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Laboratory of Neuroendocrinology, The Babraham Institute, Cambridge CB2 4AT, United Kingdom
Address all correspondence and requests for reprints to: Dr. Allan E. Herbison, Laboratory of Neuroendocrinology, The Babraham Institute, Cambridge, CB2 4AT, United Kingdom. E-mail: allan.herbison{at}bbsrc.ac.uk
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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15%) and A14 (25%) neurons expressing ERs was similarly
unaffected by photoperiod. The number of ßE neurons detected in the
arcuate nucleus was 50% lower (P < 0.05) in SD
vs. LD ewes, whereas NPY-immunoreactive cell numbers in
the median eminence were 300% higher (P < 0.05).
Approximately 3% of NPY neurons in the median eminence, and 10% in
the arcuate nucleus, expressed ER immunoreactivity in a
photoperiod-independent manner. These studies indicate that changes in
photoperiod may regulate ER expression within the preoptic area and
suggest that hypothalamic NPY and ßE neurons are involved in the
seasonal regulation of reproductive activity in the ewe. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The GnRH neurons do not express nuclear estrogen receptors (ERs) in either ovariectomized (5, 6) or anestrous (7) ewes and, at present, the only ER-expressing neuronal cell populations implicated in the seasonal regulation of ovine GnRH secretion are the hypothalamic dopaminergic and ß-endorphin (ßE) neurons and the GABA-containing cells of the preoptic area (POA) (5, 6, 7, 8, 9, 10, 11, 12, 13, 14). Although hypothalamic neuropeptide Y (NPY) neurons have only, as yet, been demonstrated to express ERs in the rat (15), a preliminary report has shown changes in NPY messenger RNA (mRNA) expression with season in the arcuate nucleus of the sheep (16). It is possible, therefore, that photoperiod may influence the biosynthetic and/or electrical activity of one or several of these neuronal cell populations to bring about the different seasonal effects of estrogen on GnRH neurons. We have begun to address this hypothesis by examining whether photoperiod influences the number of immunocytochemically detectable tyrosine hydroxylase (TH), ßE, and NPY cells in the hypothalamus of the ewe. As photoperiod may also influence ER expression within specific brain regions and neuronal cell populations, we have examined the effect of photoperiod on ER immunoreactivity within the hypothalamus and POA as well as within identified cell populations. In this study, we set out to provide a baseline set of data in the gonadal-intact animal and have performed experiments using paired, long day (LD)- and short day (SD)-exposed ewes. To ensure that levels of circulating estrogen were similar between the two groups, all SD animals were killed in the midluteal phase (11). Using this experimental model, we now report that substantial photoperiod-induced immunocytochemical changes occur within specific neurochemical- and ER-defined cell populations of the ovine hypothalamus and POA.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Single-labeling immunocytochemistry
Free-floating sections were washed in a 40% methanol/TBS
solution containing 1%H2O2 for 10 min before
several TBS washes and incubation in either monoclonal mouse anti-ER
(1:10; ID5, gift of G. Delsol, CHU Purpan, Toulouse, France),
monoclonal mouse anti-TH (1:4 000, MAB 318, Chemicon, Harrow, UK),
polyclonal rabbit anti-NPY (1:8 000, N-9528, Sigma, Poole, UK) or
polyclonal rabbit anti-ßE (1:1 000, Affinity Research Products,
Nottingham, UK) antibodies for 40–50 h at 4 C. Sections from the LD:SD
paired animals were processed together in the same well. Three of the
six sets of sections were incubated in either the TH, ßE, or NPY
antibodies while two sets from each animal were placed with the ER
antibody. After the primary antibody, sections were washed in TBS and
incubated in secondary antisera (1:400 biotinylated horse antimouse for
ER and TH, and 1:200 biotinylated goat antirabbit for NPY and ßE) for
90 min at room temperature. After further washes in TBS, the Vectastain
Elite kit (1:50; Vector, Labs, Burlingame, CA, for ER) and
peroxidase-labeled avidin-biotin complex (1:200; Amersham, Little
Chalfont, UK for other antibodies) were applied for 90 min at room
temperature. Visualization of immunoreactivity was performed with
nickel-DAB as described previously (5). Each set of sections
immunoreacted for TH, ßE, or NPY were mounted on gelatinized slides
and coverslipped. Half of one set of sections immunoreacted for the ER
were mounted.
Double-labeling immunocytochemistry
The remaining sections stained for the ER (one and a half sets
per ewe) were divided into three equal lots and used for
double-labeling immunocytochemistry by washing in 40% methanol/TBS/1%
H2O2 solution for 10 min and placing in either
the TH, NPY, or ßE antiserum for 40 h as described above.
Secondary antibodies (1:400 peroxidase-labeled goat antirabbit for NPY
and ßE and 1:400 peroxidase-labeled horse antimouse for TH; both from
Vector) were applied for 2 h at room temperature and
immunoreactivity detected using DAB immunocytochemistry without nickel
(5). Sections were mounted and coverslipped.
Antibodies and controls
Production of the ER and TH antibodies has been reported (17, 18) and the latter used previously for identifying dopaminergic neurons
in the sheep brain (19). The monoclonal mouse ID5 antibody is directed
against the N-terminal region of recombinant human ER (17).
Liquid-phase adsorption control experiments were performed by overnight
incubation of the ID5 antibody (1:10; 4 C) with a 0.5 mg/ml
concentration of an N-terminal mouse ER fragment (residues 1–182)
generated by C. Chapman (The Babraham Institute, Cambridge, UK) from a
GST-AF1 construct provided by M. Parker and F. L’Horset of Imperial
Cancer Research Fund (London, UK). The specificity of the NPY antibody
directed against porcine NPY has been established in the rat brain (20)
and liquid-phase adsorption control experiments were performed in the
present study by overnight incubation of 1 ml NPY antibody (1:8000; 4
C) with 10 nM of NPY (Sigma). The ßE antibody was raised
against synthetic ßE and exhibits no cross-reactivity with
enkephalin, substance P, vasoactive intestinal peptide, or calcitonin
gene-related peptide. In all adsorption experiments, adsorbed and
unadsorbed antibodies were applied to different sections from the same
ewe. Other controls included the omission of primary antibodies from
the incubation procedure in both single and double-labeling
experiments. In all cases, the use of adsorbed antibodies or their
omission resulted in a complete absence of specific immunostaining.
Analysis
The density of ER-immunoreactive nuclei within a brain region
and the area of each stained nucleus were determined using a Leitz
Laborlux S microscope coupled to a SeeScan Sonata 2 image analyzer
(Seescan, Cambridge, UK). Sections from each LD:SD pair of ewes
containing the rostral POA, ventrolateral division of the ventromedial
nucleus (VMN), and arcuate nucleus (ARN) were matched, and all cells
within a 0.5 mm by 0.5 mm square placed over the ER-immunoreactive
cells were counted. The coronal levels at which the brain regions were
analyzed are shown in Fig. 2
. For each of the rostral POA, VMN and ARN,
four brain sections containing the brain region of interest were
selected at random from the half set of mounted ER-only stained
sections and cells analyzed on both sides of the brain. As sections
from the first pair of ewes were not immunoreacted with the ID5
antibody, a total of 5 SD and 5 LD ewes were evaluated. After
subtraction of background gray levels, the image analyzer counted the
total number of nuclear profiles within the field and then determined
the area of staining for each object. Between 500 and 1500 nuclear
profiles were analyzed for each brain region in each ewe.
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For the analysis of NPY and ßE immunoreactivity, sections containing the mediobasal hypothalamus were divided into those containing the rostral and caudal halves of ARN and immunoreactive cell numbers counted in a minimum of four sections from each half. As only one of the six sets of identical sections was reacted for each antibody, individual sections analyzed for NPY or ßE cell numbers were at least 150 µm apart in the coronal plane. Because many NPY-immunoreactive cell profiles were identified in the median eminence (ME), the number of positive cells in the caudal and rostral median eminence were also counted. In rostral sections, a line drawn along the edge of the ventricle and continued down through the ME was used to distinguish ARN (lateral to line) from ME (medial to line) cells. In caudal sections, the lateral boundaries of the ME are more readily apparent through the clear point of attachment that is observed between the ME and hypothalamus. Each cell exhibiting cytoplasmic immunoreactivity with a nuclear exclusion was considered a single cell profile.
The analysis of double-labeled sections was carried out in the same brain regions and manner as described above. In this case, the total number of TH- or NPY-immunoreactive cells with or without ER-immunoreactive nuclei was counted in a minimum of three brain sections from the five LD:SD pairs in each region of interest. In all cases, an average value was obtained for each ewe, and statistical analysis of paired LD:SD ewes (n = 5 or 6) was undertaken with Student’s paired t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Progesterone concentrations above 1
ng/ml were indicative of the luteal phase and the time of the midluteal
phase of the estrous cycle was calculated for each SD ewe. Anestrous
ewes exhibited progesterone levels below 1 ng/ml for the whole 3-week
period. Reproductive status was confirmed by visual inspection of the
ovaries at autopsy.
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) as described previously (5, 22).
Intense immunostaining was restricted to the cell nucleus, whereas
faint to moderate cytoplasmic staining was noted in subpopulations of
cells exhibiting strong nuclear staining in the POA and VMN (Fig. 2B).
Nuclear and cytoplasmic immunoreactivity were both absent after the
incubation of sections in adsorbed ID5 antibody.
The density of ER-immunoreactive cells within the POA differed
significantly between LD and SD ewes (Fig. 3). Animals
exposed to SD had approximately 20% fewer ER-stained cell nuclei than
LD animals (P < 0.05), although single cell nuclear
area measurements were not different between experimental groups (Fig. 3). Both SD and LD ewes exhibited cytoplasmic staining associated with
nuclear immunoreactivity. The density of ER-immunoreactive cells in the
VMN and ARN did not differ significantly with photoperiod, and nuclear
area was similarly unchanged (Fig. 3).
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). Within the ME,
NPY-immunoreactive neurons were scattered throughout its internal zone
and exhibited a variety of morphologies (Fig. 4C)
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and 5). The number of NPY-immunoreactive cell profiles
identified in both the rostral and caudal ME were 3- to 4-fold greater
in SD animals compared with LD ewes (P < 0.05; Figs. 4, C and D, and 5). Although the same trend was apparent in the rostral
ARN (Fig. 4, A and B), this failed to reach significance and,
similarly, no difference was found in the caudal ARN (Fig. 5).
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, E and F). The total number of double-labeled cells detected were
small in both SD (rostral: 0.4 ± 0.2; caudal: 0.2 ± 0.1
cells/section) and LD ewes (rostral: 0; caudal: 0.2 ± 0.2) and
represented only 0.1–3.0% of all NPY-immunoreactive profiles detected
within the ME at both rostral and caudal levels (Fig. 5). Larger
numbers of double-labeled cells were detected in the ARN where they
were concentrated in the dorsomedial aspect of the nucleus. A clear
rostro-caudal bias in the expression of ER immunoreactivity by
NPY-positive cells was suggested (Fig. 5). Approximately 3% of all
NPY-immunoreactive cells in the rostral ARN were found to express ERs
(SD; 1.0 ± 0.3 double-labeled cells/section and LD; 0.8 ±
0.6) compared with approximately 10% in the caudal ARN (SD; 3.8
± 1.4 double-labeled cells/section and LD; 2.8 ± 1.0). No effect
of photoperiod was detected on double-labeled cell numbers in either
the ME or ARN (Fig. 5).
Tyrosine hydroxylase immunoreactivity
Cells immunoreactive for TH were detected throughout the POA and
hypothalamus as described previously (21). Cells comprising the A14
group were divided into those found within the periventricular area of
the POA, including the OVLT (POA-A14), and those detected in the
periventricular and ventral regions of the anterior hypothalamus
(AHA-A14). These A14 cells usually exhibit a bipolar morphology (Fig. 6A). Cell count analysis found no effect of photoperiod
upon the number of TH-immunoreactive cells comprising the A12, POA-A14,
AHA-A14, or A15 populations (Fig. 7).
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) and A14 cell
(Fig. 6, A and D) groups but no coexpression in the A15 (Fig. 6C). No
ER immunoreactivity was detected in the TH cells of the lateral
hypothalamus belonging to the A14 group or in the A13 cells
concentrated within the dorsal hypothalamus (not shown). No significant
differences in the number of TH-immunoreactive cells expressing the ER
were detected with changing photoperiod (Fig. 7). Within the POA-A14,
13–18% of the small number of detected cells contained ERs, while up
to 25% of all TH cells in the AHA-A14 were positive for the ER. Within
the A12 population of the ARN, we found that approximately 15% of
TH-immunoreactive cells were stained for the ER (Fig. 7).
ß-Endorphin immunoreactivity
Cells immunoreactive for ßE were found in the ARN only, as
described previously (23, 24). Cells exhibited a variety of
morphologies and were located throughout the ARN including in its most
lateral extent (Fig. 8). Animals exposed to the SD
photoperiod exhibited reduced numbers of ßE-immunoreactive cells in
both the rostral and caudal ARN (Figs. 8 and 9). The
fall in ßE cell numbers did not quite reach the 5% significance
level in either the rostral (P = 0.11) or caudal
(P = 0.06) ARN, but when combined and analyzed for the
whole ARN, a significant (P < 0.05) 35% reduction in
ßE-immunoreactive cell number was evident in SD ewes compared with LD
animals (Fig. 9). Insufficient pairs of SD/LD ewes underwent ER-ßE
double labeling immunocytochemistry to enable statistical comparisons
to be made.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Using an immunocytochemical approach, which has enabled a cellular analysis of ER expression, we now report that the numbers of ER-expressing cells within the POA are elevated by around 20% in anestrous ewes compared with luteal phase animals. It is interesting to note that Bittman and Blaustein (27) identified a similar, but nonsignificant, increase in ER binding within the POA of anestrous ewes. We have taken care to compare luteal phase animals with anestrous ewes to ensure that circulating estrogen concentrations are similar (11), and we believe, therefore, that the elevation in ER immunoreactive cell numbers observed in anestrous ewes is not secondary to any influence of estrogen on ER expression (27). Although we cannot discount the possibility that the seasonal changes in ER expression within the POA may be attributable to the fluctuating progesterone profile of cycling ewes, we note that Blache and colleagues (28) were unable to find any effect of progesterone administration on ER-immunoreactive cell density in the POA. The absence of any significant changes in ER immunoreactivity in the VMN and ARN of the present study highlights the specificity of estrogen-receptive cells within the POA in terms of potential photoperiodic regulation.
The physiological significance of this change in the number of ER-expressing cells within the POA is not known. In terms of LH secretion, it seems most likely that estrogen acts indirectly upon GnRH neurons to inhibit their secretory activity during anestrus (7). Preliminary data indicate that the ER-expressing cells of the rostral POA, but not other regions, are activated by estrogen in anestrous ewes (29), and we now show that greater numbers of ER-immunoreactive cells exist in the POA at this time. Together, these observations suggest that a subset of rostral POA neurons may be induced to express ERs by an LD photoperiod and that these cells may play a role in facilitating the inhibitory effects of estrogen on GnRH neurons during anestrus. The neurochemical phenotype of the POA neurons induced to express ERs by LD photoperiod remains to be determined.
Photoperiod and tyrosine hydroxylase
A substantial body of evidence implicates dopamine as one of the
neurotransmitters involved in mediating the inhibitory effect of
estrogen on LH secretion in anestrous ewes. Dopamine D2 receptors are
involved in the estrogen-dependent suppression of LH pulse frequency in
anestrous ewes (30, 31, 32), and lesion studies suggest that this involves
the A14 and/or A15 dopaminergic cell populations of the anterior
hypothalamus (10, 33). Recent investigations have shown that both cell
populations are activated by estrogen during anestrus but not the
breeding season (34, 35). In the present study, we report that
photoperiod does not influence the number of TH-immunoreactive cells
detected per section in either of these dopaminergic cell populations
or in the A12 cells of the ARN. This result appears to concur with
others who have shown that photoperiod does not influence TH enzyme
activity in the A12, A14, or A15 cells (12) or TH mRNA content in the
A15 (36). Hence, in contrast to TH activity in the ME (12), photoperiod
may not cause appreciable alterations in TH synthesis or activity
within dopaminergic perikarya of the hypothalamus.
Because estrogen influences the A14 and A15 neurons only in anestrus, we questioned whether photoperiod may alter ER expression within these cell populations. As reported previously in ovariectomized ewes (6, 8), we were also unable to detect ER immunoreactivity within A15 cells regardless of the prevailing photoperiod. Recent evidence that the A15 neurons do not project to the ME (35, 37), where the season-dependent effects of dopamine on GnRH secretion occur (12, 38, 39), suggests that these cells may influence LH secretion indirectly. In terms of the A14 neurons, we show here that up to 25% of TH-immunoreactive cells located in the ventral periventricular region of the AHA express ERs, although this percentage does not change with season. Hence, in terms of ER immunoreactivity, we can find no evidence to support the hypothesis that changes in the level of ER expression by A14 or A15 neurons are involved in their season-dependent activation by estrogen. The basis for this phenomenon may lie instead in photoperiod-induced changes in ER-dependent transcriptional or translational events within these cells and/or the alteration of any estrogen-sensitive afferent input. In this regard, the increased numbers of ER-expressing cells identified within the POA of anestrous ewes may be of importance.
Photoperiod and NPY
We have found that SD photoperiod induces a 3-fold increase in the
number of NPY-immunoreactive cells detected throughout the ME. A
similar trend was observed in the rostral ARN but failed to reach
statistical significance. Although the ME was not examined in a
preliminary report by Yang and colleagues (16), they did provide
evidence that NPY mRNA expression in the ARN is elevated in breeding
season ewes compared with anestrous animals. This suggests that the
increased number of NPY-immunoreactive cells observed here in breeding
season ewes may result from photoperiodic influences that increase NPY
synthesis. Equally, however, we cannot discount that our observations
may represent an alteration in NPY transport within ME neurons and
future studies will be necessary to establish whether the NPY mRNA
content of neurons in the ME is also regulated by photoperiod. The
mechanisms underlying the changes in NPY immunoreactivity are not
established, but the low (<3%), photoperiod-independent number of NPY
neurons expressing ERs in the ME makes altered efficacy of direct
estrogen action on these cells unlikely. The elevated progesterone
concentrations associated with reproductive activity may have a role
but, again, the mode of progesterone action, if any, on NPY cells is
unknown.
The role of NPY in regulating GnRH neurons in the ewe is not entirely clear. The ovine GnRH neurons receive a direct NPY input (40), but the icv or iv administration of NPY has been shown to increase (41, 42), decrease (43, 44, 45) or exert no effect (46) on LH release. The icv immunoneutralization of NPY does, however, appear to consistently abolish or delay the LH surge in breeding season ewes (42, 46). Hence, it seems likely that, as in the rat (47) and monkey (48), NPY has an excitatory influence on GnRH secretion. Our observation of a positive correlation between reproductive activity and the elevated NPY immunoreactivity in ME neurons would, therefore, be in general agreement with the hypothesis that SD photoperiod induces a change in the activity of NPY neurons that may contribute to the increased GnRH/LH release occurring during the breeding season.
Photoperiod and ß-endorphin
The involvement of endogenous opioid peptides in the regulation of
GnRH secretion in the ewe is well established. The ßE neurons of the
ARN appear to represent the most important opioid population, and there
is good evidence that ßE can regulate GnRH secretion at the level of
the terminal (24) as well as the GnRH cell body (49, 50). We report
here that the number of ßE-immunoreactive neurons detected within the
ARN is approximately 35% lower in luteal-phase breeding season animals
compared with anestrous ewes. As is the case for our results with NPY
immunoreactivity, which show an opposite pattern of
photoperiod-dependent staining, we are unable to determine whether the
reduced numbers of ßE cells in SD ewes results from a decrease in
ßE synthesis or an increase in ßE transport away from the cell
body. Recent work in the male hamster has revealed a clear suppression
of POMC mRNA expression by SD (51). Although further work must been
done to determine the mechanism by which photoperiod influences ßE
neurons in the ewe, it remains highly likely that the ßE content of
ARN cell bodies is substantially different in anestrous and
luteal-phase breeding season ewes.
Previous studies suggest a seasonal variation in the role of opioid peptides in regulating LH secretion in the ewe. In anestrus, ßE is unlikely to exert any strong influence on GnRH secretion (13, 14), whereas, in the luteal phase of the breeding season, there is a consensus that opioid peptides effect the negative feedback actions of progesterone on LH secretion (14, 52, 53). Little evidence implicates ßE in the estrogen negative feedback actions of estrogen on GnRH secretion (54). The gradual increase in ßE release within the ME that occurs in concert with the rising estrogen concentrations of the follicular phase suggest a possible role for ßE in the timing of the LH surge (24). In this setting, one plausible explanation for our immunocytochemical observations would be that the elevated activity of ßE neurons in the breeding season involves increased ßE transport and release and, hence, reduced cell body ßE content and immunoreactivity as compared with anestrus.
Summary
The present study has revealed a number of neurochemical and ER
immunocytochemical changes within the hypothalamus of intact ewes
exposed to different photoperiods. In summary, cycling animals exposed
to SD photoperiods exhibit fewer ER-expressing cells in the rostral
POA, fewer ßE-immunoreactive cells within the ARN, and more
NPY-positive neurons in the ME. No changes were found in TH
immunoreactivity or in the density of ER-expressing cells in the VMN or
ARN. Such findings highlight the potential for photoperiod to
orchestrate changes in the synthetic and/or electrical activity of
specific neuronal cell populations in the ovine brain.
In terms of understanding the mechanisms through which estrogen regulates GnRH neurons in the different seasons, our most important observation is that the LD photoperiod appears to induce ER expression within a subpopulation of rostral POA cells. We speculate that these cells may be involved in mediating part of the negative feedback effects of estrogen on GnRH neurons during anestrus. Although we have been able to demonstrate relatively high ER expression in ventral hypothalamic A14 dopaminergic neurons and the presence of ERs in NPY neurons, we have found no significant effect of photoperiod on the ability of these cells to display ER immunoreactivity. Together, these data suggest that only specific estrogen-receptive neuronal cell populations, such as those of the POA, may be influenced by photoperiod to alter their level of ER expression. By identifying substantial changes in NPY and ßE immunoreactivity, this study provides an insight into which neuronal cell populations may be functioning differently in intact SD- and LD-exposed ewes. Future studies will now be required to establish whether such changes result from a direct action of photoperiod or are secondary to the different gonadal steroid profiles characteristic of anestrous and cycling ewes.
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Acknowledgments |
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Footnotes |
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2 Lister Institute-Jenner Fellow.
Received December 31, 1996.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C. D. Foradori, L. M. Coolen, M. E. Fitzgerald, D. C. Skinner, R. L. Goodman, and M. N. Lehman Colocalization of Progesterone Receptors in Parvicellular Dynorphin Neurons of the Ovine Preoptic Area and Hypothalamus Endocrinology, November 1, 2002; 143(11): 4366 - 4374. [Abstract] [Full Text] [PDF]
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N. Scanlan and D. C. Skinner Estradiol Modulation of Growth Hormone Secretion in the Ewe: No Growth Hormone-Releasing Hormone Neurons and Few Somatotropes Express Estradiol Receptor {alpha} Biol Reprod, May 1, 2002; 66(5): 1267 - 1273. [Abstract] [Full Text]
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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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T. Ichimaru, Y. Mori, and H. Okamura A Possible Role of Neuropeptide Y as a Mediator of Undernutrition to the Hypothalamic Gonadotropin-Releasing Hormone Pulse Generator in Goats Endocrinology, June 1, 2001; 142(6): 2489 - 2498. [Abstract] [Full Text] [PDF]
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M.-L. Goubillon, R. A. Forsdike, J. E. Robinson, P. Ciofi, A. Caraty, and A. E. Herbison Identification of Neurokinin B-Expressing Neurons as an Highly Estrogen-Receptive, Sexually Dimorphic Cell Group in the Ovine Arcuate Nucleus Endocrinology, November 1, 2000; 141(11): 4218 - 4225. [Abstract] [Full Text] [PDF]
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R. L. Goodman, J.-C. Thiery, B. Delaleu, and B. Malpaux Estradiol Increases Multiunit Electrical Activity in the A15 Area of Ewes Exposed to Inhibitory Photoperiods Biol Reprod, November 1, 2000; 63(5): 1352 - 1357. [Abstract] [Full Text]
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C. J. Scott, A. J. Tilbrook, D. M. Simmons, J. A. Rawson, S. Chu, P. J. Fuller, N. H. Ing, and I. J. Clarke The Distribution of Cells Containing Estrogen Receptor-{alpha} (ER{alpha}) and ER{beta} Messenger Ribonucleic Acid in the Preoptic Area and Hypothalamus of the Sheep: Comparison of Males and Females Endocrinology, August 1, 2000; 141(8): 2951 - 2962. [Abstract] [Full Text] [PDF]
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M. Mizuno, M. Gearing, and E. Terasawa The Role of Neuropeptide Y in the Progesterone-Induced Luteinizing Hormone-Releasing Hormone Surge in Vivo in Ovariectomized Female Rhesus Monkeys Endocrinology, May 1, 2000; 141(5): 1772 - 1779. [Abstract] [Full Text] [PDF]
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I. Stefanovic, B. Adrian, H. T. Jansen, M. N. Lehman, and R. L. Goodman The Ability of Estradiol to Induce Fos Expression in a Subset of Estrogen Receptor-{alpha}-Containing Neurons in the Preoptic Area of the Ewe Depends on Reproductive Status Endocrinology, January 1, 2000; 141(1): 190 - 196. [Abstract] [Full Text] [PDF]
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E. L. Bittman, M. L. Tubbiola, G. Foltz, and C. M. Hegarty Effects of Photoperiod and Androgen on Proopiomelanocortin Gene Expression in the Arcuate Nucleus of Golden Hamsters Endocrinology, January 1, 1999; 140(1): 197 - 206. [Abstract] [Full Text]
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F. Bertrand, C. Viguie, S. Picard, and B. Malpaux Median Eminence Dopaminergic Activation Is Critical for the Early Long-Day Inhibition of Luteinizing Hormone Secretion in the Ewe Endocrinology, December 1, 1998; 139(12): 5094 - 5102. [Abstract] [Full Text] [PDF]
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 A. E. Herbison Multimodal Influence of Estrogen upon Gonadotropin-Releasing Hormone Neurons Endocr. Rev., June 1, 1998; 19(3): 302 - 330. [Abstract] [Full Text]
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A. Caraty, C. Fabre-Nys, B. Delaleu, A. Locatelli, G. Bruneau, F. J. Karsch, and A. Herbison Evidence That the Mediobasal Hypothalamus Is the Primary Site of Action of Estradiol in Inducing the Preovulatory Gonadotropin Releasing Hormone Surge in the Ewe Endocrinology, April 1, 1998; 139(4): 1752 - 1760. [Abstract] [Full Text] [PDF]
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