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. 2009 Aug;150(8):3664-71.
doi: 10.1210/en.2009-0247. Epub 2009 May 14.

Circadian regulation of Kiss1 neurons: implications for timing the preovulatory gonadotropin-releasing hormone/luteinizing hormone surge

Jessica L Robertson  1 , Donald K Clifton, Horacio O de la Iglesia, Robert A Steiner, Alexander S Kauffman
Affiliations

Circadian regulation of Kiss1 neurons: implications for timing the preovulatory gonadotropin-releasing hormone/luteinizing hormone surge

Jessica L Robertson et al. Endocrinology. 2009 Aug.

Abstract

The preovulatory GnRH/LH surge depends on the presence of estradiol (E(2)) and is gated by a circadian oscillator in the suprachiasmatic nucleus (SCN) that causes the surge to occur within a specific temporal window. Although the mechanisms by which the clock times the LH surge are unclear, evidence suggests that the SCN is linked to GnRH neurons through a multisynaptic pathway that includes neurons in the anteroventral periventricular nucleus (AVPV). Recently, Kiss1 neurons in the AVPV have been implicated in the surge mechanism, suggesting that they may integrate circadian and E(2) signals to generate the LH surge. We tested whether Kiss1 neurons display circadian patterns of regulation in synchrony with the temporal pattern of LH secretion. Mice housed in 14 h light, 10 h dark were ovariectomized, given E(2) capsules (or nothing), and transferred into constant darkness. Two days later, the mice were killed at various times of day and their LH and Kiss1 levels assessed. In E(2)-treated females, LH levels were low except during late subjective day (indicative of an LH surge). Similarly, AVPV Kiss1 expression and c-fos coexpression in Kiss1 neurons showed circadian patterns that peaked coincident with LH. These temporal changes in Kiss1 neurons occurred under steady-state E(2) and constant environmental conditions, suggesting that Kiss1 neurons are regulated by circadian signals. In the absence of E(2), animals displayed no circadian pattern in LH secretion or Kiss1 expression. Collectively, these findings suggest that the LH surge is controlled by AVPV Kiss1 neurons whose activity is gated by SCN signals in an E(2)-dependent manner.

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Figures

Figure 1
Figure 1
Representative locomotor actogram of a female mouse housed in 14-h light, 10-h dark for approximately 1 wk. The animal was OVX and implanted with an E2-containing capsule (indicated by an asterisk) on the morning of d 9 and then transferred into constant darkness later that night (indicated by two asterisks). The mouse was killed 2 d after receiving the E2 capsule, which was at CT 12 (indicated by the black arrow). Animals in other groups were killed at various time points throughout the second day in constant darkness, as indicated by the horizontal dashed line (see Materials and Methods for specific times). Shaded areas represent the time of darkness (<1 lux dim red light). Note that CT 12 (indicated here by the black arrow) is slightly earlier than the extrapolated time of lights off. Therefore, CT 12 was calculated individually for each animal based on its own specific activity onset.
Figure 2
Figure 2
A, Mean (±sem) serum levels of LH in OVX, E2-treated mice housed in constant conditions and killed at one of eight time points throughout the circadian day. Values with different letters differ significantly from each other (P < 0.05). B, Percentage of animals at each time point displaying an LH surge (defined as an 8-fold or greater increase in LH values compared with mean CT 0 and CT 4 values) (31). n = 4–6 animals per group.
Figure 3
Figure 3
A, Representative dark-field photomicrographs showing Kiss1 mRNA-expressing cells (as reflected by the presence of white clusters of silver grains) in the AVPV of OVX, E2-treated female mice that were housed in constant conditions and killed at different times throughout the circadian day. 3V, Third ventricle. B, Mean (±sem) number of Kiss1-expressing cells in the AVPV across the circadian day displayed a trend (P < 0.09) for more Kiss1 neurons during the late subjective afternoon/early evening. C, The amount of Kiss1 mRNA per cell, as indicated by the number of silver grains per cell, was significantly different across circadian time points, with highest values at CT 11 and CT 12 (P < 0.01); values with different letters differ significantly from each other. n = 4–6 animals per group.
Figure 4
Figure 4
A, Representative photomicrographs of Kiss1 mRNA and c-fos mRNA coexpression in the AVPV of OVX, E2-treated female mice housed in constant conditions and killed at different times throughout the circadian day. Kiss1-containing neurons were visualized with Vector Red substrate, and c-fos mRNA was marked by the presence of silver grains. White arrows denote example Kiss1 cells lacking c-fos; yellow arrows denote example Kiss1 cells coexpressing c-fos. B, Mean (±sem) percentage of Kiss1 mRNA-containing neurons in the AVPV that coexpress c-fos in OVX, E2-treated female mice killed at one of eight times throughout the circadian day. There was a significant effect of time (P < 0.01) with increased coexpression of Kiss1 and c-fos in the late afternoon/early evening. Values with different letters differ significantly from each other. n = 4–6 animals per group.
Figure 5
Figure 5
Mean (±sem) plasma LH in OVX mice housed in constant conditions and killed at one of eight times throughout the circadian day. There was no significant difference in LH levels between any of the time points. n = 4–5 animals per group.
Figure 6
Figure 6
Lack of a circadian pattern in Kiss1 gene expression in OVX females. A, Representative dark-field photomicrographs showing Kiss1 mRNA-expressing cells in the AVPV of OVX mice housed in constant conditions and killed at different time points throughout the circadian day. B, Mean (±sem) number of Kiss1 mRNA-expressing neurons in the AVPV of OVX female mice housed in constant conditions and killed at one of eight time points throughout the circadian day. C, Mean (±sem) number of silver grains per Kiss1 cell in the AVPV of OVX mice killed across the circadian day. D, Mean (±sem) percentage of Kiss1 mRNA-containing neurons in the AVPV that coexpress c-fos in OVX female mice. In A–C, there was no significant difference in the measures between any of the circadian time points (P > 0.90 for all measures). n = 3–5 animals per group.
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