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Relationship: 1495

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

7α-hydroxypregnenolone synthesis in the brain, decreased leads to Locomotor activity, decreased

Upstream event

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

7α-hydroxypregnenolone synthesis in the brain, decreased

Downstream event

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

Locomotor activity, 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
Inhibition of CYP7B activity leads to decreased reproductive success via decreased locomotor activity	non-adjacent	High	Moderate	Florence Pagé-Larivière (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

Term	Scientific Term	Link
Japanese quail	Coturnix japonica	NCBI
Cynops pyrrhogaster	Cynops pyrrhogaster	NCBI
Oncorhynchus keta	Oncorhynchus keta	NCBI

Sex Applicability

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

Sex	Evidence
Male

Life Stage Applicability

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

Term	Evidence
Adult, reproductively mature	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

The presence of 7α-hydroxypregnenolone in the brain is associated with locomotor activity in the salmon and in the male bird and newt. 7α-hydroxypregnenolone is a neurosteroid synthesized from pregnenolone by CYP7B in vertebrates including bird, newt, and fish. When 7α-hydroxypregnenolone concentration increases in the brain (endogenous or exogenous), these animals become active. Oppositely, decreased synthesis of 7α-hydroxypregnenolone limits locomotor activity (Matsunaga et al., 2004).

The importance of 7α-hydroxypregnenolone synthesis is sex dependent in bird and newt. In these species, only male locomotor activity is influenced by the neurosteroid (Matsunaga et al., 2004, Tsutsui et al., 2008). However, both male and female are affected by 7α-hydroxypregnenolone in salmon (haraguchi et al., 2015).

It was known before that locomotor activity in vertebrates fluctuated over a circadian and/or seasonal cycle, although the full mechanism was elusive (Saper et al., 2005). The discovery of 7α-hydroxypregnenolone activity in the brain allowed a better understanding of the locomotor activity regulation in the context of cyclic variations of the environment.

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

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 relationship between 7α-hydroxypregnenolone and locomotor activity is clearly established in quail, newt and salmon. However, the regulation of its synthesis differs in these species.

In diurnal bird such as quail, melatonin secretion during nighttime inhibits 7α-hydroxypregnenolone synthesis which is reflected by the decreased locomotor activity. Under daylight condition, melatonin secretion is abolished which induces an increase in 7α-hydroxypregnenolone and stimulates locomotor activity (Tsutsui et al., 2008).

Oppositely, newt is a nocturnal animal and melatonin secretion acts as an inducer of 7α-hydroxypregnenolone synthesis. Consequently, 7α-hydroxypregnenolone is elevated at night and drives locomotor activity (Koyama et al., 2009).

7α-hydroxypregnenolone concentration is also dependent on the peptide hormone prolactin secreted by the adenohypophysis, at least in male newt. Prolactin is a neuropeptide which secretion varies according to season. In newt, breeding season is characterized by an elevation of locomotor activity which correlates with a peak in brain prolactin concentration.

It is plausible that prolactin induces the same increase in locomotor activity in salmon during homing migration. During this period, both prolactin and CYP7B (7α-hydroxypregnenolone) are known to peak (Haraguchi et al., 2015; Onuma et al., 2010).

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

Intracranial injection of 7α-hydroxypregnenolone induced a significant increase in salmon, male quail and newt locomotor activity. The same injection had no effect on female quail and newt (Haraguchi et al., 2015).
Intracranial injection of ketoconazole, an inhibitor of 7α-hydroxypregnenolone synthesis, in male quail and newt decreases locomotor activity. The same injection had no effect on female quail and newt (Matsunaga et al., 2004, Tsutsui et al., 2008).
Intracranial delivery of melatonin, an inhibitor of 7α-hydroxypregnenolone synthesis, decreases locomotor activity in male quail (Tsutsui et al., 2008).
The concentration of 7α-hydroxypregnenolone in the male quail diencephalon is high between 7 AM and 1 PM and peaks at 11 AM. The locomotor activity follows the same pattern. However, the concentration of 7α-hydroxypregnenolone in the female brain is constantly low which correlates with their low locomotor activity.
Decreased 7α-hydroxypregnenolone in the salmon brain induced by aminoglutethimide (an inhibitor of CYP11A which induces a depletion of pregnenolone and a concurrent decline in 7α-hydroxypregnenolone concentration) abolishes salmon homing migration (Haraguchi et al., 2015).

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

No inconsistency was reported so far.

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

7α-hydroxypregnenolone injected in the quail brain (0, 10, or 100 ng) induced a dose-dependent increase of locomotor activity (Tsutsui et al., 2008).
The same experiment was conducted in the newt using 0.1, 0.5, or 1 ng. A dose-dependent increase of locomotor activity was observed (Matsunaga et al., 2004).
The same experiment was conducted in the chicken using 0.10, or 200 ng. A dose-dependent increase of locomotor activity was observed (Hatori et al., 2011).

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

Haraguchi, S., Yamamoto, Y., Suzuki, Y., Hyung Chang, J., Koyama, T., Sato, M., Mita, M., Ueda, H., and Tsutsui, K. (2015). 7alpha-Hydroxypregnenolone, a key neuronal modulator of locomotion, stimulates upstream migration by means of the dopaminergic system in salmon. Sci Rep 5, 12546.

Hatori M, Hirota T, Iitsuka M, et al. Light-dependent and circadian clock-regulated activation of sterol regulatory element-binding protein, X-box-binding protein 1, and heat shock factor pathways. Proc Natl Acad Sci U S A. 2011;108:4864–9

Koyama, T., Haraguchi, S., Vaudry, H., and Tsutsui, K. (2009). Diurnal changes in the synthesis of the neurosteroid 7alpha-hydroxypregnenolone stimulating locomotor activity in newts. Ann N Y Acad Sci 1163, 444-447.

Matsunaga, M., Ukena, K., Baulieu, E.E., and Tsutsui, K. (2004). 7alpha-Hydroxypregnenolone acts as a neuronal activator to stimulate locomotor activity of breeding newts by means of the dopaminergic system. Proc Natl Acad Sci U S A 101, 17282-17287.

Onuma, T.A., Ban, M., Makino, K., Katsumata, H., Hu, W., Ando, H., Fukuwaka, M.A., Azumaya, T., and Urano, A. (2010). Changes in gene expression for GH/PRL/SL family hormones in the pituitaries of homing chum salmon during ocean migration through upstream migration. Gen Comp Endocrinol 166, 537-548.

Saper, C.B., Lu, J., Chou, T.C., and Gooley, J. (2005). The hypothalamic integrator for circadian rhythms. Trends Neurosci 28, 152-157.

Tsutsui, K., Inoue, K., Miyabara, H., Suzuki, S., Ogura, Y., and Haraguchi, S. (2008). 7Alpha-hydroxypregnenolone mediates melatonin action underlying diurnal locomotor rhythms. J Neurosci 28, 2158-2167.