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Tupper Research Institute and Department of Medicine, Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, New England Medical Center (G.L., R.M.L.), and Department of Neuroscience, Tufts University School of Medicine (R.M.L.), Boston, Massachusetts 02111
Address all correspondence and requests for reprints to: Ronald M. Lechan, M.D., Ph.D., Professor of Medicine, Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, Box 268, New England Medical Center, 750 Washington Street, Boston, Massachusetts 02111.
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Introduction |
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At least two major sources have been established for NPY innervation of the PVN; a projection from adrenergic/noradrenergic cell groups in from the medulla oblongata where NPY extensively coexists with catecholamines (7), and a pathway from the hypothalamic arcuate nucleus (Arc) that does not contain catecholamines (11, 12). To determine the relative contribution of the Arc to the NPY innervation of hypophysiotropic TRH neurons, we investigated the distribution of NPY boutons in juxtaposition with TRH-perikarya and first order dendrites qualitatively and semiquantitatively following ablation of the Arc by neonatal monosodium glutamate (MSG) treatment (13, 14), and contrasted the results to a separate group of rats with unilateral lesions of the ascending medullary adrenergic pathway (15). These data have been reported in abstract form (16).
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Materials and Methods |
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Monosodium glutamate treatment.Timed pregnant Sprague-Dawley rats (Taconic Farms, Germantown, NY) were placed in individual plastic cages and, after delivery, male pups were selected for study. Pups received sc injections of 2 mg/g BW of MSG on postnatal days 2 and 4 followed by 4 mg/g BW on days 6, 8, and 10 (12) and were allowed to survive until the age of 2–3 months. Littermates that had been treated with with sc saline injections and normal rats of comparable age at the time of the experiments were used as controls (n = 6). To enhance the detectability of TRH in neuronal cell bodies, axonal transport was blocked in all animals by stereotaxically placed injections of colchicine (75 µg/15 µl) into the lateral cerebral ventricle (icv) under sodium pentobarbital (Nembutal) anesthesia. Following a survival period of 18 h, the animals were deeply anesthetized, and their brains were perfused via the ascending aorta with saline (30–50 ml; 30–60 sec) followed by a mixture of 3.75% acrolein and 2% paraformaldehyde in 0.1 M phosphate buffer (100–200 ml; 10–20 min) (17). After perfusion, the brains were removed, postfixed by immersion in 2% paraformaldehyde for 1–2 h, and stored in 0.01 M PBS, pH 7.4, until prepared for immunohistochemistry.
Lesioning of the ascending adrenergic bundle.Fifteen adult, male Sprague-Dawley rats (260–380 g BW) were used for this experiment. The animals were anesthetized, and a unilateral electrolytic lesion was placed into the medulla oblongata under stereotaxic guidance (-12.0 mm from Bregma anteroposterior; 1.1 mm lateral from midline; 8.1 mm ventral to the skull surface according to the atlas of Paxinos and Watson (18) by passing a DC current (2.5 mA for 2–3 sec) via a monopolar electrode (15). Following a 14- to 21-day survival period, the animals were administered colchicine icv and perfused for histology as described above.
Single labeling immunohistochemistry
For all animal treatment groups, blocks of the hypothalamus
beginning from the anterior part of the PVN to the caudal pole of the
arcuate nucleus were sectioned coronally at 30 µm thickness on a
Vibratome and collected into vials containing PBS. In animals with an
electrolytic lesion in the brain stem, 50-µm sections were also taken
from the medulla oblongata. Sections were treated sequentially with 1%
sodium borohydride in 0.05 M phosphate buffer for 30 min
and 0.5% hydrogen peroxide in PBS for 15 min. To improve antibody
penetration, sections for light microscopy were washed in PBS
containing 0.5% Triton X-100 for 1 h. Sections for electron
microscopy were rinsed in PBS only. After preincubation in 10% normal
horse serum for 1 h, the hypothalamic sections were placed in a
rabbit antiserum against NPY (gift of Prof. Julia Polak, Hammersmith
Hospital, London, UK) at 1:15,000–30,000 for light microscopy and at
1:15,000 for electron microscopy. Antiserum was diluted in PBS
containing 1% normal horse serum, 0.008% sodium azide and 0.1% Kodak
Photo-Flo (Eastman-Kodak, Rochester, NY) and incubated with the tissue
sections for 3 days at 4 C under continuous gentle agitation on a
rotary shaker. Sections of the brain stem lesion sites and PVN sections
from corresponding animals were incubated in a sheep anti-PNMT
antiserum (Chemicon, Temecula, CA) at 1:7,500–10,000. The sections
were then washed in PBS (3 x 30 min) and incubated in
biotinylated antirabbit or biotinylated antisheep IgG (1:200, Vector
Labs) for 3 h at room temperature. After washes in PBS (3 x
10 min), the sections were incubated in avidin-biotin-peroxidase
complex (ABC Elite, 1:100, Vector Labs, Burlingame, CA) for 1 h,
rinsed in 0.05 M Tris buffer, and immunolabeling was
visualized with a mixture of 0.025% diaminobenzidine (DAB) and
0.0036% hydrogen peroxide for 7 min.
Double-immunolabeling for NPY and TRH in the PVN
To visualize neuroanatomical associations of NPY-ir nerve
terminals and TRH-ir neurons in the PVN, a double-labeling
immunoperoxidase using distinct chromogens for the two peptides was
performed. First, NPY-fibers were detected with DAB in PVN sections
treated either for light or electron microscopy as described above.
This was followed by washes in 0.1 M phosphate buffer, then
incubation in the TRH antiserum (at 1:24,000) (19) for 1 day at 4 C,
which was developed using benzidine dihydrochloride (BDHC) (20). BDHC
yields a final product distinguishable from DAB both at light and
electron microscopic levels due to its green color by light microscopy
and its electron dense, crystalline appearance by electron microscopy.
Following sequential incubation in biotinylated antirabbit IgG followed
by the ABC reagents, the sections were washed in PBS (3 x 10 min)
then once in 0.05 M PB (pH 6.5). The sections were
preincubated for 1 min in 0.01% BDHC and 0.025% sodium nitroprusside
in 0.01 M PB. The reaction mixture was then replaced with a
fresh BDHC solution containing 0.0048% hydrogen peroxide in which the
sections were further treated for 45 sec. The development was
terminated by rinses in 0.05 M PB at pH 6.5. Sections for
light microscopy were mounted onto gelatin-coated slides and air-dried
overnight then rehydrated in 0.01 M PB (pH 6.5) and lightly
osmicated in vertical staining jars with 0.2% osmium tetroxide for 5
min. After rinsing in the same buffer, sections were rapidly dehydrated
in an ascending series of ethanol, cleared with three changes of
Histosol and coverslipped. Free-floating sections for electron
microscopy were treated with 1% osmium tetroxide in 0.05 M
PB at pH 6.5 for 30–45 min at room temperature, then dehydrated in an
ascending series of ethanol followed by propylene oxide. Sections were
infiltrated with epoxy resin (Durcupan ACM, Fluka, Ronkonkoma, NY) and
flat-embedded onto liquid release agent (Electron Microscopy Sciences,
Fort Washington, PA)-coated slides, and the resin was polymerized at 56
C for 2 days. Although sections prepared by the light microscopic
protocol contained higher numbers of labeled terminals and were
suitable for photography, semiquantitative analysis (see below) of
contacts between NPY-terminals and TRH neurons was conducted on
flat-embedded sections treated for electron microscopy because of the
improved preservation of individual fibers and depth-of-field.
Semiquantitative evaluation of contacts between NPY boutons and TRH
neurons at light microscopic level
The relative number of close contacts between NPY terminals and
TRH perikarya were determined by light microscopic examination in
resin-embedded, osmicated, double-immunolabeled sections of the PVN
taken at 150-µm intervals. Appositions of NPY-ir nerve terminals onto
TRH-ir neurons were counted by direct visual examination using a 100x
oil immersion lens in the medial parvocellular and periventricular
subdivisions of the PVN containing the main cluster of hypophysiotropic
TRH neurons (19) (1.8–2.1 mm caudal to Bregma) and in the
parvocellular dorsal cap of the PVN, a site of nonhypophysiotropic
parvocellular neurons based on the rat brain atlas of Paxinos and
Watson (18). Close appositions of NPY-terminals were counted on the
soma and first order dendrites of at least 100 medial parvocellular and
periventricular TRH neurons and 25 TRH neurons in the dorsal cap region
from three control and three MSG-treated rats. Values were averaged per
animal and compared statistically by ANOVA using StatView (Abacus
Concepts, Inc., Surrey, UK).
In the brain stem-lesioned rats, close contacts between NPY boutons and TRH neurons in the PVN were determined as described above, except that the values were compared between the lesioned and unlesioned sides in the same animals.
Electron microscopy
To analyze contacts between NPY-terminals and TRH neurons in the
PVN at the ultrastructural level, areas of interest were cut out from
the embedded material and glued onto empty resin blocks. Ultrathin
sections were prepared with an ultramicrotome (MT 6000, RMC, Inc.,
Tuscon, AZ) and examined with a Philips CM-10 transmission electron
microscope.
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Results |
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, A and B). In NPY-immunolabeled
sections from control animals, numerous NPY-ir perikarya were observed
throughout the rostrocaudal extent of the Arc and NPY-ir nerve fibers
with varicosities were also present in high concentrations (Fig. 1C).
MSG treatment resulted in loss of NPY-ir from nerve fibers and the
almost complete disappearance of NPY-labeled cell bodies from the Arc.
Only few, lightly immunolabeled NPY-perikarya remained in the atrophied
dorsal periventricular region of the Arc (Fig. 1D).
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). Beaded nerve fibers, preterminal
axonal varicosities, and terminal-like structures formed a particularly
dense network in the dorsal part of the medial parvocellular
subdivision. The magnocellular division exhibited a comparatively lower
density of fibers, although this NPY-innervation was still strikingly
more pronounced than that of the surrounding area making the entire PVN
stand out of the medial hypothalamus at low power of magnification
(Fig. 2A). At the caudal one-third of the PVN, the densest accumulation
of NPY fibers coincided with the cluster of hypophysiotropic TRH
neurons in the dorsal part of the medial parvocellular and
periventricular subdivisions (Fig. 3, A,
C, E). At higher magnification, numerous NPY-terminals appeared in
close contact with TRH-immunolabeled perikarya and dendrites (Fig. 3E).
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, compare with Fig. 2A). Nevertheless, remaining fibers
were still readily detectable in all compartments of the PVN.
Occasionally, faintly labeled NPY-ir cell bodies (1–2 cells per
section) appeared in MSG treated animals at the ventral or lateral
margin of the magnocellular division (data not shown).
Double-immunolabeling revealed that the density of NPY-ir terminals
surrounding TRH-positive perikarya in the caudal part of the medial
parvocellular subdivision was greatly reduced (Fig. 3, B, D, F). Some
residual NPY-ir nerve fibers in MSG-lesioned animals were still
observed in close apposition to non-TRH-immunoreactive parvocellular
peri-karya (Fig. 3, D and F).
At the electron microscopic level, TRH-labeled perikarya in the medial
parvocellular subdivision of the PVN of normal animals were commonly
surrounded by several NPY-terminals, often with synaptic contacts
(Fig. 4A). Large TRH-dendrites were also
frequently contacted by NPY-axon terminals (Fig. 4B). By contrast,
in MSG-lesioned rats, NPY boutons were either not found in close
contact with TRH neurons (Fig. 5A), or
only rare examples of single immunoreactive NPY-containing boutons were
seen in close association with TRH perikarya and proximal dendrites
(Fig. 5B). NPY contacts persisted, however, with unlabeled neuronal
(mostly dendritic) profiles in the PVN (Fig. 5B).
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). Numbers of NPY boutons in
contact with TRH neurons in the parvocellular dorsal cap of the PVN,
which do not have hypophysiotropic function (1, 2) were also reduced by
MSG treatment, but less severely, corresponding to a 32% reduction
compared with controls (Table 1).
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, A and B). Three rats
satisfying these criteria were selected for quantitative analysis of
the association between NPY-fibers and TRH neurons in the PVN.
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), medullary lesions caused only small changes in the distribution
and density of NPY-ir fibers in the medial parvocellular subdivision
and dorsal cap region of the PVN (Fig. 6C). Quantitative assessment of
close contacts between NPY-ir boutons and TRH-ir neurons of the PVN is
shown in Table 1. No significant reduction in NPY contacts on TRH
neurons was observed in the medial parvocellular and periventricular
subdivisions of the PVN ipsilateral to the lesion compared with the
unlesioned side. In contrast, a statistically significant reduction of
14.7% in the number of NPY-terminals contacting TRH neurons was
recorded for the parvocellular dorsal cap. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine the specific contribution of NPY neurons in the Arc to the innervation of hypophysiotropic TRH neurons, we performed double-immunolabeling studies of the PVN at the light and electron microscopic levels following chemical ablation of the Arc with monosodium glutamate. In keeping with the observations by Kerkerian and Pelletier (12), obliteration of nearly all NPY neurons in the arcuate nucleus by neonatal administration of monosodium glutamate resulted in a partial depletion of NPY-containing fibers in the PVN. The NPY innervation to TRH neurons in the medial parvocellular subdivision of the PVN, however, was substantially depleted, estimated at 82% of normal control animals. NPY-containing boutons were lost on both TRH perikarya and first order dendrites, indicating that the arcuate nucleus represents the predominant source for the NPY-ergic innervation of hypophysiotropic TRH neurons. In contrast, no significant depletion of NPY-contacts on hypophysiotropic neurons was observed following medullary lesions that dramatically decreased the adrenergic innervation to the PVN. This suggests that the adrenergic innervation of hypophysiotropic TRH perikarya and their proximal dendrites cocontains little if any NPY. Residual NPY boutons in contact with TRH perikarya in the medial parvocellular PVN, therefore, may arise from the small number of remaining NPY neurons in the lesioned arcuate nucleus or other loci in the CNS. One region of potential interest is the hypothalamic dorsomedial nucleus as this nucleus heavily projects to the parvocellular PVN (24) and has been recently shown in the genetically obese agouti mouse to contain a substantial population of NPY messenger RNA (mRNA) containing neurons (25). Another minor projection from NPY-containing neurons of the intergeniculate leaflet may also exist (26), which might reach the periventricular area of the PVN via the geniculo-hypothalamic tract (27).
Nevertheless, ablation of the medullary catecholamine pathway to the
PVN did result in a 14.7% reduction in the number of NPY boutons
contacting TRH neurons in the parvocellular dorsal cap region, a
subdivision of the PVN that is not believed to have a hypophysiotropic
role (1, 2). Rather, this region may be involved with regulation of the
autonomic nervous system by way of descending projections to the lower
brain stem (28). In addition, ablation of NPY neurons in the Arc only
partially depleted the PVN of NPY-containing fibers and
ultrastructurally, synaptic contacts of remaining NPY-containing
boutons were seen in contact with perikarya and dendrites not labeled
with the TRH antiserum. The possibility that NPY afferents to the PVN
derive from multiple sources in the brain to target specific cell
populations, therefore, seems likely and may provide a way that a
single peptide can exert diverse actions in a discrete region of the
brain. Even within the Arc itself, NPY neurons may be functionally
heterogeneous as there is now anatomical evidence for a population of
NPY neurons that also contains the inhibitory neurotransmitter
-aminobutyric acid (GABA) in the dorsomedial part of the Arc,
whereas a subset of non-GABAergic NPY cells exists in the ventral Arc
(29).
The functional significance of the target-specific innervation of TRH neurons by NPY-fibers from the arcuate nucleus may be seen in the potential role of Arc-derived NPY to reset the hypothalamic-pituitary-thyroid axis under certain physiological conditions (3, 4, 5, 6). Starvation, for example, results in substantial reductions in circulating thyroid hormone levels but is accompanied by a paradoxic reduction in proTRH mRNA in hypophysiotropic neurons in the PVN and inappropriately normal or low circulating TSH levels (3, 4). These changes occur simultaneously with a marked increase in NPY gene expression in the arcuate nucleus and concomitant increase in NPY release in the PVN (30, 31, 32). The up-regulation of NPY in the arcuato-paraventricular neural pathway has been implicated in the potent central stimulatory action of NPY on food intake (32, 33). Moreover, rats with streptozotocin-induced diabetes show similar alterations in the hypothalamic-pituitary-thyroid axis as starved rats (34, 35) and also have an increased NPY content in the Arc and the PVN (36, 37). Conversely, recent studies from our laboratory have demonstrated that the administration of leptin, a fat cell-derived hormone with anorectic activity that reduces the biosynthesis of NPY in the Arc (38), prevents the fall in circulating thyroid hormone levels and the reduction of proTRH mRNA in the PVN (6). Because NPY may be inhibitory to the thyroid axis (39), circumstantial evidence is provided to suggest that NPY derived from the arcuate nucleus may modulate the setpoint for feedback regulation on hypophysiotropic TRH neurons in the PVN during starvation by lowering the threshold of these neurons to feedback inhibition by circulating levels of thyroid hormone. Mice with deletion of the NPY gene, however, still have a fall in T4 levels during fasting (40), suggesting that other mechanisms in addition to NPY may also be operable or that alternative neuronal pathways were induced during development of the CNS that may not be normally present.
In summary, the present study demonstrates that the majority of NPY fibers innervating hypophysiotropic TRH neurons originate from the arcuate nucleus. This finding provides a neuroanatomical basis to hypothesize that the NPYergic arcuato-paraventricular pathway may contribute to the resetting of the hypothalamic-pituitary-thyroid axis during fasting.
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Footnotes |
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Received February 2, 1998.
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