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Relationship: 2955

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

Disruption, neurotransmitter release leads to Impairment, Learning and memory

Upstream event

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

Disruption, neurotransmitter release

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
Activation of MEK-ERK1/2 leads to deficits in learning and cognition via disrupted neurotransmitter release	adjacent	Moderate		Travis Karschnik (send email)	Under development: Not open for comment. Do not cite
Binding and activation of GPER leading to learning and memory impairments	adjacent	Moderate		Zedong Ouyang (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 Do not cite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

Term	Scientific Term	Evidence	Link
Rattus norvegicus	Rattus norvegicus	Moderate	NCBI
Mus musculus	Mus musculus	Moderate	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	High

Life Stage Applicability

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

Term	Evidence
All life stages	High

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

Neurotransmitters and their receptors are essential for brain functioning, learning, and memory. Catecholamines, including dopamine and norepinephrine, are the main neurotransmitters that mediate a variety of central nervous system (CNS) functions, such as motor control, cognition, emotion, memory processing, and endocrine modulation, determined by recent molecular genetic approaches in mice (Handra et al., 2019).

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

This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. The KER is referenced in publications which were cited in the originating work for the putative AOP "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis", Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework, Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June.

This evidence was assembled from a literature search relying on standard search engines such as PubMed, Web of Science, Google Scholar, Environmental Index, Scopus, Toxline, and Toxnet and the search strategy included terms related to metal mixtures, individual metals (e.g., arsenic, lead, manganese, and cadmium), neurodevelopmental health outcomes, and associated Medical Subject Headings (MeSH) terms.

Evidence Supporting this KER

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

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

The N-methyl-D-aspartate receptor (NMDAR) plays an essential role in hippocampus-mediated learning and memory, based on studies showing that intra-ventricular administration of an NMDAR antagonist (aminophosphonovaleric acid (APV)) in rats resulted in spatial learning impairments similar to those encountered with hippocampal lesions (Morris et al., 1982; Morris et al., 1986).

Memory acquisition is considered to involve both short-term changes in electrical properties and long-term structural alterations in synapses. Short-term changes may include LTP and LTD whereas long-term morphological alterations may involve synaptogenesis and neuropil growth (Burns and Augustine 1995; Edwards 1995). Since BDNF significantly modulates both forms of synaptic changes and the expression is upregulated during memory acquisition, as described above, it may play a role in learning and memory (Lo DC 1995; Thoenen 1995; McAllister et al., 1999).

Cortical acetylcholine release increases (1) during acquisition but not during recall of a rewarded operant behavior (Orsetti et al., 1996), (2) during acquisition of operant tasks when demands on attentional processing are high (Muir et al., 1996),(3) during conditioned taste aversion (Miranda et al., 2003), and (4) during performance of visual attentional tasks (Himmelheber et al., 2001). It has been also related to attentional effort (Himmelheber et al., 2001). Furthermore, in the hippocampus, ACh release increases during the performance of a learned spatial memory task (Ragozzino et al., 1996; Stancampiano R, et al., 1999) and the increase is positively correlated to performance improvement during task learning (Fadda et al., 2000), showing that cholinergic neurons are modified functionally during learning and become progressively more active. Also, the initial use of a place strategy coincided with an immediate increase in hippocampus ACh release (Chang and Gold 2003). Furthermore, as rewarded spontaneous alternation testing progressed, a switch to a repetitive response strategy accompanied an increase in striatum ACh release (Pych JC et al., 2005).

The release of acetylcholine in different brain areas appears to be involved in processes of attention (Marrosu et al., 1995), detection of novelty or saliency (Baxter et al., 1999), and during the consolidation of different types of long-term memory (Power 2004; McIntyre et al., 2003; Hasselmo 1999).

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

Miranda 2007 reviews many studies which demonstrate the activation of neurotransmitters such as glutamate, noradrenaline, and dopamine in several types of learning and during several stages of memory formation. The results of innumerable studies indicate that during memory formation different regions of the brain act in coordinated fashion through different neurotransmission systems (Miranda 2007).

Targeted knockout of the NMDAR in the hippocampus impairs spatial learning (Neal and Guilarte 2010), lending further support to the role of the NMDAR in hippocampus-mediated learning processes.

A neurotransmitter system that has been previously linked with the cognitive functions is the glutamate NMDA receptor system (May Simera and Levin 2003; Li et al., 2013). In 1991, Izquierdo, with the help of NMDA receptor antagonists (which impaired spatial working memory), concluded that if repeatedly stimulated, this system can regulate cognition (Izquierdo 1991). What is more, it was observed that blocking the NMDA receptor induces a resembling degree of memory impairment as the excision of the hippocampus (Lupușoru et al., 2017).

Learning-induced increases of ACh in the hippocampus and cortex have two important characteristics that strongly suggest that these increases are involved in memory consolidation (Power et al., 2003). First, the ACh increases induced during acquisition persist for at least 15 min after the end of the task (Orsetti et al., 1996; Ragozzino et al., 1996; Kopf et al., 2001; Miranda and Bermúdez-Rattoni 1999; Toumane et al., 1988). It is well established that during this posttraining period memory consolidation is strongly influenced by endogenous hormones and is highly susceptible to disruption and modulation by pharmacological interventions (McGaugh and Izquierdo 2000; McGaugh 2000). Furthermore, the persistence of the ACh levels in the hippocampus and cortex is correlated with the duration of these structures’ involvement in memory consolidation (Power et al., 2003).

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

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

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

Response-response Relationship

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

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

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

References

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

A. Toumane, T. Durkin, A. Marighetto, D. Galey, R. Jaffard Differential hippocampal and cortical cholinergic activation during the acquisition, retention, reversal and extinction of a spatial discrimination in an 8-arm radial maze by mice Behavioural Brain Research, 30 (1988), pp. 225-234

Ann E. Power, Almira Vazdarjanova, James L. McGaugh, Muscarinic cholinergic influences in memory consolidation, Neurobiology of Learning and Memory, Volume 80, Issue 3, 2003, Pages 178-193, ISSN 1074-7427

Baxter MG, et al. Impairments in conditioned stimulus processing and conditioned responding after combined selective removal of hippocampal and neocortical cholinergic input. Behav Neurosci. 1999;113:486.

Burns ME, Augustine GJ. Synaptic structure and function: dynamic organization yields architectural precision. Cell 1995; 83: 187–94.

Chang Q, Gold PE. Switching memory systems during learning: changes in patterns of brain acetylcholine release in the hippocampus and striatum in rats. J Neurosci. 2003;23:3001.

Dalley JW, et al. Distinct changes in cortical acetylcholine and noradrenaline efflux during contingent and noncontingent performance of a visual attentional task. J Neurosci. 2001;21:4908.

Edwards FA. Anatomy and electrophysiology of fast central synapses lead to a structural model for long-term potentiation. Physiological Reviews 1995; 75: 759–87.

Fadda F, Cocco S, Stancampiano R. A physiological method to selectively decrease brain serotonin release. Brain Res Brain Res Protoc. 2000;5:219.

Handra, Claudia, et al. "The connection between different neurotransmitters involved in cognitive processes." Farmacia 67.2 (2019): 193-201.

Hasselmo ME. Neuromodulation: acetylcholine and memory consolidation. Trends Cogn Sci. 1999;3:351.

Himmelheber AM, Sarter M, Bruno JP. Increases in cortical acetylcholine release during sustained attention performance in rats. Brain Res Cogn Brain Res. 2000;9:313.

Izquierdo, Ivan. "Role of NMDA receptors in memory." Trends in Pharmacological Sciences 12.4 (1991): 128-129.

J.L. McGaugh Memory—a century of consolidation Science, 287 (2000), pp. 248-251

J.L. McGaugh, I. Izquierdo The contribution of pharmacology to research on the mechanisms of memory formation Trends in Pharmacological Sciences, 21 (2000), pp. 208-210

Li S, Nai Q, Lipina TV, Roder JC, Liu F, α7nAchR/NMDAR coupling affects NMDAR function and object recognition. Mol Brain, 2013, 6: 1-10.

Lo DC. Neurotrophic factors and synaptic plasticity. Neuron 1995; 15: 979–81.

Lupușoru CE, Popa EG, Sandu RB, Buca BR, Mititelu-Tarțău L, Lupușoru RV, The influence of Bidens tripartita extracts on psychomotor abilities and cognitive functions in rats. Farmacia, 2017; 65(2): 284-288.

M.I. Miranda, F. Bermúdez-Rattoni Reversible inactivation of the nucleus basalis magnocellularis induces disruption of cortical acetylcholine release and acquisition, but not retrieval, of aversive memories Proceedings of the National Academy of Sciences of the United States of America, 96 (1999), pp. 6478-6482

Marrosu F, et al. Microdialysis measurement of cortical and hippocampal acetylcholine release during sleep–wake cycle in freely moving cats. Brain Res. 1995;671:329.

May-Simera H, Levin ED, NMDA systems in the amygdala and piriform cortex and nicotinic effects on memory function. Cogn Brain Res., 2003; 17:475-483

McAllister AK, Katz LC, Lo DC. Neurotrophins and synaptic plasticity. Annual Review of Neuroscience 1999; 22: 295–318

McIntyre CK, Marriott LK, Gold PE. Cooperation between memory systems: acetylcholine release in the amygdala correlates positively with performance on a hippocampus-dependent task. Behav Neurosci. 2003;117:320.

Miranda MI, et al. Role of cholinergic system on the construction of memories: taste memory encoding. Neurobiol Learn Mem. 2003;80:211.

Miranda MI. Changes in Neurotransmitter Extracellular Levels during Memory Formation. In: Bermúdez-Rattoni F, editor. Neural Plasticity and Memory: From Genes to Brain Imaging. Boca Raton (FL): CRC Press/Taylor & Francis; 2007. Chapter 7.

Morris RG, Garrud P, Rawlins JN, O’Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683

Morris RGM, Anderson E, Lynch GS, Baudry M (1986) Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319:774–776

Muir JL, Everitt BJ, Robbins TW. The cerebral cortex of the rat and visual attentional function: dissociable effects of mediofrontal, cingulate, anterior dorsolateral, and parietal cortex lesions on a five-choice serial reaction time task. Cereb Cortex. 1996;6:470.

Neal AP, Guilarte TR. Molecular neurobiology of lead (Pb2+): Effects on synaptic function. Molecular Neurobiology, 2010; 42:151–160.

Orsetti M, Casamenti F, Pepeu G. Enhanced acetylcholine release in the hippocampus and cortex during acquisition of an operant behavior. Brain Res. 1996;724:89.

Power AE. Muscarinic cholinergic contribution to memory consolidation: with attention to involvement of the basolateral amygdala. Curr Med Chem. 2004;11:987.

Pych JC, et al. Acetylcholine release in hippocampus and striatum during testing on a rewarded spontaneous alternation task. Neurobiol Learn Mem. 2005;84:93.

Ragozzino ME, Unick KE, Gold PE. Hippocampal acetylcholine release during memory testing in rats: augmentation by glucose. Proc Natl Acad Sci USA. 1996;93:4693.

S. Kopf, M. Buchholzer, M. Hilgert, K. Loffelholz, J. Klein Glucose plus choline improves passive avoidance behavior and increases hippocampal acetylcholine release in mice Neuroscience, 103 (2001), pp. 365-371

Stancampiano R, et al. Serotonin and acetylcholine release response in the rat hippocampus during a spatial memory task. Neuroscience. 1999;89:1135.

Thoenen H. Neurotrophins and neuronal plasticity. Science 1995; 270: 593–8.