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Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520
Address all correspondence and requests for reprints to: Dr. Tamas L. Horvath, Yale University School of Medicine, 333 Cedar Street, FMB 336, New Haven, Connecticut 06520. E-mail: HorvathTA{at}Maspo1.Mas.Yale.Edu
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Abstract |
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This experiment provided evidence that the circadian pacemaker suprachiasmatic nucleus sends efferents onto neuroendocrine cells, but has no contacts with fenestrated capillaries. It was found that a population of median eminence-projective cells targeted by suprachiasmatic axons in the hypothalamus contains dopamine. These observations indicate no direct effect of the circadian pacemaker on the anterior hypophysis, but offer an indirect pathway via circadian signals, mediated by hypothalamic neural systems, that may regulate pituitary hormone secretion, in particular PRL.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Secretion of anterior pituitary hormones, including gonadotropins and PRL, is regulated by various hypothalamic neurohormones. It is known that the median eminence conveys both humoral and neural signals from the brain to the pituitary. In the external layer of the median eminence, the terminals of hypophysiotropic hormone-producing neurons release their products into the phenestrated portal capillaries that provide the link between the hypothalamus and the anterior pituitary (2). Neuroendocrine cells are located in various hypothalamic sites, including the medial preoptic area, periventricular areas, and mediobasal hypothalamus as well as in the medial septum and diagonal band of Broca.
Previous morphological studies failed to demonstrate suprachiasmatic efferents in the median eminence or organum vasculosum laminae terminalis (3), indicating that the circadian clock has no direct effect on pituitary hormone secretion, but acts indirectly by regulating the activity of hypophysiotropic hormone-producing neurons. In support of this view, several hypothalamic areas that contain median eminence-projective neurons, such as the medial preoptic area, periventricular areas, and lateral arcuate nucleus, were found to be targets of considerable numbers of SCN efferents (3, 4). However, it is not known whether those neurons that send projections to portal vessels receive inputs from the SCN.
Several neurotransmitter- and peptide-producing hypothalamic neuronal populations were shown to release their product to the portal vessels of the median eminence. These include dopamine, which is thought to be the mayor hypothalamic regulatory signal in PRL secretion and also participates in the regulation of other pituitary hormones, including gonadotropins (5). Evidence has accumulated indicating that the synthesis and/or release of dopamine show diurnal patterns. For example, in rats, the activity of hypothalamic dopamine neurons is circadian, underlying the diurnal secretion pattern of preovulatory PRL secretion (6). Despite this experimental evidence, our understanding regarding the morphological basis of the circadian secretory function of hyophysiotropic hormones and regulatory peptides is limited.
The objective of the present experiment was to reveal connectivity between the circadian pacemaker and hypothalamic neuroendocrine cells, to demonstrate the relationship between hypothalamic dopamine neurons and suprachiasmatic efferents, and to confirm that SCN efferents have no direct access to fenestrated capillaries. The combination of anterograde and retrograde tracing and light and electron microscopic double and triple immunocytochemistries was used.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Phaseolus vulgaris leucoagglutinin (PHA-L) injections
The projection field of SCN neurons was visualized using PHA-L
[2.5% in 10 mM phosphate buffer (PB), pH 7.8; Vector
Laboratories, Burlingame, CA] as an anterograde tracer. This was
unilaterally applied with iontophoresis via a glass micropipette (tip
diameter, 15 µm; 5 µA positive current applied every other 5 sec
for 15 min using a constant current source that is capable of
generating up to 2000 V; CS-3 Transcientic System, Canton, MA) into
different areas of the SCN [coordinates: anterio-posterior, -0.8 to
-1.3 mm; lateral, 0.2 mm; ventral, 9.6 mm; according to Paxinos and
Watson (7)].
Fluorogold (FG) injection
Simultaneously with the PHA-L injections, animals received a
single ip injection of FG (20 mg/BW; Fluorochrome, Englewood, CO) to
label neurons that send projections to regions in the central nervous
system that lack the blood-brain barrier (8, 9).
Fixation
Fifteen days after PHA-L/FG injections, rats were killed under
ether anesthesia by transaortic perfusion with 50 ml heparinized saline
followed by 250 ml fixative. The fixative consisted of 4%
paraformaldehyde, 15% picric acid, and 0.2% glutaraldehyde in 0.1%
PB, pH 7.4. The brains were dissected out, and 3-mm thick coronal
blocks containing the hypothalamus were postfixed for an additional
1–2 h in glutaraldehyde-free fixative.
Tissue preparation and immunostaining
Tissue blocks were rinsed in several changes of PB, and 50-µm
Vibratome (Lancer) sections were prepared and rinsed four times for
15 min each time in PB. Sections for electron microscopy were
transferred into vials containing 0.5 ml 10% sucrose (in PB) and
rapidly frozen by immersing the vial in liquid nitrogen to enhance
antibody penetration. They were then thawed to room temperature and
repeatedly washed in PB. Subsequently, sections for both light and
electron microscopy were treated with 1% sodium borohydride in PB for
10 min to eliminate unbound aldehydes from the tissue.
Immunostaining for PHA-L, FG, and tyrosine hydroxylase (TH) was carried out according to the following protocol: incubation in biotinylated rabbit anti-PHA-L (1:250 in PB) containing 1% normal goat serum and 0.3% Triton X-100 for 48 h at 4 C. After several washes in PB, sections were incubated in avidin-biotin-peroxidase (1:500 in PB; ABC Kit, Vector Laboratories, Burlingame, CA), followed by a modified version of the nickel-diaminobenzidene (Ni-DAB) reaction (15 mg DAB, 0.12 mg glucose oxidase, 12 mg ammonium chloride, 600 µl 0.05 M nickel ammonium sulfate, and 600 µl 10% ß-D-glucose in 30 ml PB for 5–10 min at room temperature; dark-blue reaction product) to visualize the tissue-bound peroxidase. After several rinses in PB, sections were further immunostained for FG. In this procedure, after a 48-h (at 4 C) incubation in rabbit anti-FG antiserum (Biogenesis, Franklin, MA; 1:5000 in PB containing 0.1% sodium azide and 1% normal goat serum), sections were further processed in the secondary antibody (biotinylated goat antirabbit IgG, 1:250 in PB; Vector Laboratories) for 2 h at room temperature, than rinsed in PB three times for 10 min each time and incubated for 2 h at room temperature with ABC Elite (1:250 in PB; ABC Elite Kit, Vector Laboratories), followed by the above-described Ni-DAB reaction. After several rinses in PB, every other section was placed on gelatin-coated slides, dehydrated through increasing ethanol concentrations, and mounted with Permount. The remaining sections were further immunostained for TH. In this procedure, after a 48-h (at 4 C) incubation in mouse anti-TH antiserum (Incstar; 1:1000 in PB containing 0.1% sodium azide and 1% normal horse serum), sections were incubated in the secondary antibody (goat antimouse IgG; 1:50 in PB) for 2 h at room temperature, followed by peroxidase-antiperoxidase:rabbit peroxidase-antiperoxidase (1:100 in PB). Between each incubation step, sections were rinsed three times for 15 min each time in PB. In this case, the tissue-bound peroxidase was visualized by a light brown DAB reaction (15 mg DAB and 165 µl 0.3% H2O2 in 30 ml PB for 5–10 min at room temperature; brown reaction product). After immunostaining of the third tissue antigen, sections were thoroughly rinsed in PB, placed on gelatin-coated slides, dehydrated through increasing ethanol concentrations, and mounted with Permount (Fisher Scientific, Fairlawn, NJ). In control experiments, one or two primary antibodies were replaced with normal serum, resulting in single or double immunolabeling.
For electron microscopic analysis, sections were processed the same way as for light microscopy, except the labeling of TH was carried out using 5-nm immunogold-conjugated goat antimouse IgG (Polysciences, Warrington, PA) as secondary antiserum. Subsequently, sections were postosmicated (1% OsO4 in PB) for 30 min, dehydrated through increasing ethanol concentrations (using 1% uranyl acetate in 70% ethanol for 30 min), flat-embedded in Araldite between liquid release (Electron Microscopy Sciences, Fort Washington, PA)-coated slides and coverslips, and placed in an oven to polymerize for 48 h at 60 C. Flat-embedded sections were fixed with a drop of embedding medium on the top of cylindrical araldite blocks and cured again for 48 h at 60 C. Then, blocks were trimmed using light micrographs as a guide in recognizing the selected retrogradely labeled cells and contacts. Ribbons of ultrathin sections (Reichert-Jung Ultramicrotome, Leica Instruments, Deerfield, IL) were collected on Formvar-coated (Electron Microscopy Sciences, Ft. Washington, PA) single slot grids and examined using a Philips CM-10 electron microscope (Rahway, NJ).
Semiquantitative analysis
To gain insight into the extent of colocalization of FG and TH
and to approximate the frequency of interconnections between SCN
efferents and dopaminergic cells, a semiquantitative analysis was
carried out manually on light microscopic material from two animals,
using every other section from the beginning of the third ventricle
through the hypothalamus up to the anterior part of the mammillary
body. When assessing the size of the population of dopaminergic cells
that is neuroendocrine, only cell bodies of TH-immunoreactive neurons
were analyzed. Putative contacts between dark PHA-L-immunoreactive axon
terminals and anything other than cell bodies or proximal dendrites of
the light brown TH-immunoreactive and/or FG-labeled neurons were
ignored. An axo-somatic or axo-dendritic contact was noted only if a
bouton-like structure was in close proximity to a cell body or dendrite
and was found as a continuation of its axon by changing the focus
plane.
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Results |
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Single labeled profiles
PHA-L injection and immunolabeling. Ten animals
received PHA-L injections. Histological examination showed that four
injections were restricted within the boundaries of the SCN, whereas
the rest involved surrounding areas as well. These latter animals were
excluded from this study.
All four injections were placed in the SCN (Fig. 1A
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The number of labeled neurons was between 200–250, representing
approximately 2% of the SCN neuron population. Labeled axon terminals
were seen in each region of the SCN. The majority of PHA-L-labeled
fibers were seen to leave the SCN in the dorsal direction. Few axons
were found to run toward and through the contralateral SCN or the
ipsilateral optic tract. Sections taken from the diencephalon and
adjacent areas showed that anterogradely labeled axons and axon
terminals reached ventral aspects of the lateral septum, medial septum,
bed nucleus of the stria terminalis medial preoptic area, anteroventral
periventricular nucleus, medial preoptic nucleus periventricular
region, parvicellular region of the paraventricular nucleus,
subparaventricular zone, retrochiasmatic area, anterior
hypo-thalamic nucleus, supraoptic decussation, ventrolateral
aspects of the ventromedial hypothalamus, the cell-sparse zone between
the ventromedial nucleus and the arcuate nucleus, dorsomedial
hypothalamic nucleus, and zona incerta. Anterogradely labeled processes
were also detected in the optic tract posterior to the injection site,
and in the intergeniculate leaflet of the ventrolateral geniculate
body. The most abundant network of labeled fibers was detected in the
subparaventricular zone, and the least abundant was found in the zona
incerta. Although the predominant labeling was observed in the
ipsilateral side, some axons were detected in contralateral areas as
well.
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, B–D). Fewer cells could be seen
in the periventricular area, including the subparaventricular zone and
retrochiasmatic area, and in the lateral hypothalamus. No labeled
neurons were detected in the suprachiasmatic nucleus. The distribution
of retrogradely labeled hypothalamic cells corresponded to previous
descriptions (8).
FG immunolabeling resembled that of horseradish peroxidase labeling,
whereby the retrogradely transported peroxidase is confined to small
cytoplasmic granules (see
Figs. 1–3). Electron microscopic analysis
indicated that the FG immunostaining was associated with lysosome-like
structures (Fig. 3).
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, B–D). Labeled cell
bodies and dendrites were found in the anteroventral periventricular
nucleus, medial preoptic area, periventricular area, parvocellular
division of the paraventricular nucleus, anterior hypothalamus, arcuate
nucleus, and zona incerta. Axonal processes were abundant in most of
the hypothalamic nuclei. The median eminence contained an abundant
network of TH-immunoreactive axonal processes in both its internal and
external divisions (Fig. 1B). Immunolabeled processes were also
detected in the organum vasculosum of laminae terminalis and
subfornical organ. The appearance of TH-containing profiles in this
experiment was in accordance with previous reports (10, 11, 12, 13).
Double labeled profiles
FG-TH double labeling. The granular appearance of FG
immunoreactivity allowed for the labeling of cytoplasmic TH. In all of
the hypothalamic areas in which TH immunoreactivity was detected,
retrogradely transported FG was detected in a subpopulation of dopamine
(TH) neurons (Figs. 1, B–D, and Fig. 2, D and E). The
highest incidence of double labeled cells was found in the arcuate
nucleus (A 12 dopaminergic cell group), where of 2593 TH-immunoreactive
cells, 2083 (80%) were also immunolabeled for fluorogold. In the
periventricular area (A 12), 1442 TH-immunoreactive cells were analyzed
of which 453 (31%) were retrogradely labeled. In the preoptic area (A
14), 42% (349 of 833) of TH-immunoreactive cells were FG
immunopositive as well. In the zona incerta, no retrogradely labeled
dopamine cells were detected, whereas numerous nearby neurons contained
FG (Fig. 1D). The extent of colocalization of FG and TH in this study
corresponds to earlier descriptions of neuroendocrine dopaminergic
cells of the hypothalamus (10, 14, 15).
PHA-L-FG double labeling. PHA-L immunoreactive dark blue
fibers were detected in several regions that contained retrogradely
labeled FG-immunoreactive neurons. These regions included the medial
septum, medial preoptic area, periventricular areas, the
subparaventricular zone just adjacent to the injection site, and a
region between the arcuate and ventromedial nuclei. In these regions,
PHA-L-labeled SCN efferents could be frequently found in close
proximity to FG-labeled cell bodies and proximal dendrites (Fig. 2C).
Although quantitative analysis could not be carried out in this
material, the frequency of these connections was highest in the medial
septum-diagonal band-medial preoptic area axis and in the cell-sparse
zone between the arcuate and ventromedial nuclei. Fewer connections
were found in the periventricular area and parvicellular division of
the paraventricular nucleus (see Fig. 4). The vast majority of the
putative connections were observed in the side ipsilateral to the
injection, although few connections were seen on the contralateral
side. PHA-L-immunoreactive fibers could not be detected in the organum
vasculosum laminae terminalis, supraoptic nucleus, magnocellular
division of the paraventricular nucleus, and arcuate nucleus, where the
highest number of retrogradely labeled neurons was found.
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, A and B, and Fig. 3).
The majority of the appositions occurred between
PHA-L-containing axons and the proximal dendrites of TH cells (Fig. 2, A and B). However, axo-somatic connections could also be detected (Fig. 3). In this case, again, connections between SCN efferents and dopamine
cells were predominantly seen on the side ipsilateral to the injection.
However, in a few instances they were also found on the contralateral
side.
Triple labeled cells
In the hypothalamic regions (see above), where dopamine
cells were detected to be retrogradely labeled, dark blue PHA-L boutons
were found in contact with light brown TH-immunoreactive cell bodies
and proximal dendrites containing retrogradely transported dark blue
FG-immunopositive granules (Fig. 2, D and E). In a light microscopic
semiquantitative analysis it was found that in the arcuate nucleus,
where the majority of TH-immunoreactive cells were retrogradely
labeled, of 2083 neuroendocrine dopamine cells, 145 (7%) were
contacted by PHA-L-immunoreactive, SCN efferents. In the
periventricular area, 5% (27 of 453) of the neuroendocrine and 10%
(93 of 998) of the nonneuroendocrine dopamine cells were targeted by
SCN efferents. In the preoptic area, PHA-L-immunoreactive axon
terminals were in close proximity to 6% (21 of 349) of the
neuroendocrine and 7% (34 of 484) of the nonneuroendocrine dopamine
cells.
Electron microscopic analysis of this material revealed synaptic
connections between PHA-L-immunoreactive axon terminals and
retrogradely labeled TH cells (Fig. 3). The synaptic membrane
specializations seemed to be symmetrical (Fig. 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Intraperitoneal administration of FG results in retrograde labeling in neural cells that project to areas that lack a blood-brain barrier (8). These areas in the central nervous system include the so-called circumventricular organs, i.e. the organum vasculosum laminae terminalis, subfornical organ, median eminence, and area postrema (16). In addition, the pineal gland and the posterior pituitary lack the blood-brain barrier (16). Therefore, the interpretation of the present observations without the results of previous anatomical studies delineating the contributions of various hypothalamic nuclei to the innervation of the aforementioned circumventricular organs, cannot be complete. For example, it is known that neurons in the medial septum-diagonal band-medial preoptic area region send projections to the organum vasculosum laminae terminalis, subfornical organ, and median eminence (for review, see Ref.16). On the other hand, the region of the mediobasal hypothalamus is considered to project predominantly to the median eminence and not to the other circumventricular organs (16).
SCN efferents to neuroendocrine- and/or TH-containing neurons
The present results show that a large number of hypothalamic sites
are innervated by the SCN and, therefore, are potentially the terminal
field for relaying circadian messages. Detailed description of the
anterogradely labeled SCN efferents was not in the scope of this
report; however, it can be concluded that the present results are in
absolute agreement with the elaborated studies of Watts et
al. (3, 4). It should be noted that the PHA-L injections were
placed in the ventral aspects of the SCN, and only about 2% of SCN
perikarya were labeled. Therefore, it could not be ruled out that other
SCN cells may send processes to the median eminence. However, the lack
of FG labeling in cells of the SCN after peripheral injection of this
retrograde tracer indicates that neurons in this area do not have
direct access to vessels lacking the blood-brain barrier. In light of
the estimation that approximately 2% of SCN efferents were labeled in
these experiments, the semiquantitative analysis of the connectivity
between SCN efferents and neuroendocrine/nonneuroendocrine dopamine
cells has to be interpreted with caution. In vivo, a higher
incidence of interaction is expected.
In most of the hypothalamic nuclei where FG was observed,
anterogradely labeled SCN efferents were found to be in close
apposition to FG-immunopositive cell bodies and dendrites (Fig. 5). Previous pharmacological and morphological
experiments demonstrated that hypothalamic neural systems that have a
direct access to the portal vessels and, therefore, can be retrogradely
labeled by peripheral FG injection contain a variety of neuropeptides
and neurotransmitters (for review, see Ref.17), including LHRH (18, 19), CRF (20), GH-releasing hormone (21), TRH (22), somatostatin (23),
dopamine (24), serotonin (25, 26), galanin (9), and 
-aminobutyric
acid (27, 28). Our present observations of SCN efferents on
neuroendocrine cells suggests that at least some of these systems may
be directly regulated by the SCN. In accordance, recent studies
indicated that LHRH neurons are indeed targets of axon terminals
originating in the SCN (29, 30, 31).
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). A population of these dopaminergic neurons was
retrogradely labeled, indicating that they contact portal capillaries
in either the external layer of the median eminence or the portal
capillaries of the posterior and intermediate lobes of the pituitary.
In either case, dopamine released into portal vessels can influence
lactotrophs in the anterior pituitary as well as the release of other
hypophysyotropic hormones, such as LHRH. On the other hand, dopamine
neurons that lacked retrogradely transported FG were also found to be
targets of SCN efferents. These cells are known to innervate a wide
variety of regions in the central nervous system (10, 11). For example,
most of the hypophysiotropic hormone-producing neural systems,
including LHRH (34), are targets of a considerable number of
TH-containing axon terminals. Thus, the current findings suggest that
SCN signals may reach hypophysiotropic hormone-producing neural systems
indirectly as well, via dopamine interneurons.
Functional implications
The present results provide a morphological basis for the
information flow between the circadian pacemaker suprachiasmatic
nucleus and neuroendocrine neurons (Fig. 5). The majority of SCN-target
retrogradely labeled neurons were found in the medial preoptic area,
periventricular area, and lateral aspects of the arcuate nucleus. The
vast majority of these neurons send their projections to the median
eminence, whereas a portion of cells in the medial preoptic area may
have been labeled from the organum vasculosum laminae terminalis (8).
Although there is a paucity of information on the function of the
organum vasculosum laminae terminalis, the role of the median eminence
and its portal vessel system in the regulation of anterior pituitary
functions is well established (2).
Neurons with direct access to portal veins contain different neurotransmitters and modulators as well as specific trophic and static hormones that are released from the nerve terminals to the portal capillaries, reach the anterior pituitary, and alter the production and secretion of pituitary hormones. The secretion of most of the anterior pituitary hormones, including gonadotropins and PRL, shows diurnal variations (35, 36, 37, 38, 39, 40, 41, 42, 43). Under normal physiological conditions, the entrainment of these rhythms is by the light-dark cycle (41). The light-dark cycle influences the neuroendocrine hypothalamus at least in part through direct retinal projections to the SCN (41, 44).
PRL secretion. The production and secretion of PRL show diurnal patterns and are under the control of the mediobasal hypothalamus. Dopamine secreted into the portal capillaries is considered to be the major regulatory substance in PRL production and release (5, 45). On the day of proestrus, and every day in estrogen-primed ovariectomized rats, PRL secretion from the anterior pituitary is increased in the afternoon (46). This elevation of PRL is at least in part due to decreased dopamine release induced by the preovulatory estrogen surge (47). It was demonstrated that in ovariectomized, estrogen-primed rats, significant decreases in median eminence dihydroxyphenylacetic acid and dehydroxyphenylalanine occur in parallel with the increased PRL secretion (6). The nature of these events is circadian (48), and destruction of the suprachiasmatic nucleus abolishes the development of afternoon PRL surges (6, 49). The present study demonstrating a direct connection between the SCN and neuroendocrine dopamine cells offers a neural pathway by which circadian signals alter PRL secretion.
Gonadotropin secretion. Circadian activity is also
characteristic for both the daily release and the preovulatory release
of gonadotropins (41). It is suggested that the release from the
inhibitory tone on LHRH neurons initiates both the afternoon and
preovulatory gonadotropin surges. As a population of dopamine neurons
in the periventricular areas was shown to project to the preoptic area
and terminate on LHRH neurons (34), the innervation of nonretrogradely
labeled TH cells in the same regions by SCN efferents raises the
possibility that suprachiasmatic signals may reach LHRH cell bodies via
these catecholamine neurons. On the other hand, neuroendocrine dopamine
cells, too, may convey circadian signals to LHRH cells at the level of
the median eminence. It is reasonable to postulate that as the SCN
efferents are probably inhibitory in nature (vasoactive intestinal
polypeptide and -aminobutyric acid content) (50, 51), the activation
of SCN neurons may inhibit the dopamine neuronal network, resulting in
a disinhibition of LHRH neurons at the level of either the cell bodies
(preoptic area) or the axon terminals (median eminence).
Conclusions
This study using anterograde and retrograde tracing techniques in
combination with immunocytochemistry, provided evidence that 1) the
circadian pacemaker suprachiasmatic nucleus sends direct efferents onto
neuroendocrine cells of different hypothalamic nuclei; 2) a
subpopulation of SCN target neuroendocrine cells contains dopamine; and
3) suprachiasmatic efferents do not reach fenestrated capillaries.
These observations suggest that the circadian pacemaker has no direct
effect on the regulation of anterior pituitary functions, but indicate
a pathway by which circadian signals are integrated into the
hypothalamo-pituitary-gonadal axis. It needs to be explored whether the
integration of hormonal and circadian signals, a mandatory process in
the regulation of the anterior pituitary, which was indicated to occur
in populations of hypothalamic neurons (52), may be the same cells that
were found to be neuroendocrine in the present study.
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Acknowledgments |
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Footnotes |
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Received September 6, 1996.
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References |
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