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Institut National de la Recherche Agronomique, Laboratoire de Neuroendocrinologie Sexuelle, URA Centre National de la Recherche Scientifique 1291, 37380 Nouzilly, France; and Universidad Autónoma Agraria Antonio Narro (G.D.), Carretera a Sta. Fe y Periférico, Apartado Postal 940, Torreón, Coahuila, Mexico
Address all correspondence and requests for reprints to: Benoît Malpaux, INRA-PRMD, 37380 Nouzilly, France. E-mail: malpaux{at}tours.inra.fr
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Introduction |
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To clarify where melatonin acts in the hypothalamus, two experiments were performed in the ewe. First, the ovine diencephalon was screened by quantitative autoradiography to characterize the specific changes in regional densities in melatonin binding and to delimit precisely the areas with the most intense melatonin binding. Secondly, to establish the physiological importance of the hypothalamic area with highest melatonin binding, microimplants of melatonin were inserted in and near the identified area. The effect of these microimplants on LH and PRL secretion was assessed in comparison with microimplants placed in a neighboring hypothalamic area characterized by low melatonin binding.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Exp 1: distribution of melatonin binding sites in the
hypothalamus
Five 2.5-yr-old ewes, kept in natural photoperiod, were killed
between 1400 and 1530 h by decapitation by a licensed butcher in
an official slaughterhouse in October (n = 3) and in December
(n = 2). The brain was removed from the skull within less than 2
min after slaughter and the hypothalamus dissected and rapidly frozen
by immersion in isopentane cooled to -50 C in nitrogen. It was then
stored at -80 C until sectioning.
Coronal hypothalamic (15 µm) sections were cut with a cryomicrotome in the area ranging from the mammillary bodies to the optic chiasm. These sections were collected on TESPA (3 amino Propyl tri Ethoxy Silane; Sigma, L’Isle d’Abeau, France) gel-coated slides and returned to -20 C until the time of incubation. The total time elapsed between an animal’s death and incubation ranged from 1–3 months.
One section for every 180 µm was used to analyze melatonin binding. Sections were first washed with PBS buffer (0.01 M) at 4 C, incubated for 1 h at room temperature with 200 µl PBS containing 125I-labeled melatonin 75 pM (specific activity of 2000 Ci/mmol), rinsed twice at 4 C with PBS, fixed with 4% paraformaldehyde at 4 C for 10 min, and dipped in water for 10 min. Additional sections were incubated with a 200-fold excess of cold melatonin to assess nonspecific binding.
Autoradiograms were generated with air-dried sections placed in x-ray cassettes with Hyperfilm RPN 2116 (Amersham, Les Ulis, France). All sections (total and nonspecific binding) of a single animal were grouped in the same cassette. 125I microscale standards were generated with 7 amounts of 125I-melatonin in solution in pure ethanol dispersed on TLC silicate gel (Prolabo, Fontenay-sous-Bois, France; values on the scale ranged from 5000–78 cpm, with a 2-fold reduction between successive values). 125I-melatonin brain paste standards, prepared from whole sheep brain, were used to calibrate the standards, as described by Nazareli et al. (19). A linear relationship was found between binding values expressed in the two standard systems (r = 0.98), and the equation generated was used to correct the values obtained with the silicate standards. Exposure time was 7 days at room temperature. To identify histological structure, sections adjacent to the total binding sections were stained by the Klüver and Barrera methods (20).
The intensity of binding was assessed by an image analysis system
(Biocom Histo 500, Les Ulis, France), as described in Fig. 1
. The density of gray was measured in 16
1-mm2 squares of each section (see Fig. 1, for position of
each square). The analysis was performed on both sides of the
hypothalamus, and values from symmetrical squares were pooled. In
addition, the gray density was measured on five sections of PT.
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Exp 2: functional importance of the melatonin binding sites present
in the premammillary area of the hypothalamus (PMH)
Surgical positioning of the microimplants. The guide
cannulae for the melatonin implants were placed in the brain of the
ewe, as described previously (11). All the guide cannulae were
constructed from a stainless steel luer-lock needle (od, 1.20 mm; id,
0.86 mm; Elite, Paris, France), which had the tube end blunted and were
cut to a length of 40 mm. The cannulae were placed 3 mm above the
target site at least 20 days before the onset of the experiment.
The melatonin microimplants consisted of stainless steel tubing (od, 0.70 mm; id, 0.45 mm) fixed inside a luer-lock male part. The microimplants were made as previously described (11). The release rate of melatonin from similar microimplants has been measured previously (11). After an initial peak (>10 µg/day), the rate of release stabilizes after 3–5 days at 5.5 ± 0.4 µg/day (mean ± SEM).
Design. Twenty-six ewes (previously held in short days for 90 days or in natural photoperiod until January 22) were transferred from short to long days (8-h light, 16-h dark; and 16-h light, 8-h dark) and remained in this long photoperiod until the end of the experiment. After 92 days on the long-day regime, when LH secretion was suppressed, 2 bilateral microimplants of melatonin were placed in the PMH of 11 ewes. At the same time, 8 ewes received the same treatment in the anterior/MBH (AH/MBH), used as a negative control for the presence of melatonin receptor. For sham-operated controls, 6 ewes were given bilateral empty microimplants in the PMH.
All microimplant insertions were performed on the same day, which was taken as day zero. The experiment was terminated 80 days later.
Blood sampling and assays. Blood samples (3 ml) were obtained twice weekly between 1400 h and 1600 h, by jugular venepuncture, for the duration of the experiment; and the plasma was separated and stored at -20 C until assayed. LH was assayed in duplicate 100-µl aliquots of plasma using the RIA method of Pelletier et al. (21), modified by Montgomery et al. (22). Sensitivity (2 SD from buffer controls) was 0.23 ± 0.02 ng/ml of 1051-CY-LH (2 assays). The intraassay coefficient of variation for three plasma pools averaged 7.0% (two assays). The interassay coefficient of variation for these plasma pools averaged 5.5%. The LH concentration in samples was taken as an indicator of activity of the reproductive neuroendocrine axis. In this model, elevated LH levels correspond to the breeding season of intact ewes, and periods of low LH indicate anestrus (23, 24).
The effect of the microimplants was also assessed by examining the mean circulating PRL concentration. Elevated and low PRL levels are indicative of exposure to long and short days, respectively (25). Thus, on days -10 and 80, blood samples were collected every 20 min for 5 h, starting at 1200 h, to determine the mean circulating PRL secretion on that day. Samples from the first h were discarded to avoid the interference of stress, associated with the initiation of bleeding, on PRL secretion. PRL was assayed in duplicate 10 µl-aliquots of plasma using the RIA of Kann (26). Sensitivity was 8.5 ng/ml NIDDK-oPRL-19. All samples were included in a single assay, and the intraassay coefficient of variation for three plasma pools averaged 9.3%.
Histology. At the end of the experiment, animals were decapitated. The brains were treated in the same way as in Exp 1, and sections obtained around the implantation sites were used to localize the microimplants, in relation to brain structures. The site of implantation was determined by use of Richard’s Atlas (27).
Analysis of data. After logarithmic transformation, the LH levels were analyzed by a two-factor ANOVA (group, as a between factor; time of experiment, as a within factor). In addition, for each ewe, the time when circulating LH levels started to rise was determined by the first of at least three consecutive values exceeding 1 ng/ml. For the ewes that did not show an increase in LH secretion during the experiment, this time was set to 80 days (end of experiment). PRL data were logarithmically transformed and analyzed by a three-factor repeated-measures ANOVA (group, as a between factor; time of day, and day relative to treatment, as within factors).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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; P <
0.0001, interaction between section number and position on the
section), and a higher level of binding was found in the posterior
hypothalamus (Fig. 2, B3 and B4). In all five ewes, an area of higher
binding was found on eight consecutive sections, ranging rostrally from
the infundibular recess to the anterior limit of the mammillary bodies
(Fig. 3). This binding was displaced by a
200-fold excess of cold melatonin (Fig. 2, C3 and C4). At its largest,
this binding area (delimited dorsally by the fornix) extended ventrally
to the base of the brain (Fig. 2). It also extended medially by 3 mm on
either side of the third ventricle. This area of higher binding
encompasses a series of nerve structures, including the premammillary
nucleus and the tuberomammillary nucleus, as defined by Welento
et al. (28). Compared with a basal level of 0.2–0.4 fmol/mg
protein in the more dorsal or lateral areas of the hypothalamus,
binding in this area increased to 2 fmol/mg protein (Fig. 3).
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) may seem to be continuous with the PT region, histological
examination of A3 and A4 insures that no PT tissue contributes to the
signal over the PMH. In this rostro-caudal plane, the pituitary stalk
is separated from the base of the hypothalamus.
Another area of binding was found in the AH (Fig. 3). This area is much
more diffuse (Fig. 2B1); and, although observed in all animals, higher
binding was detected on a single section with a maximal binding
intensity of 1 fmol/mg protein.
The analysis of the autoradiograms also showed that the largest density
of melatonin binding sites is found in the PT (Fig. 2). As a
comparison, the labeling intensity in the PT of the animals was
34.3 ± 3.8 fmol/mg protein.
Exp 2: functional importance of the melatonin binding sites present
in the PMH
Effect of melatonin on LH secretion. Mean LH levels were low
in all 3 groups of ewes at the beginning of the study. LH levels
remained basal (<0.5 ng/ml) throughout the study, in the 6
sham-operated ewes that received empty microimplants in the PMH (Fig. 4). In contrast, in 10 of the 11 animals
that received melatonin microimplants in the PMH, a large increase in
LH levels was observed from day 44.5 ± 5.3 until the end of the
study (Fig. 4). In one animal of this group (no. 26), LH levels
remained low until the end of the study. In 6 of the 8 animals that
received melatonin microimplants in the AH/MBH, LH levels remained
basal (LH < 0.5 ng/ml) throughout the experiment. Another animal
(no. 25) displayed a large increase in LH secretion from day 42 until
the end of the study, and another (no. 23) showed a marginal increase
between days 53 and 63 (4 elevated values fluctuating between 1.6 and
2.1 ng/ml).
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The anatomical localization of the microimplants in each animal is
illustrated in Fig. 5, with respect to
the localization of melatonin binding in the PMH described in Exp 1. A
clear relationship between the position of the implant, relative to the
binding area, and the LH response is evident. All the animals that had
at least one of their microimplants within the area of receptors or
within 1 mm of it showed a stimulation of LH secretion during the study
(ewe nos. 2, 4, 5, 6, 10, 12, 17, 20, 22, and 28; all from the PMH
group). Two other animals, which belonged to the AH/MBH group, showed a
stimulation of LH secretion: no. 25 and no. 23. It is worth noting that
no. 25 had one of its implants (left) located within 0.4 mm
of the third ventricle and that no. 23 had its two implants located
very dorsally. The animal from the PMH with no LH response (no. 26) had
its implants placed very dorsally, relative to the area of interest
(1.2 and 2 mm, Fig. 5, top).
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; SHAM: from 189 ± 19.5 to
108.3 ± 14.9 ng/ml; AH/MBH: 162.0 ± 24.9 to 87.1 ±
22.8 ng/ml, PMH: 122.9 ± 12.2 to 96.3 ± 25.5 ng/ml).
However, no effect of group (P > 0.16), nor any
interaction between day of experiment and groups (P >
0.7), was found (indicating that the changes in PRL levels were not
related to the experimental treatments).
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Discussion |
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The binding study that we performed was centered around the MBH, because we had previously demonstrated that the sites of action of melatonin were located in this vicinity. The quantification of melatonin binding allowed us to identify two areas with higher specific binding displaced by an excess of cold melatonin. The first was found in the AH: binding is diffuse, being found around and ventral to the fornix. This area seems to correspond, at least in its ventral part, to the tuberal anterior hypothalamic area identified by Bittman and Weaver (6). The second area of binding that our study identified is much larger and was found in the posterior hypothalamus. This area is more discrete and easier to delimit: it is located at the base of the brain and limited dorsally by the fornix; it extends 3 mm on either side of the third ventricle, is posterior to the infundibular recess, and is delimited caudally by the mammillary bodies. For this last reason, we used the terminology premammillary area of the hypothalamus to describe it. The area of higher binding encompasses a series of nerve structures, such as the premammillary nucleus and the tuberomammillary nucleus, as defined by Welento et al. (28). The description of binding in this area is consistent with the description of receptors by Chabot et al. (17) in the posterior hypothalamus. The Scatchard analysis of melatonin receptors in this area revealed a concentration of approximately 1 fmol/mg protein with a Kd in the low picomolar range. The values of the maximal number of binding sites in that study were 20–100 times lower than that of the PT, which is consistent with the difference in relative binding between the PT and the PMH found in this study.
In most of the binding studies preceding that of Chabot et al. (17), the existence of binding in the posterior hypothalamus had not been mentioned (6, 7). The reason for the discrepancy between these earlier studies and that of Chabot et al. (17) and ours is unclear, but several parameters (e.g. age, sex, breed, physiological status, time of day of slaughter, etc.) could explain the difference. It should be noted that higher binding in the PMH was found both in intact ewes (17) and in ovariectomized and estradiol-treated ewes (this study). Furthermore, although Bittman and Weaver (6) did not detect binding in the PMH (unlike the present study), both studies were conducted during the breeding season and at a similar time of year (October–December). The present study, by a full screening of the hypothalamus, extends the results of previous studies by describing the limits of this area of binding in the premammillary hypothalamus, a necessary step for performing functional studies to assess its physiological importance.
A clear relationship was observed between the proximity of the melatonin microimplants to the area of binding and the physiological change in LH secretion that these microimplants induced. First, a highly significant difference in the changes in LH concentration was found between the group that received implants in or close to the PMH and that receiving implants in the AH or MBH. Although these implants were not directly aimed at the AH area of binding, the vicinity of some of these implants to this area and the absence of response suggest that this anterior hypothalamic area may not be involved in transducing the effects of melatonin on LH secretion. Second, the present results show that all the 10 animals with at least one of their microimplants positioned within 1 mm from the area of binding in the PMH displayed an increase in LH secretion. This is important because, in a previous study (11), we had estimated that melatonin diffused about 1 mm from the microimplants. Of the 9 animals that did not meet this criteria, only 2 animals showed a stimulation of LH secretion. In one (no. 23), the amplitude and duration of the LH increase were lower than the typical response; and in the other one (no. 25), the localization of one of the microimplants close to the border of the ventricle made it possible for melatonin to reach the ventricle; it is known that microimplants inserted in the third ventricle can stimulate LH secretion (10). The present study also clarifies why we had found that only microimplants positioned in the MBH could stimulate LH secretion but that this effect was observed in only 50% of the animals (9, 11). The comparison of the position of the earlier implantations with the present ones reveals that they were located more rostrally (1–2 mm). It is therefore possible that melatonin released from these implants acted by diffusing to the premammillary hypothalamus. However, because of the distance, only a limited amount of melatonin may have reached the active sites, which may not have been sufficient to induce a response in all animals. Such a possibility is reinforced by the fact that, in Soay rams, a smaller animal (therefore, with a shorter MBH-PMH distance), all animals receiving similar microimplants in the MBH showed a reactivation of FSH secretion and of testicular size (12, 13). Our present results, with the observation of the response in all animals with implants in the close vicinity of the PMH, enable us to conclude more strongly that melatonin targets are located in the PMH.
The use of melatonin microimplants has allowed us to identify a putatively important hypothalamic area in the control of LH secretion. However, this approach has two drawbacks that future studies will need to clarify. First, the release of melatonin by the implants is constant. Although the short-day-like effects of melatonin implants are well demonstrated in sheep (3), it is widely accepted that the daily pattern of melatonin secretion conveys information about photoperiod (2). Second, although the dose released by the microimplants (230 ng/h) is much lower than the systemically effective dose (44 µg/h) (29), it is much higher than that found effective in Siberian hamsters (about 1 pg/h) (30). This difference is probably partly explained by the change in the size of the brain between juvenile Siberian hamsters and adult sheep. An advantage of the unambiguous and repeatable response induced in the animals implanted in the PMH will be to allow the performance of studies with devices allowing to control the dose and the timing of in situ melatonin delivery in the PMH to reinforce the functional significance of the present results. Also, although we cannot fully exclude the possibility that vascular flow or cerebrospinal fluid may have transported melatonin from the implanted sites, it is worth noting that, because of the directional flow of cerebrospinal fluid, it is unlikely that the action of melatonin in the PMH results from melatonin being conveyed from the implanted sites in the posterior hypothalamus to other hypothalamic or pituitary sites.
In the first experiment, the intensity of binding was measured on the same animals in the PMH and in the PT. As observed in a previous study (17), binding is at least 20 times as intense in the PT. Despite this high binding in the PT, the present data reinforce the hypothesis that the target sites of melatonin for acting on reproduction are hypothalamic (9, 10). This hypothesis is also strengthened by results obtained in Syrian hamster, because lesions of the dorsomedial hypothalamus melatonin binding sites block the gonadotropic response of male Syrian hamsters to short photoperiod or melatonin (31). Furthermore, an overlap between melatonin binding and androgen receptor immunoreactivity is found in the dorsomedial nucleus, and it was suggested that sensitivity to steroid feedback, a key mechanisms of the action of melatonin on gonadotropin secretion, might be influenced in this area in Syrian hamsters (16). In this regard, it is interesting to note that an overlap between melatonin and estradiol receptors is not very likely in the PMH in the ewe. Indeed, no estradiol receptor immunoreactivity has been found in the mammillary nuclei (32). Furthermore, the sites of action of estradiol to induce the seasonal inhibition of LH secretion seem to be located in the retrochiasmatic hypothalamic area (33). The understanding of mechanisms of melatonin action on LH secretion will require the description of the pathways by which the premammillary area may be connected to the LHRH neurons. Very limited information is available about projections of the premammillary area to other brain areas in sheep. In rats, the tuberomammillary nucleus projects widely to more rostral or caudal parts of the brain (34). The ventral premammillary nucleus, where melatonin binding is the most intense, projects to most regions of the periventricular zone of the hypothalamus (35). If similar projections exist in sheep, they could connect the premammillary area to hypothalamic areas involved in the control of LHRH secretion.
Our PRL data need to be interpreted with caution for two reasons. First, there is no positive control in the study for an effect of melatonin on PRL secretion, and therefore, the absence of difference between negative controls and experimental animals may simply reflect an inability of melatonin to inhibit PRL secretion in the present experimental situation. Second, in all groups including the sham-operated animals, a large decrease in PRL level was observed between the two time-points, which might have prevented the detection of an effect of melatonin in one of the two studied structures. Nevertheless, the absence of effect of melatonin either in the AH/MBH or the PMH is consistent with the hypothesis that melatonin acts primarily in the PT to control PRL secretion. Support for this hypothesis was provided by the demonstration that PRL secretion was still modulated by melatonin in pituitary-disconnected rams (8). Further support for a PT site of action on PRL release came from the fact that microimplants located in the PT have a stronger inhibitory effect on PRL secretion than implants located in the MBH (9). Similarly, lesions of the dorsomedial hypothalamus in Syrian hamster block the effect of melatonin on gonadotropin secretion without blocking the effect on PRL secretion (31). Finally, a factor released in vitro by PT cells is stimulatory of PRL secretion by pars distalis cells and, therefore, could mediate the effect of melatonin on PRL secretion (36). Therefore, the effect of melatonin on PRL secretion seems to be mediated, at least in part, at the level of the PT. Whether there are also hypothalamic targets for melatonin in that action remains a possibility, but if such a hypothalamic site is functionally crucial, our data would suggest that it is different from hypothalamic sites involved in the control of LH secretion. In addition, the absence of effect of the PMH microimplants on PRL secretion demonstrates that a diffusion of melatonin from the PMH to the PT is most unlikely and reinforces the importance of the PMH in the action of melatonin on LH secretion.
In conclusion, these data have reinforced the hypothesis that melatonin acts in the hypothalamus to control reproductive activity in sheep and have allowed us to identify a putative hypothalamic area for melatonin action, the premammillary area. Experiments, using techniques of selective ablation, will be necessary to confirm the importance of this area. A fundamental step will also be the identification of the target cells of melatonin within this area.
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Acknowledgments |
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Footnotes |
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Received September 8, 1997.
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H. J. Billings, C. Viguie, F. J. Karsch, R. L. Goodman, J. M. Connors, and G. M. Anderson Temporal Requirements of Thyroid Hormones for Seasonal Changes in LH Secretion Endocrinology, July 1, 2002; 143(7): 2618 - 2625. [Abstract] [Full Text] [PDF]
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H. Tricoire, A. Locatelli, P. Chemineau, and B. Malpaux Melatonin Enters the Cerebrospinal Fluid through the Pineal Recess Endocrinology, January 1, 2002; 143(1): 84 - 90. [Abstract] [Full Text] [PDF]
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 T. A. Wehr, W. C. Duncan Jr, L. Sher, D. Aeschbach, P. J. Schwartz, E. H. Turner, T. T. Postolache, and N. E. Rosenthal A Circadian Signal of Change of Season in Patients With Seasonal Affective Disorder Arch Gen Psychiatry, December 1, 2001; 58(12): 1108 - 1114. [Abstract] [Full Text] [PDF]
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 D. G. Hazlerigg, P. J. Morgan, and S. Messager Decoding Photoperiodic Time and Melatonin in Mammals: What Can We Learn from the Pars Tuberalis? J Biol Rhythms, August 1, 2001; 16(4): 326 - 335. [Abstract] [PDF]
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B. Malpaux, M. Migaud, H. Tricoire, and P. Chemineau Biology of Mammalian Photoperiodism and the Critical Role of the Pineal Gland and Melatonin J Biol Rhythms, August 1, 2001; 16(4): 336 - 347. [Abstract] [PDF]
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G. A. Lincoln, S. M. Rhind, S. Pompolo, and I. J. Clarke Hypothalamic control of photoperiod-induced cycles in food intake, body weight, and metabolic hormones in rams Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2001; 281(1): R76 - R90. [Abstract] [Full Text] [PDF]
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J. Pelletier, L. Bodin, E. Hanocq, B. Malpaux, J. Teyssier, J. Thimonier, and P. Chemineau Association Between Expression of Reproductive Seasonality and Alleles of the Gene for Mel1a Receptor in the Ewe Biol Reprod, April 1, 2000; 62(4): 1096 - 1101. [Abstract] [Full Text]
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D. C. Skinner and B. Malpaux High Melatonin Concentrations in Third Ventricular Cerebrospinal Fluid Are Not due to Galen Vein Blood Recirculating through the Choroid Plexus Endocrinology, October 1, 1999; 140(10): 4399 - 4405. [Abstract] [Full Text]
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