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The Journal of Neuroscience, February 15, 1998, 18(4):1546-1558
An Alternate Pathway for Visual Signal Integration into the
Hypothalamo-Pituitary Axis: Retinorecipient Intergeniculate Neurons
Project to Various Regions of the Hypothalamus and Innervate
Neuroendocrine Cells Including Those Producing Dopamine
Tamas L.
Horvath
Department of Obstetrics and Gynecology, Yale University School of
Medicine, New Haven, Connecticut 06520
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ABSTRACT |
Using tract tracing and immunocytochemistry, this study explored
the connectivity between lateral geniculate efferents and neurons of
the hypothalamus, including those producing dopamine, that have direct
access to fenestrated capillaries. It was also determined whether the
intergeniculate neurons that give rise to hypothalamic projections are
targeted by retinal axons.
Within the hypothalamus, Phaseolus vulgaris
leucoagglutinin-labeled, lateral geniculate efferents were observed in
the suprachiasmatic nucleus, subparaventricular area, periventricular
nuclei, medial preoptic areas, and between the arcuate and ventromedial
nuclei. In these sites, intergeniculate efferents contacted populations of neurons that were retrogradely labeled from fenestrated capillaries by the intraperitoneal injection of fluorogold. Hypothalamic dopamine neurons, a population of which was neuroendocrine, were also synaptic targets of lateral geniculate efferents. After injection of the retrograde tracer fluorogold into these hypothalamic projection sites
in parallel with bilateral enucleation, retrogradely labeled perikarya
were restricted to the intergeniculate leaflet. All of the labeled
perikarya contained infolded nuclei, and their distal dendrites were
frequently found to be contacted by degenerated, retinal fibers.
This study provides morphological evidence for a signaling pathway from
the retina through the intergeniculate leaflet to hypothalamic cells
that participate in neuroendocrine regulations. These observations
raise the possibility that visual signals independent of the circadian
clock may also influence the hypothalamo-pituitary axis. In light of
the overlapping distribution of intergeniculate and suprachiasmatic
efferents in the hypothalamus and their similar relationship with
neuroendocrine cells, it is suggested that integration of circadian and
visual signals can occur outside of the suprachiasmatic nucleus to
regulate endocrine rhythms.
Key words:
retina; intergeniculate leaflet; hypothalamus; neuroendocrine cells; dopamine; anterior pituitary
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INTRODUCTION |
The circadian timing system of
mammals supports different functions in reproduction. The appropriate
alternation of light/dark cycles and the interaction among the visual,
circadian, and neuroendocrine systems are essential in the maintenance
of rhythmic secretion of prolactin and luteinizing hormone (LH)
(Antunes et al., 1967 ; Brown-Grant and Raisman, 1977; Kawakami et al.,
1980; Pan and Gala, 1985). For example, exposure to constant light
induces the emergence of impaired LH and prolactin secretions, leading
to the failure of ovarian cycles (Critchlow, 1963; Brown-Grant et al.,
1973; Pieper and Gala, 1979; Vaticon et al., 1980; Sartin et al., 1981;
Watts and Fink; 1981a,b; Nir and Hirschmann, 1982; Sterner and Cohen
1995).
It was postulated that a tightly coupled relationship exists between
the retino-recipient suprachiasmatic nucleus (SCN) and the principal
regulatory cells in gonadotropin and prolactin secretion, the
luteinizing hormone-releasing hormone (LHRH)- and dopamine-producing neurons, because: (1) there is a lack of SCN efferents in the median
eminence, the site where neurohormones are released into the portal
capillaries and are transported to the anterior pituitary; and (2) the
LHRH and dopamine cells are located in areas of the hypothalamus that
are targeted by SCN efferents (Chan-Palay et al., 1984; van den Pol et
al., 1984; Watts and Swanson, 1987; Watts et al., 1987; Kawano and
Daikoku, 1987). Recent evidence confirmed this suggestion by
demonstrating synaptic interactions between SCN efferents and
LHRH-producing (van der Beek et al., 1997) and dopamine-producing
hypothalamic perikarya (Horvath, 1997). These observations provided a
signaling pathway for circadian regulation of the hypothalamo-pituitary
axis. However, the constant light-induced malfunctioning of the
anterior pituitary cannot be easily understood by this signaling
modality; during constant light, the circadian pacemaker free runs
(Honma and Hiroshige, 1978). However, the circadian daily and
preovulatory gonadotropin and prolactin secretions are abolished
(Critchlow, 1963; Brown-Grant et al., 1973; Sartin et al., 1981; Watts
and Fink, 1981a,b). Although arrhythmicity in SCN activity was also
detected in animals kept in constant light, which could cause impaired
hormone secretions (Morimoto et al., 1975), it may be that during
exposure to constant light, photic stimuli can continuously reach
neuroendocrine cells via a pathway that does not involve the SCN.
A brain region that has the potential to mediate
noncircadian visual information to the hypothalamus is the
intergeniculate leaflet (IGL) of the lateral geniculate nucleus (LGN);
it receives direct visual input (Hickey and Spear, 1976) and has not
been shown to have intrinsic circadian activity, and cells of the IGL innervate extrasuprachiasmatic areas of the hypothalamus (Mikkelsen, 1990a,b; Moore et al., 1996). The present study explored the
interconnection between LGN efferents and neurons of the hypothalamus,
including those producing dopamine that are neuroendocrine; i.e., they
have direct access to fenestrated capillaries. These cells can release their products to the portal vessels in the median eminence that provides the humoral link between the hypothalamus and the anterior pituitary. This study also aimed to determine whether intergeniculate neurons that give rise to hypothalamic projections are direct targets
of retinal axons.
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MATERIALS AND METHODS |
Animals
Female Sprague Dawley rats (250-280 gm body weight) were kept
under standard laboratory conditions: tap water and standard rat chow
ad libitum and 12 hr light/dark cycle. Two sets of
experiments were performed on two groups of randomly selected females
(the status of the estrous cycle was not determined). One group
included animals (n = 6) in which LGN efferents were
labeled with Phaseolus vulgaris leucoagglutinin (PHA-L) and
neuroendocrine cells with systemic fluorogold (FG) injections. In
another group of rats (n = 6), retrograde labeling of
LGN neurons was performed on enucleated animals by iontophoretic
injections of FG into extrasuprachiasmatic regions of the hypothalamus.
All of the experimental procedures were approved by the Yale Animal
Care Committee.
PHA-L injections
The projection field of LGN neurons was visualized by 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 by 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 Transcientics System, Canton, MA) into
different areas of the IGL [coordinates: anteroposterior (AP),  4.2
mm; lateral (L), 3.6 mm; ventral (V), 5.3 mm, according to Paxinos and
Watson, 1986].
Fluorogold (FG) injection
Simultaneously with the PHA-L injections, animals received
a single intraperitoneal injection of FG (20 mg/kg body weight in
saline; Fluorochrome, Inc., Englewood, CO) to label neurons that send
projections to regions in the CNS that lack blood-brain barrier
(Merchenthaler, 1991).
In a group of animals that were binocularly enucleated (see below), FG
(2% FG in saline) was applied into extrasuprachiasmatic sites where
LGN efferents contacted neuroendocrine cells (AP, 0.0-1.3 mm; L, 0.2 mm; V, 9.4-8.8 mm, according to Paxinos and Watson, 1986). These FG
injections were applied iontophoretically, using the same parameters as
for the PHA-L experiments (see above).
Bilateral enucleation
In a group of animals, in parallel with the FG injections, both
eyes of the animals were surgically removed under ketamine anesthesia.
Fixation and tissue preparation
Fifteen days after PHA-L and FG injections and 5 d after FG
and enucleation, rats were killed under metofane anesthesia by transaortic perfusion with 50 ml of heparinized saline followed by 250 ml of fixative. The fixative consisted of 4% paraformaldehyde, 15%
picric acid, and 0.2% glutaraldehyde in 0.1 M PB, pH 7.4. The brains were dissected out, and 3-mm-thick coronal blocks containing the diencephalon were post-fixed for an additional 1-2 hr in
glutaraldehyde-free fixative. Tissue blocks were rinsed in several
changes of PB, and 50 mm vibratome (Lancer) sections were prepared and
rinsed four times for 15 min each 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
PHA-L and FG studies. Immunostaining for PHA-L, FG,
and tyrosine hydroxylase (TH) was performed according to a recently
published protocol (Horvath, 1997). First, sections were incubated in
biotinylated rabbit anti-PHA-L, 1:250 in PB containing 1% normal goat
serum and 0.3% Triton X-100 for 48 hr at 4°C. After several washes
in PB, sections were incubated in avidin-biotin-peroxidase, 1:500 in
PB (ABC kit, Vector), followed by a modified version of the Ni-DAB
reaction (15 mg of DAB, 0.12 mg of glucose oxidase, 12 mg of ammonium
chloride, 600 ml of 0.05 M nickel ammonium sulfate, and 600 ml of 10%  -D-glucose in 30 ml of PB; dark blue reaction product) to visualize the tissue-bound peroxidase. Then, sections were
further immunostained for FG. In this procedure, after a 48 hr (at
4°C) incubation in rabbit anti-FG antiserum (Biogenesis, Inc.,
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 anti-rabbit IgG, 1:250 in PB; Vector) for 2 hr at room temperature and then rinsed in PB three times for 10 min
each, and incubated for 2 hr at room temperature with ABC Elite
(Vector), 1:250 in PB, 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 hr (at
4°C) incubation in mouse anti-TH antiserum (Chemicon, Temecula, CA;
1:1000 in PB containing 0.1% sodium azide and 1% normal horse serum),
sections were incubated in the secondary antibody (goat anti-mouse
IgG), 1:50 in PB for 2 hr at room temperature, followed by
peroxidase-anti-peroxidase (PAP), rabbit PAP, 1:100 in PB. Between
each incubation step, sections were rinsed three times for 15 min each
in PB. In this case, the tissue-bound peroxidase was visualized by a
light brown DAB reaction (15 mg of DAB, 165 µl of 0.3%
H2O2 in 30 ml of PB, 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. In control experiments, one
or two primary antibodies were replaced with normal serum resulting in
only single or double immunolabeling.
For electron microscopic analysis, sections were processed the same way
as for light microscopy, except the labeling of TH was performed before
PHA-L and FG immunostaining using 5 nm immunogold-conjugated goat
anti-mouse IgG (Polysciences, Warrington, PA) as secondary antiserum.
Subsequently, sections were post-osmicated (1% OsO4 in PB)
for 30 min, dehydrated through increasing ethanol concentrations (using
1% uranyl acetate in the 70% ethanol, 30 min) and 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 hr 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 hr 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) were collected on Formvar-coated
single-slot grids and examined using a Philips CM-10 electron
microscope.
FG and enucleation studies. In this case, only single
labeling for FG was performed as described above using the polyclonal antiserum against FG and an ABC procedure followed by a DAB reaction (see above).
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RESULTS |
PHA-L, FG, and TH labeling
PHA-L injection and immunolabeling
Six animals received PHA-L injections. Three of these injections
were placed predominantly in the IGL as revealed by immunolabeling for
PHA-L. Only tissues from these latter animals were fully processed according to the protocol.
Labeled perikarya were most abundant in the IGL, whereas
PHA-L-immunoreactive cells were also found in the adjacent areas of
both the ventral LGN (vLGN) and dorsal LGN (dLGN) (Fig.
1A,B). Labeled axons
and axon terminals were detected in all parts of the LGN. In accordance
with the labeled cell bodies, LGN efferents were observed in all
previously reported projection sites of these nuclei, including the
superior colliculus, posterior commissure, and contralateral LGN. This
study focused on the hypothalamic projection sites.
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Figure 1.
Anterograde labeling of LGN efferents by PHA-L.
A, B, Typical injection site of the anterograde tracer
PHA-L in the LGN. Although PHA-L-immunoreactive cells are present in
all regions of the LGN, including the dLGN and the vLGN, the vast
majority of labeled cells are located in the IGL. B,
High-power magnification of the IGL area indicated on A.
C-G, Anterogradely labeled LGN efferents in the
subparaventricular region (subPV; C), lateral
hypothalamus (LH), periventricular area
(Pe), and posterior SCN (D),
anterior SCN (E) MPO (F),
and the anteroventral periventricular nucleus (AVPv; G).
Labeled processes are also visible in the optic tract (D) and chiasm (E-G). On
the other hand, the magnocellular region of the paraventricular nucleus
(PVN on C) that contained a high number
of FG-labeled cells after peripheral injection of the retrograde tracer
does not seem to receive IGL efferents. H-J, High-power light micrographs showing axon arborizations and axon terminals in the
posterior arcuate nucleus (ARC; H), MPO
(I) and the AVPv (J). Scale bars: A-C, H-J, 100 µm; D-G, 300 µm.
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Sections taken from the diencephalon and adjacent forebrain areas
showed that anterogradely labeled axons and axon terminals reached
ventral aspects of the lateral and medial septal nuclei, diagonal band
of Broca, bed nucleus of the stria terminalis, medial preoptic area
(MPO), anteroventral periventricular nucleus (AVPv), medial preoptic
nucleus periventricular region, parvocellular region of the
paraventricular nucleus, subparaventricular zone, retrochiasmatic area,
anterior hypothalamic nucleus, supraoptic decussation, suprachiasmatic
nucleus, dorsomedial nucleus, ventrolateral aspects of the ventromedial
nucleus, and the cell-sparse zone between the arcuate and ventromedial
nuclei (Figs. 1C-H, 2). LGN efferents could also be detected in the ipsilateral optic tract and in
both the ipsilateral and contralateral optic nerve (Fig. 1A,D). The most abundant network of labeled fibers
could be seen in the ventral aspects of the SCN and the
subparaventricular zone. No labeled processes could be detected in the
median eminence and organum vasculosum laminae terminalis, and only
trespassing axons were found within the core of the arcuate nucleus and
the magnocellular region of the paraventricular nucleus. Although most
of the labeling was observed in the ipsilateral side, some axons were
detected in contralateral areas as well. Contralateral innervation was
the most pronounced in the SCN and the subparaventricular area. In the
case of the SCN, collaterals from the same axon could frequently be
followed to both the ipsilateral and contralateral SCN.
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Figure 2.
Distribution of LGN and SCN efferents in the
hypothalamus. A-L, Camera lucida drawings of coronal,
hypothalamic vibratome sections after immunostaining for PHA-L-filled
LGN efferents (blue processes). Red
processes represent PHA-L-labeled SCN efferents that were superimposed
from matching vibratome sections of another experiment (Horvath, 1997).
Circles represent neuroendocrine cells immunoreactive
for fluorogold. Black filled circles are neuroendocrine cells that were TH-immunoreactive. Sections were taken between 0.2 and
4.3 mm in the anteroposterior axis, the number indicating the
distance between the coronal level and bregma. MS,
Medial septum; OVLT, organum vasculosum laminae
terminalis; DBB, diagonal band of Broca;
oc, optic chiasm; ac, anterior
commissure; MPA, medial preoptic nucleus;
AVPv, anteroventral periventricular nucleus; LPO, lateral preoptic area; Pe,
periventricular area; MPO, medial preoptic area;
SCN, suprachiasmatic nucleus; SO,
supraoptic nucleus; III, third ventricle;
f, fornix; PVN, paraventricular nucleus; AH, anterior hypothalamus; Rch,
retrochiasmatic area; ARC, arcuate nucleus; VMN, ventromedial nucleus;
ZI, zona incerta; DMN, dorsomedial nucleus; ME, median eminence; PMD, dorsal
premammillary nucleus; OT, optic tract.
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In an attempt to compare the distribution pattern of SCN and IGL
efferents in the hypothalamus, we analyzed serial vibratome sections
immunostained for PHA-L from animals that received the tracer in the
IGL (present studies) and the SCN (a previous experiment; see Horvath,
1997). On superimposing camera lucida drawings from the two
experiments, it could be seen that the projection field of IGL
efferents within the hypothalamus almost completely overlapped that of
the SCN (Fig. 2). Also note that although a quantitative analysis could
not be performed, the extent of the IGL innervation of different
hypothalamic nuclei seemed to be comparable to that of the SCN.
FG immunolabeling
FG-immunopositive cell bodies and dendrites could be seen
throughout the hypothalamus. Retrogradely labeled cells were abundant in the medial septum, medial preoptic area, organum vasculosum of
laminae terminalis, diagonal band of Broca, supraoptic and paraventricular nuclei, arcuate nucleus, the area between the arcuate
nucleus and ventrolateral parts of the ventromedial nucleus, and the
zona incerta. 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 SCN
or IGL. The distribution of retrogradely labeled hypothalamic cells
corresponded to earlier descriptions (Merchenthaler, 1991; Horvath,
1997). In accordance with previous studies (Morin and Blanchard, 1993),
the intraperitoneal administration of FG resulted in a different
appearance of the immunoperoxidase reaction product in cells than
resulted from the iontophoretic application (see below). FG labeling in
the former had a granular appearance, whereas, in the latter, FG
labeling was homogeneously distributed in the IGL cells. It is likely
that this difference is the result of the low levels of FG in the
circulation, in contrast to the concentration given for iontophoretic
application.
TH immunostaining
Immunolabeling for TH resulted in extensive staining throughout
the hypothalamus. Labeled cell bodies and dendrites were found in the
AVPv, MPO, 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. The appearance of TH-containing profiles in this experiment
was in accordance with previous reports (Chan-Palay et al., 1984; van
den Pol et al., 1984; Horvath et al., 1992a,b).
FG-TH double labeling
The granular appearance of FG immunoreactivity permitted the
detection of the labeling of cytoplasmic TH. In all of the hypothalamic areas where TH immunoreactivity was detected, retrogradely transported FG was detected in a subpopulation of TH-immunoreactive, putative dopamine neurons (Figs. 3,
4E-G2). The highest
incidence of double-labeled cells was found in the arcuate nucleus (A12
dopaminergic cell group) followed by the periventricular area and the
preoptic area (A14 dopaminergic cell group). In the zona incerta, no
retrogradely labeled dopamine cells were detected, whereas numerous
neurons nearby contained FG. The extent of colocalization of FG and TH in this study corresponds to earlier descriptions of neuroendocrine dopaminergic cells of the hypothalamus (Jonsson et al., 1971; van den
Pol et al., 1984; Kawano and Daikoku,1987; Horvath, 1997).
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Figure 3.
Distribution of dopamine-containing and/or
neuroendocrine cells in the hypothalamus. Schematic illustrations of
hypothalamic sections at the level of the medial preoptic area
(AVPv, MPO; A), suprachiasmatic-periventricular areas
(Pe; B), retrochiasmatic-anterior hypothalamus area
(C), and arcuate nucleus (ARC; D).
Shown are the distribution patterns of TH-immunoreactive
(diamonds) and fluorogold-labeled
(circles) cells, their colocalization
(circles in diamonds), and those
dopaminergic (filled diamonds) and/or neuroendocrine (filled circles) cells that were
found to be targets of IGL efferents. ac, Anterior
commissure; oc, optic chiasm; Pe, periventricular area; f, fornix; V, third
ventricle; mt, mammillothalamic tract;
ZI, zona incerta; ot, optic tract;
SO, supraoptic nucleus; DMH, dorsomedial
hypothalamic nucleus.
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Figure 4.
LGN efferents contacting hypothalamic
neuroendocrine and/or dopamine cells. Light micrographs of a
hypothalamic section after visualization for PHA-L-containing LGN
efferents (dark blue boutons; arrows),
retrogradely labeled, fluorogold-containing neuroendocrine cells
(dark blue cytoplasmic inclusions), and TH (homogeneous brown cytoplasmic staining) in neuronal perikarya
representing dopamine (DA)-producing cells. A,
B, Dark blue boutons originating in the LGN in
close proximity to an FG-containing perikaryon and dendritic process of
the MPO and the periventricular area (Pe), respectively.
C, D, Putative connections between IGL efferents (PHA-L-immunoreactive axon terminals; arrows) and
non-neuroendocrine (FG-negative) dopamine cells in the anteroventral
periventricular nucleus (AVPv) and Pe.
E-G1, Retrogradely labeled (FG granules) dopamine cells
(TH-immunoreactive) contacted by PHA-L-containing putative axon
terminals (arrows) in the Pe (E),
AVPv (F), and the lateral aspects of the arcuate
nucleus (ARC) (G1). G2,
Same cells as in G1 but at a different focus plane to
enhance the visibility of FG-immunoreactive cytoplasmic inclusions.
Scale bars, 10 µm.
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PHA-L-FG double labeling
PHA-L-immunoreactive dark blue fibers were detected in several
regions that contained retrogradely labeled FG-immunopositive neurons
(Fig. 2). These regions included the medial septum, MPO, periventricular areas, subparaventricular zone, and a region between the arcuate and ventromedial nuclei (Fig. 3). In these regions, PHA-L-labeled LGN efferents could often be found in close proximity to
distinct populations of FG-labeled cell bodies and proximal dendrites
(Fig. 4A,B). Similar to the experience with SCN
efferents (Horvath, 1997), the frequency of these connections was
highest in periventricular areas, including the anteroventral
periventricular nucleus, and in the cell-sparse zone between the
arcuate and ventromedial nuclei. Fewer connections were found in the
parvocellular division of the paraventricular nucleus. The putative
connections were observed predominantly in the side ipsilateral to the
injection, although a few connections were seen on the contralateral
side as well.
PHA-L-TH double labeling
PHA-L-immunoreactive fibers were seen in close apposition to
TH-immunolabeled cells within the MPO, AVPv, periventricular and
retrochiasmatic regions, dorsomedial nucleus, and an area between the
arcuate nucleus and the ventromedial nucleus (Figs. 2, 3,
4C,D). The IGL target catecholaminergic cells were
homogeneously distributed in the AVPv. In the periventricular region,
most of these cells were located in ventral areas, whereas in the
subparaventricular zone most of these cells were concentrated in the
bordering regions of the parvocellular paraventricular nucleus,
dorsomedial nucleus, and anterior hypothalamus. The majority of the
appositions were between PHA-L-containing axons and the proximal
dendrites of TH cells. However, axosomatic connections could also be
detected.
Triple-labeled cells
In the hypothalamic regions (see above) where dopamine cells were
detected to be retrogradely labeled, but most extensively in the AVPv,
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 (Figs. 3,
4E-G2). Electron microscopic analysis revealed predominantly symmetrical synapses between PHA-L-immunoreactive boutons
and neuroendocrine and/or dopamine-producing cell bodies and dendrites
(Fig. 5).
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Figure 5.
Synaptic interaction between IGL efferents and
hypothalamic cells. Electron micrograph taken of the arcuate nucleus
(A), periventricular area
(B), MPO (C), and
anteroventral periventricular nucleus (D) from
the material triple immunolabeled for PHA-L, TH
(arrowheads on A, D point
to immunogold), and FG (arrows). PHA-L-immunoreactive boutons originating in the IGL establish symmetric axosomatic (A-C) and axodendritic (D)
synaptic contacts (large arrows) with hypothalamic cells
that contain TH and/or FG immunolabeling. Scale bars, 1 µm.
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FG and enucleation experiments
Animals that were binocularly enucleated and received FG
injections into hypothalamic sites were perfused 5 d after the
parallel interventions. This survival period was previously shown to be sufficient for the detection of anterogradely degenerated retinal axon
terminals in the LGN (Takatsuji et al., 1991) and to allow FG to travel
a distance of 5-6 mm.
FG labeling
FG injection sites could be detected by fluorescence microscopy in
discrete areas of the hypothalamus, including the anteroventral periventricular nucleus (Fig.
6A1) medial preoptic
area (Fig. 6B1), and an area above the
suprachiasmatic nucleus (Fig. 6C1). For this experiment,
only those animals in which the FG injection avoided the SCN were
used.
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Figure 6.
FG injection sites in the anterior hypothalamus
and their relationships to local TH-immunoreactive cells.
A1-C2, Micrographs taken from hypothalamic vibratome
sections of animals that received FG injections in different anterior
hypothalamic sites. A1, B1, C1, FG injection sites
(arrows) using ultraviolet light in the anteroventral
periventricular nucleus (AVPv) (A1), MPO
(B1), and an area above the SCN (A3).
Only the labeled cells around the tip of the iontophoretic injection
(arrows) have a high enough concentration of fluorogold
to emit fluorescent light after immunostaining for FG. A2, B2,
C2, Light micrographs of the areas corresponding to the FG
injections immunostained for TH. TH-immunoreactive
(irTH), putative dopaminergic cells are present
in the areas where FG was injected (compare A1 with
A2, B1 with B2, and
C1 with C2). Scale bar, 50 µm.
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Retrogradely labeled FG-immunoreactive perikarya and dendrites were
observed throughout the hypothalamus. Although almost all regions
contained retrogradely labeled cells, the highest number of
FG-accumulating neurons were found in the medial preoptic area,
periventricular areas, and the arcuate nucleus.
In the LGN, FG-immunoreactive perikarya were restricted to the
IGL (Fig. 7). No retrogradely labeled
neurons could be observed in either the vLGN or dLGN. Within the IGL,
hypothalamo-projective neurons showed a homogeneous distribution (Fig.
7). Although retrogradely labeled cells were present predominantly in
the IGL ipsilateral to the injection site, numerous labeled perikarya
could also be detected in the contralateral IGL.
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Figure 7.
Distribution of retrogradely labeled IGL cells
after hypothalamic FG injections. A, Light micrograph
that demonstrates that retrogradely labeled, fluorogold-immunoreactive
(irFG) LGN cells are restricted to the IGL and are not
present in the dLGN or vLGN. B, C,
High-power magnifications of FG-immunoreactive IGL cells. Arrows
C point to FG-immunoreactive cells and dendrites within the
IGL. Scale bars: A-C, 100, 25, and 10 µm,
respectively.
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The immunoperoxidase labeling for FG was homogeneously distributed
within the perikarya and dendrites of IGL neurons. Electron microscopic
analysis revealed that all of the FG-immunoreactive perikarya of the
IGL contained nuclei with numerous invaginations (Fig.
8A), whereas nearby
neurons with round nuclei (not infolded) never contained
immunoperoxidase. Although degenerated myelinated and unmyelinated
axons and axon terminals were detected in the IGL, these fibers were
never observed in close apposition to labeled or unlabeled cell bodies
or proximal dendrites in the IGL. On the other hand, asymmetric
synaptic contacts were frequently observed between degenerated retinal
axon terminals and distal dendrites of both retrogradely labeled (Fig.
8B,C) and unlabeled IGL neurons.
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Figure 8.
Electron microscopic analysis of the IGL after
hypothalamic FG injection and binocular enucleation. A,
Ultrastructural analysis of a hypothalamus-projective (FG) IGL cell
demonstrates that the nucleus contains several infoldings
(arrows), and the immunolabeling for FG is homogeneously
distributed in the cytoplasm. B, C, Asymmetrical synapses (open arrowheads) between degenerated retinal
fibers and distal dendrites of IGL neurons containing immunoperoxidase for FG. Scale bars, 1 µm.
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DISCUSSION |
LGN efferents innervated various hypothalamic sites. Although an
abundant network of LGN fibers was detected in the SCN, a comparable
innervation of the subparaventricular zone and other periventricular
structures was also observed (Fig. 2). These results are in agreement
with previous demonstrations of LGN efferents in various regions of the
hypothalamus (Swanson et al., 1974; Ribak and Peters, 1975; Mikkelsen,
1990a,b; Moore et al., 1996). However, with the exception of a recent
preliminary report (Moore et al., 1996), this study is the first to
provide a detailed description of LGN efferents throughout the entire
rat hypothalamus and to demonstrate an almost complete overlap between
SCN and IGL projections in different hypothalamic nuclei.
The exclusive appearance of retrogradely labeled cells in the IGL after
hypothalamic FG injections is also in accordance with the result of
Moore et al. (1996). In anterograde tracing experiments, they found
that the IGL and not the vLGN contributes to the innervation of the
hypothalamus. Our electron microscopic analysis revealed that the
retrogradely labeled IGL perikarya contained exclusively infolded
nuclei, and IGL projections established symmetric synaptic contacts
with hypothalamic target cells. These characteristics are associated
with inhibitory neurons (Ribak and Seress, 1983). Previous
immunocytochemical studies demonstrated that IGL neurons produce
enkephalin, neuropeptide Y, and GABA (Mantyh and Kemp, 1983; Takatsuji
and Tohyama, 1989). It was also shown that IGL neurons and their
projections to the SCN colocalize NPY and GABA (Moore and Speh, 1993;
Moore and Card, 1994), and that these peptidergic terminals, in part,
established symmetric synaptic contacts (Moore et al., 1984). Thus, it
is likely that the geniculohypothalamic tract innervating
extrasuprachiasmatic sites may also be a GABAergic, NPY-containing
pathway.
These experiments revealed that a population of LGN-targeted neurons in
the hypothalamus are neuroendocrine cells; i.e., they have direct
access to the portal vasculature of the median eminence or the organum
vasculosum laminae terminalis. These cells, including those producing
dopamine, were most frequently found in periventricular areas. The same
hypothalamic cell populations were previously found to receive SCN
input (Horvath, 1997), raising the possibility of convergent SCN and
IGL inputs on the same hypothalamic perikarya. In light of the fact
that the parent cells of the IGL efferents were found to receive direct
visual input, it is reasonable to suggest that the integration of
visual and circadian signals into the hypothalamo-pituitary axis may
occur on the final output neurons of the hypothalamus (Fig.
9), adding another level of redundancy to
the pathways via which the environment may regulate hormone secretions.
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Figure 9.
Schematic illustration of the relationship among
visual, circadian, and neuroendocrine cells in the hypothalamus.
Retinal efferents (green) innervate IGL neurons
(filled blue circles) that project to the
hypothalamus (blue lines) and innervate different populations of neurons. Subpopulations of these neurons in the MPO,
periventricular area (Pe), and arcuate nucleus
(ARC) contain dopamine (DA) and/or are
neuroendocrine (ne) revealed by systemic fluorogold
labeling. A population of neurochemically unidentified (?) neuroendocrine cells were also found to
receive IGL efferents. Neurons of the SCN (filled red
circles) receive retinal (green) and IGL
efferents (blue) and innervate (red
lines) the same population of hypothalamic cells as IGL
processes. V, Third ventricle; oc, optic
chiasm; ot, optic tract. Dashed black
lines indicate projections to fenestrated capillaries.
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An increasing body of data indicate that visual signals may be conveyed
to hypothalamic sites by pathways other than the SCN. In addition to
direct retinal input to different hypothalamic sites (Hendrickson et
al., 1972; Moore and Lenn, 1972; Pickard and Silverman, 1981; Riley et
al., 1981; Johnson et al., 1988; Mikkelsen, 1992; Levine et al., 1994),
the present and previous studies (Mikkelsen, 1990a,b; Moore et al.,
1996) found that there is an extensive projection of IGL neurons to
hypothalamic sites, including the medial septum, diagonal band of
Broca, bed nucleus of the stria terminalis, MPO, AVPv, periventricular
areas, subparaventricular zone, dorsomedial nucleus, and a cell-sparse
zone between the arcuate nucleus and the ventromedial hypothalamic
nucleus. It was also demonstrated that retinorecipient IGL neurons
innervated neuroendocrine cells, including those producing dopamine.
These observations indicate that the participation of the IGL in the regulation of central mechanisms may not be restricted to the alteration of SCN activity, but the IGL may directly convey photic stimuli to neuroendocrine cells.
Functional considerations
Production and secretion of prolactin and LH from the anterior
pituitary 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 prolactin
production and release (Ben-Jonathan et al., 1977; Ben-Jonathan, 1985).
On the day of proestrus and every day in estrogen-primed,
ovariectomized females, prolactin and LH secretions from the anterior
pituitary increase in the afternoon (Smith et al., 1976). This
elevation of prolactin is, at least in part, attributable to decreased
dopamine release (Neill et al., 1971). Significant decreases of median
eminence dihidroxyphenilacetic acid and dehydroxyphenylalanine also
occur in parallel with the increased prolactin secretion (Mai et al.,
1994). Regarding LH secretion, it is suggested that the release from
the inhibitory tone on LHRH neurons initiates both the afternoon
(Kawakami et al., 1980) and preovulatory gonadotropin surges.
The SCN constitutes an essential component for normal control of LH and
prolactin secretion in rodents. Destruction of the circadian clock
blocks the preovulatory LH and prolactin surges and induces persistent
estrus accompanied by hyperprolactinemia in intact female rats (Mai et
al., 1994). A similar outcome occurs during constant light exposure,
which first induces a delay (Watts and Fink, 1981a) but then abolishes
the daily and preovulatory gonadotropin and prolactin surges
(Critchlow, 1963; Brown-Grant et al., 1973; Watts and Fink, 1981b).
Interestingly, under these conditions, the circadian SCN activity will
free run (Honma and Hiroshige, 1978). A plausible cause for altered
hormone secretions could be that the rhythm of the free-running
circadian pacemaker during constant light eventually will split into
two running cycles (Pittendrigh and Daan; 1976; Morin and Cummings,
1982; Pickard and Turek; 1982; Swan and Turek, 1982, 1985). This, in
turn, will impair most circadian rhythms and also underlies split daily
surges of LH (Swan and Turek, 1982, 1985). Because these changes in
circadian function were not described in rats, it is likely that during constant light exposure, there is a continuous signal from the eye to
the final output neurons of the hypothalamus that maintains a subtle
but steady activation of anterior pituitary cells producing LH and
prolactin.
Our results elucidate a pathway through which these continuous signals
can be conveyed from the eye to hypothalamic cells via the IGL. The
observation that exposure to constant light induces the continuous
expression of the early proto-oncogene c-fos in IGL cells but not in
SCN neurons (Park et al., 1993; Edelstein and Amir, 1996) raises the
possibility that the neuroendocrine cells described as receiving IGL
(present study) and SCN (Horvath, 1997) inputs may be continuously
altered by IGL rather than SCN signals. To elucidate the interaction of
SCN and IGL signals further in the regulation of these hypothalamic
cells exposed to constant light, the localization and possible
segregation of these inputs on the same hypothalamic perikarya need to
be determined.
Of particular interest regarding prolactin and LH secretions are those
IGL-targeted dopamine cells that are located in the anteroventral
periventricular nucleus. The critical role of this extrasuprachiasmatic
area in the rhythmic regulation of anterior pituitary hormones has been
recognized; similar to the effects of constant light exposure, it was
found that selective destruction of this area abolishes ovarian cycles
and results in the emergence of constant vaginal estrus (Wiegand and
Terasawa, 1982). Therefore, it is likely that the IGL input to
neuroendocrine and non-neuroendocrine dopamine cells of the AVPv may
significantly contribute to the development of altered anterior
pituitary hormone secretion induced by constant light exposure.
Prolactin secretion
Neuroendocrine dopamine cells of the AVPv and arcuate nucleus are
known to send efferents to the median eminence region (van den Pol et
al., 1984; Kawano and Daikoku, 1987) to participate in the suppression
of prolactin secretion (Ben-Jonathan, 1985). Because the excitatory
visual input on IGL neurons may be translated to an increased
inhibitory tone on the neuroendocrine dopamine cells (putative
inhibitory projections from the IGL), the consequent decreased dopamine
secretion can underlie a steady elevation of prolactin secretion during
constant light.
Gonadotropin secretion
Dopamine interneurons of the AVPv were found to innervate GnRH
cells (Horvath et al., 1993) and to receive IGL efferents (present study). Therefore, an increased inhibitory input (from the IGL) on
these dopamine cells induced by constant light may affect the activity
of GnRH neurons leading to a continuous, steady trigger for LH
secretion.
In conclusion, this study provides evidence for a monosynaptic pathway
between IGL neurons and hypothalamic cells outside of the SCN. It was
demonstrated that IGL efferents innervate neuroendocrine cells,
including those producing dopamine, and that their parent cells
received direct retinal input. Therefore, it is suggested that a
signaling modality exists between the eye and hypothalamic cells not
involving the SCN that can regulate neuroendocrine and autonomic
functions.
| |
FOOTNOTES |
Received Sept. 19, 1997; revised Nov. 26, 1997; accepted Dec. 4, 1997.
This work was supported by National Institutes of Health Grant
NS-36111. Part of this study was presented at the 26th Annual Meeting
of the Society for Neuroscience, Washington DC, 1996, abstract
65.6.
Correspondence should be addressed to Dr. Tamas L. Horvath, Yale
Medical School, Department of Obstetrics and Gynecology, 333 Cedar
Street, FMB 339, New Haven, CT 06520.
| |
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T. L. Horvath, S. Diano, and A. N. van den Pol
Synaptic Interaction between Hypocretin (Orexin) and Neuropeptide Y Cells in the Rodent and Primate Hypothalamus: A Novel Circuit Implicated in Metabolic and Endocrine Regulations
J. Neurosci.,
February 1, 1999;
19(3):
1072 - 1087.
[Abstract]
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G. Legradi and R. M. Lechan
The Arcuate Nucleus Is the Major Source for Neuropeptide Y-Innervation of Thyrotropin-Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus
Endocrinology,
July 1, 1998;
139(7):
3262 - 3270.
[Abstract]
[Full Text]
[PDF]
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Abstract
Introduction
