Upstream event7α-hydroxypregnenolone synthesis in the brain, decreased
Locomotor activity, decreased
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Inhibition of CYP7B activity leads to decreased reproductive success via decreased locomotor activity||non-adjacent||High||Moderate|
|Japanese quail||Coturnix japonica||NCBI|
|Cynops pyrrhogaster||Cynops pyrrhogaster||NCBI|
|Oncorhynchus keta||Oncorhynchus keta||NCBI|
Life Stage Applicability
|Adult, reproductively mature||High|
Key Event Relationship Description
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 Supporting this KER
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).
- 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
No inconsistency was reported so far.
Quantitative Understanding of the Linkage
- 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).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.