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

Many experimental studies have recommended that cholinergic neurotransmission dysfunction in the cerebral hippocampus and cortex plays an important role in cognitive impairment [R. Schliebs and T. Arendt et al., 2006].

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
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

In vertebrates, ACh is released during neurotransmission via cholinergic neurons, are found in the brain and spinal cord, including the basal forebrain. Brain cholinergic systems regulate vital cognitive processes including learning, memory (Rima, M et al., 2020). In human: Patients experiencing cholinergic poisoning constricted or pinpointed pupils are commonly reported in clinical cohort studies casing organophosphate exposure (, Wadia, 1974, Peter, 2014).  In embryonic fish and frogs: Spontaneous movements in developing fish and frog embryos are demarcated as flexing or side-to-side motion of the trunk or tail and free-swimming activity. The number of movements per minute was recorded by embryonic study under a dissection microscope. In zebrafish embryos spontaneous motion were observed at 1 day post fertilization and in Xenopus at 2 day post fertilization (, Watson, 2014).


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

Ahmed NY, Knowles R, Dehorter N. New Insights Into Cholinergic Neuron Diversity. Front Mol Neurosci. 2019 Aug 27;12:204. doi: 10.3389/fnmol.2019.00204. PMID: 31551706; PMCID: PMC6736589.

Ballinger EC, Ananth M, Talmage DA, Role LW. Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline. Neuron. 2016 Sep 21;91(6):1199-1218. doi: 10.1016/j.neuron.2016.09.006. PMID: 27657448; PMCID: PMC5036520.

Ballinger EC, Ananth M, Talmage DA, Role LW. Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline. Neuron. 2016 Sep 21;91(6):1199-1218. doi: 10.1016/j.neuron.2016.09.006. PMID: 27657448; PMCID: PMC5036520.

Bartus RT, Dean RL 3rd, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982; 217:408–414. [PubMed: 7046051].

Bekdash, R.A. The Cholinergic System, the Adrenergic System and the Neuropathology of Alzheimer’s Disease. Int. J. Mol. Sci. 2021, 22, 1273.

Berman JA, Talmage DA, Role LW. Cholinergic circuits and signaling in the pathophysiology of schizophrenia. Int Rev Neurobiol. 2007;78:193-223. doi:10.1016/S0074-7742(06)78007-2

Dannenberg H, Pabst M, Braganza O, Schoch S, Niediek J, Bayraktar M, Mormann F, Beck H. Synergy of direct and indirect cholinergic septo-hippocampal pathways coordinates firing in hippocampal networks. J Neurosci. 2015 Jun 3;35(22):8394-410. doi: 10.1523/JNEUROSCI.4460-14.2015

Hasselmo, M.E.; Sarter, M. Modes and Models of Forebrain Cholinergic Neuromodulation of Cognition. Neuropsychopharmacology2011, 36, 52–73. [CrossRef]

Hayes, W.J.; Jr, & Laws, E.R.; Jr (1991). Organic Phosphorous Pesticides: In Handbook of Pesticide Toxicology. Vol. 3. Acad. Press,1-1189 San Diego, New York, Boston, London, Sydney, Tokyo, Toronto. ISBN-10: 0123341604.

Higley MJ, Picciotto MR. Neuromodulation by acetylcholine: examples from schizophrenia and depression. Curr Opin Neurobiol. 2014; 29:88–95. [PubMed: 24983212]

Luchicchi A, Bloem B, Viaña JNM, Mansvelder HD, Role LW. Illuminating the role of cholinergic signaling in circuits of attention and emotionally salient behaviors. Frontiers in Synaptic Neuroscience. 2014;6(24).

Peter, John Victor, Thomas Sudarsan, and John Moran. 2014. “Clinical Features of Organophosphate Poisoning: A Review of Different Classification Systems and Approaches.” Indian Journal of Critical Care Medicine 18 (11): 735–45.

Picciotto, M.R.; Higley, M.J.; Mineur, Y.S. Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior. Neuron 2012, 76, 116–129. [CrossRef]

R. Schliebs and T. Arendt, “The significance of the cholinergic system in the brain during aging and in Alzheimer’s disease,” Journal of Neural Transmission, vol. 113, no. 11, pp. 1625–1644, 2006.

Rima, M., Lattouf, Y., Abi Younes, M. et al. Dynamic regulation of the cholinergic system in the spinal central nervous system. Sci Rep 10, 15338 (2020).

Wadia RS, Sadagopan C, Amin RB, Sardesai HV. Neurological manifestations of organophosphorous insecticide poisoning. J Neurol Neurosurg Psychiatry. 1974 Jul;37(7):841-7.

Watson, Fiona L., Hayden Schmidt, Zackery K. Turman, Natalie Hole, Hena Garcia, Jonathan Gregg, Joseph Tilghman, and Erica A. Fradinger. 2014. “Organophosphate Pesticides Induce Morphological Abnormalities and Decrease Locomotor Activity and Heart Rate in Danio Rerio and Xenopus Laevis.” Environmental Toxicology and Chemistry 33 (6): 1337–45.

Wayne R. Snodgrass, Chapter 60 - Diagnosis and Treatment of Poisoning Due to Pesticides,Editor(s): Robert Krieger, Hayes' Handbook of Pesticide Toxicology (Third Edition), Academic Press, 2010, Pages 1295-1311, ISBN 9780123743671,

Woolf, N.J.; Butcher, L.L. Cholinergic Systems Mediate Action from Movement to Higher Consciousness. Behav. Brain Res. 2011,221, 488–498.