This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 384

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

Altered, Neurophysiology leads to Cognitive Function, Decreased

Upstream event

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

Altered, Neurophysiology

Downstream event

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

Cognitive Function, Decreased

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
XX Inhibition of Sodium Iodide Symporter and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	adjacent	Moderate	Low	Evgeniia Kazymova (send email)	Not under active development

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

Cognitive function and impairments thereof are measured using behavioral techniques. It is well accepted that these alterations in behavior are the result of structural or functional changes in neurocircuitry. Functional impairments are often measured using field potentials of critical synaptic circuits in hippocampus and cortex. A number of studies have been performed in rodent models that reveal deficits in both excitatory and inhibitory synaptic transmission in the hippocampus as a result of developmental thyroid insufficiency.

A well established model of memory at the synaptic levels is known as long-term potentiation (LTP). Deficiencies in LTP are generally regarded as potential substrates of learning and memory impairments.

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

A number of studies have consistently reported alterations in synaptic transmission resulting from developmental TH disruption and impairments in behavioral tasks assessing learning and memory. It is not clear if all behavioral impairments reported can be directly tied to synaptic dysfunction in the brain regions within which neurotransmission deficits have been recorded. It is not unreasonable to posit that the mechanisms of supporting synaptic transmission and synaptic strengthening are similar in different regions of the brain that support learning and memory and that demonstration at one site where it is most readily assessed implicates this mechanism may also be impaired at other sites as well.

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

It is well accepted that alterations in synaptic transmission and plasticity contribute to deficits in cognitive function. There are a few studies that have linked exposure to TPO inhibitors (e.g., PTU, MMI) and well as iodine deficient diets, to changes in serum TH levels and have measured both alterations in both synaptic function and cognitive behaviors (Opazo et al., 2009; Dong et al., 2005; Gilbert, 2011; Gilbert and Sui, 2006).

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

Developmental hypothyroidism reduces the functional integrity in brain regions critical for learning and memory. Neurophysiological indices of synaptic transmission of excitatory and inhibitory circuitry are impaired in hypothyroid animals. Two regions of the hippocampus, area CA1 and the dentate gyrus, have received the most study due to their ease of assess and the robustness of the recorded responses in ex vivo and in vivo preparations. Both regions exhibit alterations in excitatory and inhibitory synaptic transmission following reductions in serum TH in the pre and early postnatal period (Dong et al., 2005; Gilbert, 2011; Gilbert and Sui, 2006; Sui and Gilbert, 2003; Taylor et al., 2008; Vara et al, 2002). These deficits persist into adulthood long after recovery to euthyroid status (Gilbert and Sui; 2006; Gilbert, 2011). The latter observation indicates that these alterations represent permanent changes in brain function induced from transient hormones insufficiencies induced during critical window of development.

Because the adult hippocampus is involved in learning and memory, it is a brain region of remarkable plasticity. Use-dependent synaptic plasticity is critical during brain development for synaptogenesis and fine tuning of synaptic connectivity. In the adult brain, similar plasticity mechanisms underlie use-dependency that underlies learning and memory as exhibited in long-term potentiation (LTP) model of synaptic memory. Hypothyroidism during development reduces the capacity for synaptic plasticity in juvenile and adult offspring (Taylor et al., 2008; Sui and Gilbert, 2003; Gilbert and Sui, 2006; Gilbert, 2011; Dong et al., 2005).

In animal models of developmental hypothyroidism, deficits in passive avoidance learning, spatial learning, and operant conditioning (Davenport and Dorcey 1972; Schalock et al. 1979; Tamasy et al. 1986; Akaike et al. 1991; Brosvic et al, 2002), have been reported, but these early observations are often limited to animals suffering fairly severe hormonal deprivation. At these levels of hormone deprivation, clear evidence of synaptic dysfunction and impaired plasticity has been reported (Dong et al., 2005; Vara et al., 2002; Gilbert and Pazckowski, 2003). More recent data have demonstrated persistent impairments in a variety of learning tasks with more modest reductions in serum TH induced by TPO inhibitors (Axelstad et al., 2009; Darbra et al., 2003; 2004; Gilbert and Sui, 2006; Gilbert, 2011). Subtle impairments accompanying moderate levels of hormone insufficiency require more sensitive behavioral assessments and have been observed coincident with synaptic transmission and plasticity deficits (Gilbert, 2011).

Temporal concordance of TH insufficiency and disrupted development, defined at many levels of biological organization. There are critical windows during development where permanent changes are affected. Hormone replacement studies have demonstrated that structural alterations in brain are reduced or eliminated if T4 (and/or T3) treatment is given during the critical windows (Goodman and Gilbert, 2008; Auso et al., 2004; Lavado-Autric et al., 2003; Berbel et al., 2010; Koibuchi and Chin, 2000). Induction of graded degrees of TH insufficiency in dams and pups by administering varying doses of TPO inhibitors have demonstrated, in the absence of overt signs of toxicity in dams or the pups, dose-dependent alterations in synaptic transmission, synaptic plasticity, and performance on a variety of learning and memory tasks (Gilbert and Sui, 2006; Gilbert, 2011; Dong et al., 2005; Gilbert et al., 2013; Sui and Gilbert, 2003; Taylor et al., 2008).

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

The direct relationship of alterations in synaptic function and specific cognitive deficits is difficult to ascertain given the many forms that learning and memory can take and the complexity of synaptic interactions in even the simplest brain circuit. Linking of neurophysiological assessments to learning and memory processes have, by necessity, been made across simple monosynaptic connections and largely focused on the hippocampus. Alterations in synaptic function, however, have been found in the absence of behavioral impairments (e.g., Gilbert et al., 2013; 2007). This may result from: 1) Measuring only one component in the complex brain circuitry that underlies 'cognition' 2) Behavioral tests typically used in large dose-response studies allow for processing of large numbers of animals and may not be sufficiently sensitive to detect subtle cognitive impairments 3) Behavioral tasks may be solved by a number of differnt strategies - animals develop alernative strategies as a consequence of developmental insult to compensate for impaired ability.

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

There is very limited information on the degree of change in synaptic activity required to alter cognitive behaviors. This is a result of the diversity of methods for measuring both physiology and cognitive function, that hamper cross-study analyses.

This highlights the need to develop empirical data based models of this key relationship.

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

Synaptic transmission and plasticity are acheived via mechanisms common across taxonomies. LTP has been recorded in aplysia, lizards, turtles, birds, mice, guinea pigs, rabbits and rats.

References

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

These references need to be checked. Section on acute effects T3 on LTP and PPF in adult also needs to be added to text above.

Akaike M, Kato N, Ohno H, Kobayashi T (1991) Hyperactivity and spatial maze learning impairment of adult rats with temporary neonatal hypothyroidism. Neurotoxicol Teratol 13:317-322.

Axelstad M, Hansen PR, Boberg J, Bonnichsen M, Nellemann C, Lund SP, Hougaard KS, U H. Developmental neurotoxicity of propylthiouracil (PTU) in rats: Relationship between transient hypothyroxinemia during development and long-lasting behavioural and functional changes. Toxicol Appl Pharmacol 2008;232(1):1-13.

Berbel P, et al. Distribution of parvalbumin immunoreactivity in the neocortex of hypothyroid adult rats. Neurosci Lett 1996, 204(1-2), 65-68.

Brosvic, G. M., J. N. Taylor, et al. (2002). "Influences of early thyroid hormone manipulations: delays in pup motor and exploratory behavior are evident in adult operant performance." Physiol Behav 75(5): 697-715.

Darbra, S., F. Balada, et al. (2004). "Perinatal hypothyroidism effects on step-through passive avoidance task in rats." Physiol Behav 82(2-3): 497-501.

Darbra, S., A. Garau, et al. (2003). "Perinatal hypothyroidism effects on neuromotor competence, novelty-directed exploratory and anxiety-related behaviour and learning in rats." Behav Brain Res 143(2): 209-15.

Davenport, J. W. and T. P. Dorcey (1972). Hypothyroidism: learning deficit induced in rats by early exposure to thiouracil. Horm Behav 3(2): 97-112.

Gilbert ME. Impact of low-level thyroid hormone disruption induced by propylthiouracil on brain development and function. Toxicol Sci. 2011;124(2):432-445.

Dong, J., Yin, H., Liu, W., Wang, P., Jiang, Y., and Chen, J. (2005). Congenital iodine deficiency and hypothyroidism impair LTP and decrease C-fos and C-jun expression in rat hippocampus. Neurotoxicology 26, 417–426.

Gilbert ME, Rovet J, Chen Z, Koibuchi N. Developmental thyroid hormone disruption: Prevalence, environmental contaminants and neurodevelopmental consequences. Neurotoxicology. 2012;33(4):842-852.

Gilbert ME. Impact of low-level thyroid hormone disruption induced by propylthiouracil on brain development and function. Toxicol Sci. 2011;124(2):432-445.

Gilbert ME, et al. Thyroid hormone insufficiency during brain development reduces parvalbumin immunoreactivity and inhibitory function in the hippocampus. Endocrinology 2007, 148(1), 92-102.

Gilbert, M. E., and Sui, L. (2008). Developmental exposure to perchlorate alters synaptic transmission in hippocampus of the adult rat. Environ. Health Perspect. 116, 752–760.

Koibuchi N, Chin WW. Thyroid hormone action and brain development. Trends Endocrinol Metab 2000, 11(4), 123-128.

Mirabella, G., D. Feig, et al. (2000). "The effect of abnormal intrauterine thyroid hormone economies on infant cognitive abilities." J Pediatr Endocrinol Metab 13(2): 191-4.

Opazo, M. C., Gianini, A., Pancetti, F., Azkcona, G., Alarco´n, L., Lizana, R.,Noches, V., Gonzalez, P. A., Marassi, M. P., Mora, S., et al. (2008). Maternal hypothyroxinemia impairs spatial learning and synaptic nature and function in the offspring. Endocrinology 149, 5097–5106.

Sui, L., W. L. Anderson, et al. (2005). "Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampal area CA1 following developmental thyroid hormone insufficiency." Toxicol Sci 85(1): 647-56.

Sui, L. and M. E. Gilbert (2003). "Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus." Endocrinology 144(9): 4195-203.

Sui, L., F. Wang, et al. (2006). "Adult-onset hypothyroidism impairs paired-pulse facilitation and long-term potentiation of the rat dorsal hippocampo-medial prefrontal cortex pathway in vivo." Brain Res 1096(1): 53-60.

Sui, L., F. Wang, et al. (2006). "Dorsal hippocampal administration of triiodothyronine enhances long-term memory for trace cued and delay contextual fear conditioning in rats. J Neuroendocrinol 18(11): 811-9.

Insert non-formatted text hereSchalock, R. L., W. J. Brown, et al. (1979). "Long-term effects of propylthiouracil-induced neonatal hypothyroidism." Dev Psychobiol 12(3): 187-99.

Tamasy, V., E. Meisami, et al. (1986). Rehabilitation from neonatal hypothyroidism: spontaneous motor activity, exploratory behavior, avoidance learning and responses of pituitary-thyroid axis to stress in male rats. Psychoneuroendocrinology 11(1): 91-103.

Taylor MA, Swant J, Wagner JJ, Fisher JW, Ferguson DC. Lower thyroid compensatory reserve of rat pups after maternal hypothyroidism: correlation of thyroid, hepatic, and cerebrocortical biomarkers with hippocampal neurophysiology. Endocrinology. 2008 Jul;149(7):3521-30.

Vara H, et al. Thyroid hormone regulates neurotransmitter release in neonatal rat hippocampus. Neuroscience 2002, 110(1), 19-28.

Willoughby KA, McAndrews MP, Rovet J. Effects of maternal hypothyroidism on offspring hippocampus and memory. Thyroid, 2014;24:576-584.

Zoeller, R. T. and J. Rovet (2004). "Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings." J Neuroendocrinol 16(10): 809-18.