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Neuronal network function, Decreased leads to Cognitive Function, Decreased
Key Event Relationship Overview
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||SAROJ AMAR (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
An upstream key event decrease in neuronal network function leads to deficiency of learning and memory which is the sign of cognitive deficits (downstream, adverse outcome) (Anna Bal-Price et al., 2017). Learning and memory- a cognitive function is dependent to neuronal network function. Experimental approach advocates that in hippocampal neurons cognitive-induced enhancement in neuronal excitability, as a measurement of neural network function (Anna Bal-Price et al., 2017; Saar and Barkai, 2003). Cognitive defect is the functional output of neural networks of mammalian. Exposure to the potential developmental toxicants during neuronal differentiation and synaptogenesis will increase risk of functional neuronal network damage leading to learning and memory impairment (aopwiki.org/relationships/359). Cognitive defects like learning and memory are measured using behavioral test. It is well attested that the changes in behavior are the outcome of structural/ functional changes in neuronal network. Functional impairments are typically measured by field potentials of critical synaptic circuits in hippocampus. (Wang et al., 2012; Gilbert et al., 2016).
Evidence Supporting this KER
Morris water maze (MWM) test as a means to investigate spatial learning and memory in laboratory rats reveals that the disconnection among neuronal networks are responsible for the performance impairment of MWM test rather than the damage or injury of certain part of brain . (aopwiki.org/relationships/359; D'Hooge and De Deyn, 2001). However, it is well established that alterations in synaptic transmission and plasticity contribute to deficits in cognitive function (aopwiki.org/relationships/359).
Uncertainties and Inconsistencies
One of the major difficult concerns for neuroscientists is to link neuronal network function to cognition, including learning and memory. It is quiet blind that what alterations of neuronal circuits essential to observe change in motor behavior including learning and memory (Mayford et al., 2012), thus there is no any strong evidence defining that how these two KEs are connected (aopwiki.org/relationships/359). Thus it’s difficult to establish the direct relationship of alterations in neural network function and specific cognitive deficits due to the complexity of synaptic interactions in even the simplest brain circuit. (aopwiki.org/relationships/359).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
A common mechanisms across the taxonomies is working for synaptic transmission and plasticity. Long term synaptic potential has been recorded in aplysia, lizards, turtles, birds, mice, guinea pigs, rabbits and rats (aopwiki.org/relationships/359; aopwiki.org/relationships/384).
Anna Bal-Price, Pamela J. Lein, Kimberly P. Keil, Sunjay Sethi, Timothy Shafer, Marta Barenys, Ellen Fritsche, Magdalini Sachana, M.E. (Bette) Meek. Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity, NeuroToxicology, Volume 59, 2017, Pages 240-255, ISSN 0161-813X, https://doi.org/10.1016/j.neuro.2016.05.010.
D'Hooge R, De Deyn PP. (2001). Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev. 36: 60-90.
Gilbert ME, Sanchez-Huerta K, Wood C. (2016). Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 157:774-787.
Mayford M, Siegelbaum SA, Kandel ER. (2012). Synapses and memory storage. Cold Spring Harb Perspect Biol. 4. pii: a005751.
Palop JJ, Mucke L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci. 2016 Dec;17(12):777-792. doi: 10.1038/nrn.2016.141. Epub 2016 Nov 10. PMID: 27829687; PMCID: PMC8162106
Saar, D. and Barkai, E. (2003), Long-term modifications in intrinsic neuronal properties and rule learning in rats. European Journal of Neuroscience, 17: 2727-2734. https://doi.org/10.1046/j.1460-9568.2003.02699.x.
Wang S, Teng W, Gao Y, Fan C, Zhang H, Shan Z. (2012). Early levothyroxine treatment on maternal subclinical hypothyroidism improves spatial learning of offspring in rats. J Neuroendocrinol 24:841–848