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Event: 192

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Altered, Neurophysiology

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Altered, Neurophysiology

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Organ term
brain

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
abnormal nervous system physiology abnormal

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
NIS and Neurodevelopment KeyEvent Kevin Crofton (send email) Not under active development

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
rat Rattus norvegicus High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Discrete parts of nerve cells, single neurons, simple circuits, and complex brain systems have been used to evaluate the impact of thyroid disruption on brain function. The nervous system functions as a highly integrated and organized communication and information processing network. Neurons transmit and receive information from sensory and motor organs, but the largest number of neuronal connections is with other neurons. This is largely accomplished by chemical transmission across the synaptic cleft, the space where the specialized ending of the presynaptic axon terminus of the transmitting neuron meets the specialized postsynaptic region of the neuron that is receiving that information. Activation of the presynaptic neuron to produce an action potential causes the release of neurotransmitter substances into the synaptic cleft. Most of the released neurotransmitters bind with molecules at receptors on the dendrites of the postsynaptic neuron. The chemical signal is then transduced back into an electrical impulse which travels in the receiving neuron and if of sufficient magnitude, fires the neuron, and the signal is transduced once again to a chemical signal in the next neuron along the pathway. The scale of neurophysiological techniques that can be used ranges along a broad continuum from the very small (e.g., individual ion channel fluxes) to the very large anatomical pathways (e.g., electroencephalograms) in both in vitro and in vivo preparations.

A number of studies on TH and brain function have incorporated field potentials in the hippocampus, an area critical for certain forms of learning and memory, to probe functional integrity after TH insufficiency (e.g., Dong et al., 2005; Gilbert and Sui, 2006; Opazo et al., 2008; Vara et al., 2002). Field potentials have been recorded following thyroid disruption both in vivo and in vitro, at two discrete hippocampal synaptic regions, area CA1 and the dentate gyrus. Excitatory and inhibitory synaptic transmission are assessed by recording electrical field potentials (voltage changes across large populations of neurons) across a monosynaptic circuit (e.g. axons from cortical neurons that synapse on dentate gyrus granule cells) in response to electrical pulses delivered to the incoming pathway (Gilbert and Burdette, 1995).

The synapses in this region of the brain are also intensely studied as they are imbued with a capacity for use-dependent plasticity, the best studied model being long-term potentiation (LTP). LTP is a model of information acquisition (learning) and storage (memory) at the synaptic level. It is induced by applying trains of stimulus pulses at high frequencies to the incoming pathway of the monosynaptic circuit and measuring the amplitude of the induced change in synaptic responsiveness that persists for hours, and in some instances days to weeks (Malenka and Nicoll, 1999; Martinez and Derrick, 1996; Gilbert and Burdette, 1995). The induction of LTP is believed to emulate, both at the synaptic and molecular level, the coincident firing of large numbers of neurons that are engaged during a learning event. The persistence of LTP emulates the duration of the memory of that learning event.

Field potentials are recorded from slices of hippocampus taken from exposed animals, or from indwelling electrodes placed within the appropriate hippocampal field. One electrode is placed in the afferent fiber pathway (e.g., perforant path for dentate gyrus, Schaeffer collaterals for CA1 region) and a brief electrical pulse applied to stimulate these axons. A second electrode is placed in the synaptic or cell body region to record the activity evoked by the incoming pulse. Electrodes are placed visually according to established landmarks in in vitro preparations, and acccording to stereotaxic coordinates for in vivo preparations. Once accurately placed, a series of stimulus pulses at increasing stimulus current intensities are applied to the input pathway, and the response evoked in the receiving neuronal population is recorded.

Excitatory Synaptic Transmission: Two measures, the excitatory postsynaptic potential (EPSP) and the population spike are derived from the compound field potential in response to a series of single pulse stimulations applied at increasing stimulus strengths. The function described by the relationship of current strength (input) and evoked response (output), the I-O curve is the measure of excitatory synaptic transmission.

Inhibitory Synaptic Transmission: Pairs of stimulus pulses delivered in close temporal proximity is used to probe the integrity of inhibitory synaptic transmission. The response evoked by the second pulse of the pair at brief intervals (<30msec) arrives during the activation of feedback inhibitory loops in the hippocampus. An alteration in the degree of suppression to the 2nd pulse of the pair reflects altered inhibitory synaptic function.

Long Term Potentiation (LTP): Synaptic plasticity in the form of LTP is assessed by delivering trains of high frequency stimulation to induce a prolonged augmentation of synaptic responsivity. Probe stimuli at mid-range stimulus strenghts are delivered before and after application of LTP-inducing trains. The degree of increase in EPSP and PS amplitude to the probe stimulus after train application, and the longevity of that induced enhancement are metrics of LTP. Additionally, contrasting I-O functions of excitatory synaptic transmission before and after (1-5 hours) LTP is induced is also a common measure of induced LTP.

Assays of this type are fit for purpose, have been well accepted in the literature, and are reproducible across laboratories. The assay directly measures the key event of altered neurophysiological function.

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

The majority of evidence for this key event come from work in rodent species (i.e., rat, mouse). there is a moderate amount of evidence from other species.

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Dong, J., H. Yin, et al. (2005). "Congenital iodine deficiency and hypothyroidism impair LTP and decrease C-fos and C-jun expression in rat hippocampus." Neurotoxicology 26(3): 417-26.

Gilbert, M.E. and Burdette, L.J. (1995). Hippocampal Field Potentials: A Model System to Characterize Neurotoxicity. In Neurotoxicology: Approaches and Methods. L.W Chang and W. Slikker (Eds). Academic Press:New York, 183-204.

Gilbert, M. E. and L. Sui (2006). "Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency." Brain Res 1069(1): 10-22.

Malenka RC, Nicoll RA (1999) Long-term potentiation--a decade of progress? Science, 285:1870-1874.

Martinez, J.L. and Derrick, B.E. (1996). Long term potentiation and learning. Annual Review of Psychology, 47,173-203.

Opazo MC, Gianini A, Pancetti F, Azkcona G, Alarcón L, Lizana R, Noches V, Gonzalez PA, Marassi MP, Mora S, Rosenthal D, Eugenin E, Naranjo D, Bueno SM, Kalergis AM, Riedel CA (2008), Maternal hypothyroxinemia impairs spatial learning and synaptic nature and function in the offspring. Endocrinology 149:5097-5106.

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