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Section on Behavioral Pharmacology (C.V., N.L.O.), Biological Psychiatry Branch and Laboratory of Cellular and Molecular Regulation (S.J.L.), National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-4090
Address all correspondence and requests for reprints to: Nancy L. Ostrowski, Ph.D., Eli Lilly and Co., Lilly Corporate Center, Building 22, Drop Code 2244, Indianapolis, Indiana 46285.
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Introduction |
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A second subtype of the V1 class, the V1b receptor (V1bR), has been characterized in the anterior pituitary, where it regulates AVP-mediated ACTH release by potentiating the effects of CRH (11, 12). Recent studies have detected V1bR mRNA through RT-PCR in the thymus, heart, lung, spleen, kidney, uterus, and breast (13, 14). Furthermore, Lolait et al. (13) detected V1bR mRNA in several hypothalamic and extra-hypothalamic brain regions. The cellular distribution has not been characterized to date.
Receptors for oxytocin are highly homologous to vasopressin receptors, bind both oxytocin and AVP with high affinities, and have been localized throughout brain including regions where we have detected V1bR mRNA (8). The OTR mRNA distribution has been characterized in rat brain using only the human OTR gene-derived ribonucleic acid probes (riboprobes) (15). In this paper, we describe the distribution of rat V1bR-derived mRNA in male Sprague-Dawley rat brains using in situ hybridization histochemistry and compare it to the distribution of rat OTR gene expressing cells.
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Materials and Methods |
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All work was done in accordance with National Institutes of Health guidelines for animal use and care and following approvals of protocols by the National Institute of Mental Health Animal Care and Use Committee.
Probes
The region of the AVP and OT receptor genes
demonstrating the least homology, (i.e. a sequence
corresponding to the third intracellular loop of the receptors) was
included in each of the riboprobes used. The V1bR probe was a 618-bp
Asp718/blunt end sequence (extending from the second intracellular loop
to the seventh transmembrane region of the rat cDNA) subcloned into
pGEM3Z (13). The OTR cDNA was a 633-bp PCR fragment (spanning the
second to sixth transmembrane regions) subcloned into
pGEM4Z (16). Sense and antisense probes for both V1bR and OTR
constructs were synthesized using 35S radiolabeled-UTP. One
additional V1bR probe and two additional OTR probes were prescreened in
liver, brain, kidney, uterus, and spleen. All probes yielded similar
distributions of their respective mRNAs. The probes used in these
experiments demonstrated the greatest signal to noise ratios indexed by
the density of selective tissue labeling relative to
background [(Antisense-background)–(sense-background)]. In addition
to "sense" control experiments, V1b, V1a, V2, and OTR transcript
labeling was measured in liver, kidney and pituitary.
In situ hybridization histochemistry
Whole brains were cryosectioned (24 µm-thick), thaw-mounted
(three per slide) onto glass microscope slides subbed with
gelatin-chrome-alum, and frozen at -70 C until used. Slide-mounted
sections were rapidly thawed to room temperature, immersed in 4%
formaldehyde solution, treated with acetic anhydride, rinsed,
dehydrated, and delipidated in a series of graded ethanol solutions
followed by immersion in chloroform. Slide-mounted tissue was covered
with 35S-labeled probe (1.25 million cpm per slide),
coverslipped, and incubated for 22 h at 55 C. Posthybridization
washes consisted of a series of 4x, 2x, 1x, and 0.5x saline-sodium
citrate buffer (SSC) washes, incubation in a 20 µg/ml RNase solution
at 37 C, followed by a series of 0.1x SSC washes containing
dithiothreitol at 65 and 67.5 C. Tissue was dehydrated in a series of
graded alcohol solutions containing 300 mM ammonium
acetate, then dried, apposed to autoradiographic film (Kodak B-Max;
Eastman Kodak, Rochester, NY), and exposed for 14
days.
To visualize the hybridization signal at the cellular level, slides were dipped in nuclear emulsion (Kodak NTB-2; Eastman Kodak) and exposed at 4 C for 3 (V1bR) or 4 (OTR) months. Slides were developed (Kodak D19; Eastman Kodak) and stained with thionin, and in some cases, counterstained with eosin and coverslipped. Slides were examined with a light microscope, under bright and dark field illumination. Distributions of cells expressing the respective mRNAs were plotted onto templates modified from the rat brain atlas of Paxinos and Watson (17) using Adobe Photoshop and templates similar to those used for V1aR mRNA (6).
Data analysis
Hybridization signal was quantified using the NIH Image program.
Optical densities (corrected for background signal) were obtained for
the left and right hemispheres for each region analyzed. To assess the
amount of hybridization signal in emulsion-dipped slides, individual
grains were counted. Cells covered by at least two times as many grains
as background were designated as expressing the given receptor
mRNA.
Hybridization experiments for OTR and V1bR mRNAs were conducted separately, permitting qualitative, but not quantitative comparisons.
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V1bR sense labeling was undetectable except in the dentate gyrus of the hippocampus where low levels of signal were detected similar to those observed using the antisense probe. Microscopic evaluation failed to localize dentate antisense or sense labeling to cell bodies; antisense levels did not reach criteria for specific labeling. OTR sense labeling was typically near film background levels. Film autoradiographs showed above-background levels of sense labeling in the dentate gyrus and the cerebellum. In the dentate, antisense accumulation over cell soma indicated specific labeling.
Table 1
presents brain regions that
express V1bR mRNA. Regions are rank-ordered according to film optical
density measurements for the V1bR hybridization signal. The
coexpression of OTR mRNA was determined by microscopic analyses. The
dorsomedial hypothalamic nucleus and the external plexiform layer of
the olfactory bulb express only V1bR mRNA. However, most other regions
that express V1bR transcripts also express the OTR gene.
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presents a schematic diagram of
the localizations of the V1bR and OTR transcripts in emulsion-dipped
tissues. Qualitative differences were observed in the hybridization
signals of V1bR and OTR mRNAs. Specifically, in regions where V1bR mRNA
was detected, signal intensity was usually homogeneous from cell to
cell, with a preponderance of grains localized to the nucleus and soma
of the cells. Signal intensity varied slightly from cell to cell, and
film densities typically reflect the number of cells in a given region
expressing the gene. In contrast, the OTR hybridization signal
intensity varied from region to region and from cell to cell within
specific regions. The signal was not only localized to nuclei and soma
but also to the cytoplasm of the cell.
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Olfactory bulb
V1bR mRNA was found in periodically spaced cells in the mitral
cell layer (Fig. 2, A and C) of the
olfactory bulb with densest label in the ventrolateral bulb. The
external plexiform layer weakly labeled. In contrast, OTR mRNA was
distributed throughout the granule cell layer, with a denser expression
in the mitral cell layer. The OTR gene was expressed in some
periglomerular cells (See Fig. 2, B and D).
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The anterior olfactory nucleus (Fig. 3),
tenia tecta, and piriform cortex expressed high levels of OTR mRNA.
V1bR transcripts were not visualized in the anterior olfactory nucleus.
The distribution of OTR mRNA was similar to that of V1bR mRNA in the
piriform cortex (see Fig. 4) but, whereas
OTR transcripts were abundant in the olfactory tubercle, V1bR mRNA was
not detected.
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The lateral septal nucleus, ventral pallidum, globus pallidus, and accumbens nucleus expressed very low densities of the OTR gene. In the caudate putamen, only the dorsomedial portion expressed low levels of the OTR gene.
Hypothalamus and diencephalon
V1bR mRNA was in numerous cells of the suprachiasmatic and
supraoptic nuclei (SON) of the hypothalamus (Fig. 5, A and C). There was light labeling of
cells in the periventricular nucleus. Grain counts were slightly
elevated above background but did not reach criterion for labeling in
the paraventricular nucleus of the hypothalamus (Fig. 6, A and C). V1bR transcripts were
evident in cells of the medial preoptic area, lateral hypothalamus,
anterior amgydala, and the region lateral to the SON.
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At approximately 4.3 mm caudal to Bregma, labeled cells of the piriform cortex and cells in the perirhinal cortex appeared contiguous. The posteromedial cortical amygdala nucleus (PMCo) expressed moderate amounts of V1bR mRNA, and the posterolateral cortical amygdala nucleus (PLCo) expressed low levels.
In thalamus, only a few cells in the anterior paraventricular nucleus expressed hybridization signal.
Similar to the distribution of V1bR mRNA, OTR transcripts were also
abundant in the suprachiasmatic and supraoptic nuclei (See Fig. 5
, B
and D). OTR, but not V1bR mRNA, was expressed in the paraventricular
nucleus (Fig. 6).
OTR transcripts were densest in the ventromedial nucleus (VMN) of the
hypothalamus (Fig. 7), with the
ventrolateral division expressing higher levels of transcript than the
dorsomedial division. Notably, the entire VMN, ranging from the most
anterior to the caudal poles, expressed OTR signal.
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Thalamic OTR transcript labeling was sparse with detectable signal
primarily in the anterior paraventricular nucleus of the thalamus (see
Fig. 1).
Hippocampus
V1bR mRNA was most abundant in CA2. It was uniformly expressed in
CA1 (Fig. 8, A, C, and E) whereas signal
intensity in CA3 became progressively greater more caudally. The
dentate gyrus showed low levels of V1bR gene product that could not be
localized to cell bodies and did not reach criteria for specific
labeling.
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, B, D, and F).
Midbrain
Low levels of V1bR mRNA were in cells in the ventral tegmental
area (VTA) and the substantia nigra, pars compacta (SNC),
whereas only occasional cells expressed transcript in the pars
reticulata (Fig. 9). The magnocellular
aspect of the red nucleus (Fig. 10) and
outer layers of the entorhinal cortex moderately labeled. Labeling in
the entorhinal cortex became stronger progressing caudally and extended
into the deeper layers of cortex. Strong labeling of V1bR mRNA was
evident in the dorsal raphe nucleus, with lighter labeling in the
amgydala-piriform transition area.
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), VTA and the central gray.
Hindbrain
Both V1bR and OTR transcripts were less abundant in hindbrain than
more anterior brain regions. Pontine nuclei exhibited moderate V1bR
expression, whereas light to intermediate levels of V1bR signal were
detected in the locus coeruleus, facial nucleus, dorsal motor nucleus
of the vagus (DMV), gigantocellular reticular nucleus, lateral
reticular nucleus (LRt), and trigeminal nucleus (oral and interpolar
portions). Labeled cells in the regions of the DMV appeared contiguous
with a few labeled cells in the nucleus of the solitary tract (NTS) and
hypoglossal nucleus in emulsion-dipped slides.
Hindbrain OTR transcripts were highest in the dorsal motor nucleus of the vagus (DMV) and Nucleus O. The locus ceruleus, and trigeminal and lateral reticular nuclei expressed intermediate levels of transcript, whereas the pontine, gigantocellular reticular, medial vestibular, hypoglossal nuclei, and the lateral aspect of the inferior olive nucleus expressed low hybridization signal.
OTR mRNA was also detected at low levels in blood vessels on the ventral surface of the brain, in the pineal, in intermittent large cells (may be Purkinje cells) at the border of the granule cell layer and in the molecular cell layer of the cerebellum, and cells in the lining of the ventricular walls.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Localization of V1bR mRNA
Cells that express V1bR transcripts are present in anatomically
discrete brain regions (e.g. suprachiasmatic nucleus, the
red nucleus, the substantia nigra pars compacta, and the
supraoptic nucleus) and have the morphology of neurons. V1bR
transcripts are less abundant and more restricted in their distribution
than the OTR and the V1aR transcripts. Although the OTR gene is
expressed by numerous cells and in regions that express V1bR mRNA, the
overall distribution pattern supports distinct receptor gene products.
Specifically, the anterior olfactory nucleus and the ventromedial
nucleus of the hypothalamus, regions that expressed the highest levels
of OTR transcripts did not express V1bR mRNA, excluding the possibility
that the V1bR probe cross-hybridized with OTR mRNA. Furthermore, the
brain distribution of V1bR transcripts also differed from that of V1aR
mRNA making it improbable that the V1bR riboprobe cross-hybridized with
V1aR mRNA. Again, V1bR transcripts were undetectable in the lateral
septum and the anterior olfactory nucleus, two regions that express
high levels of V1aR transcripts (6). In contrast to a previous study,
(23), we have not detected specific labeling of V2R mRNA in adult rat
brain (6, Ostrowski, unpublished).
Following the cloning of the V1bR from pituitary cDNA libraries, the receptor mRNA was detected by RT-PCR in the rat thymus, heart, lung, spleen, kidney, uterus, and breast (13, 14). Lolait et al. (13) have published RT-PCR data providing evidence for extrapituitary expression of V1bR mRNA in the olfactory bulb, caudate putamen, septum, cortex, hypothalamus, hippocampus, and cerebellum in the rat. Here, we visualized V1bR transcripts in cells in regions shown by RT-PCR to express V1bR mRNA with the exception of the caudate putamen, cerebellum and septum where we failed to detect transcript. While the reason for this discrepancy remains unclear, it is possible that the number of copies of transcripts were too low to be visually detected using emulsion autoradiography or that the RT-PCR samples included adjacent V1bR-expressing tissues. Confirmation of expression of the V1bR protein throughout brain will require the development of selective or specific V1bR radioligands and/or V1bR-specific antibodies.
Permutations in the patterns of coexpression of V1aR, V1bR, and OTR genes in specific brain regions suggest that these three gene products may be independently regulated. Moreover, their expression in structures including the hippocampus, arcuate and suprachiasmatic nuclei, may suggest alternative interpretations of some radioreceptor binding data and pharmacological effects observed after local application of AVP and other selective agonists and antagonists directly to brain (24, 25).
An interesting observation (See Table 1) was that most brain regions
that expressed V1bR signal also expressed OTR transcripts. This is
intriguing considering that V1bR mRNA was extremely restricted in its
distribution, in that the majority of discrete brain regions do not
express the V1bR gene. The coexpression of OTR in virtually all
V1bR-labeled regions suggests that there may be a physiological basis
for their coexistence.
V1bR mRNA and AVP-immunoreactive pathways
AVP immunoreactive cells or processes have been reported in most
regions where we detect V1bR mRNA. AVP and OT secreting cells originate
primarily in the SON and PVN and project to the neural lobe of the
pituitary where the hormones are released directly into the
bloodstream. Central AVP projections originate from AVP-synthesizing
parvocellular neurons in the hypothalamic PVN, a few magnocellular
neurons in the SON, the bed nucleus of the stria terminalis (BNST), the
dorsomedial hypothalamus (DMH), medial amgydala, suprachiasmatic
nucleus (SCN), and locus coeruleus (26).
V1bR mRNA was not visualized in magnocellular or parvocellular neurons in the PVN. The V1bR, therefore, is an unlikely candidate for directly regulating AVP or OT release from PVN neurons. In contrast, both OTR and V1aR (6) mRNAs were found in the PVN; the OTR mRNA was detected throughout the PVN, whereas V1aR transcripts were localized primarily in the parvocellular region. This distribution is consistent with a role for OTR in the regulation of AVP release from the PVN.
OT-containing cells in the SON project to the posterior pituitary and are well established to play a role in milk ejection during lactation (27, 28). The SON expressed both V1bR and OTR transcripts (but not V1aR, 6). Afferents include noradrenergic projections from the ventrolateral medulla (29) and smaller projections from the median preoptic nucleus, BNST and dorsomedial hypothalamic nucleus (30), the latter two of which contain AVP-synthesizing neurons. The expression of V1bR and OTR transcripts in the SON raises the possibility that the V1bR and/or the OTR may be involved in regulating OT or AVP release.
The differential localization of OTR mRNA with V1bR transcripts in the SON and with V1aR gene products in the PVN raises interesting possibilities regarding regulation and cross-talk in AVP- and OT-containing brain systems. Experimental data narrowing the possible interactions (e.g. V1b autoreceptor function; mediation of selective effects on AVP or OT transcription or release; regulation of OTR gene expression, etc.) await more precise colocalization data and physiological experiments using highly selective receptor subtype agonists and antagonists. Clearly, the selective localization of V1aR and V1bR transcripts in the PVN and SON, respectively, could function to provide a high degree of specificity in the cellular responses to brain AVP in these magnocellular nuclei.
V1bR, OTR (shown here), and V1aR (6) transcripts were expressed by cells in the SCN, where AVP-producing neurons have also been described (31, 32). The SCN plays a role in circadian rhythmicity in hormone secretions (33), body temperature (34); and sleep and waking cycles (35). AVP exhibits a rhythmic pattern of secretion, with highest levels during light periods and lowest levels during dark periods (36). The V1aR mRNA in the SCN also exhibits a circadian rhythm but it is 12 h out of phase with AVP secretion and is independent of AVP levels (37).
AVP is synthesized in the locus coeruleus and the DMH (26), two regions that also express V1bR transcripts. The BNST, while a source of AVP, does not express V1bR mRNA. Other areas where AVP immunoreactive processes and V1bR mRNA have been found include the olfactory bulb, arcuate nucleus of the hypothalamus, ventral tegmental area, hippocampus, and substantia nigra pars compacta.
Overlap of V1bR with other AVP/OT receptors
The V1a receptor has been thought to mediate most of the effects
of AVP in brain (8, 9, 38, 39, 40, 41). The finding that a number of brain
regions express V1aR, V1bR and OTR mRNAs suggests that some of AVP’s
effects on memory and learning (42), antipyresis (43), selective
aggression and partner preference (44, 45), cardiovascular responsivity
(46), blood flow to the choroid plexus and cerebrospinal fluid
production (47), smooth muscle tone in superficial brain vasculature
(48), and analgesia (49) may involve multiple receptor subtypes. All
three subtypes are expressed in the hippocampus (Fields of Ammon’s
horn), arcuate nucleus, locus coeruleus, substantia nigra pars
compacta, ventral tegmental area, suprachiasmatic nucleus, dorsal motor
nucleus of the vagus, and piriform cortex. Other regions, such as the
olfactory bulb and the hypothalamus express all three transcripts but
in markedly different patterns suggesting discrete functions for each
receptor subtype. The possibility that single cells coexpress all three
receptor genes remains to be determined. Some brain regions such as the
suprachiasmatic nucleus, piriform cortex (V1a, V1b, OTR), and the
supraoptic nucleus (V1b, OTR) appear to be likely candidates for
coexpression based on the large numbers of cells that label with each
respective hybridization probe.
Role for V1bR in brain
To date, the only function attributed to the V1bR has been the
potentiation of CRH induction of ACTH release in the pituitary (11, 12), and it is possible that V1bR may interact with CRH receptors at
other sites in brain. Several regions that are involved in processing
olfactory signals express both CRH receptors (50) and V1bR mRNA such as
the olfactory bulb (external plexiform layer), amygdala (PLCo, PMCo,
APir, AA), medial preoptic area, cortex (somatosensory, striate,
entorhinal, piriform), and pons. A role for V1bR in autonomic
regulation is suggested by its presence in hindbrain regions, some of
which are involved in cardiovascular function. V1bR transcripts were
detected in the facial nucleus, lateral reticular nucleus, the dorsal
motor nucleus of the vagus (DMV), the nucleus of the solitary tract
(NTS) and the trigeminal nucleus, areas important in AVP’s and CRH’s
autonomic effects, including those on heart rate, mean arterial blood
pressure, and plasma concentrations of epinephrine, norepinephrine,
glucose, and glucagon (46, 51). V1bR transcripts were in cells of the
locus coeruleus (LC) where AVP and norepinephrine may be colocalized
(52) and where vasopressinergic neurons may be involved in adaptation
to repeated stress (53). V1bR mRNA was also detected at low levels in
the dopamine-synthesizing regions of the substantia nigra par compacta
and ventral tegmental area. The coexpression of V1bR and OTR in many
brain regions suggests that the V1bR may play an interactive role with
OT receptive brain systems, possibly up- or down-regulating them in
conjunction with AVP release in specific pathways.
Distribution of OTR mRNA in CNS
We detected OTR transcripts in virtually all brain regions where
Yoshimura et al. (15) reported hybridization signal using
the human OTR-derived riboprobe (54). In contrast to their study, we
also visualized OTR transcripts in the suprachiasmatic nucleus and
portions of the inferior olivary nucleus. Whereas they described OTR
transcripts dorsal to the substantia nigra pars compacta, we visualized
signal throughout the medial pars compacta and ventral tegmental area.
Finally, we found OTR transcripts throughout the PVN whereas Yoshimura
and collaborators detected signal only over magnocells in the
dorso-medial portion. The subtle nature of the differences between our
results and those of Yoshimura et al. (15) suggest that they
may be attributable to the plane of section of tissue, gender or strain
differences. Overall, the degree of correspondence, rather than the
divergence, is noteworthy.
In summary, in situ hybridization data indicate that the V1bR mRNA is expressed in a restricted number of morphologically discrete brain regions. Regions expressing the highest levels of V1bR transcripts also expressed OTR mRNA although the pattern of OTR gene expression was far more extensive than that of V1bR. Both transcripts, however, were more abundant in forebrain and hypothalamus than mid- and hindbrain. The differential distributions of the genes encoding the vasopressin V1a, V1b, and OT receptors confirm that these receptor subtypes are distinct gene products and suggest that permutations in their regional coexpression is may influence brain region-specific regulation and functions. It remains to be determined whether V1aR, V1bR, and OTR transcripts colocalize in individual cells. The respective roles for these receptor subtypes in influencing cellular activity and their potential for receptor subtype interactions at the physiological level require further investigation.2
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Acknowledgments |
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Footnotes |
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2 The sequences of the V1b and OT receptor genes
can be obtained from S.J.L. upon request.
Received July 30, 1998.
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 J. P. H. Burbach, S. M. Luckman, D. Murphy, and H. Gainer Gene Regulation in the Magnocellular Hypothalamo-Neurohypophysial System Physiol Rev, July |
part; Pe, periventricular nucleus of the
hypothalamus; PF, parafascicular thalamic nucleus; PFI, paraflocculus;
PH, posterior hypothalamic area; Pi, pineal gland; Pir, piriform
cortex; PLCo, posterolateral cortical amygdala nucleus; PMCo,
posteromedial cortical amygdala nucleus; PMD, premammillary nucleus,
dorsal part; Pn, pontine nucleus; PnC, pontine reticular nucleus,
caudal part; PnO, pontine reticular nucleus, oral part; PoDG, polymorph
layer of the dentate gyrus; PPT, posterior pretectal nucleus; Pr5VL,
principal trigeminal sensory nucleus, ventrolateral part; Prb, nucleus
of Probst’s bundle; PRh, perirhinal cortex; PrH, prepositus
hypoglossal nucleus; PrS, presubiculum; PVA, paraventricular nucleus of
the thalamus, anterior part; py, pyrimidal tract; RCh, retrochiasmatic
area; RMC, red nucleus, magnocellular part; RMg, raphe magnus nucleus;
ROb, raphe obscurus nucleus; RPC, red nucleus, parvocellular part; RPO,
rostral periolivary region; RR, retrorubral nucleus; RRF, retrorubral
field; RSA, retrosplenial agranular cortex; Rt, reticular thalamic
nucleus; RtTg, reticulo-tegmental nucleus of the pons; S, subiculum;
s5, sensory root of the trigeminal nerve; scc, splenium of the corpus
callosum; SCh, suprachiasmatic nucleus; scp, superior cerebellar
peduncle, brachium conjunctivum; SFO, subfornical organ; SI, substantia
inominata; Sim, simple lobule; sm, stria medullaris of the thalamus;
SNR, substantia nigra, reticular part; SNC, substantia nigra, compact
part; SO, supraoptic nucleus; Sol, nucleus of the solitary tract; sol,
solitary tract; SOR, supraoptic nucleus, retrochiasmatic; SPTg,
subpeduncular tegmental nucleus; SPO, superior periolivary nucleus;
sp5, spinal trigeminal nucleus; Sp51, spinal trigeminal nucleus, caudal
part; Sp5O, spinal trigeminal nucleus, oral part; st, stria terminalis;
Stg, stigmoid hypothalamic nucleus; STh, subthalamic nucleus; SuM,
supramammillary nucleus; Te, temporal cortex; tfp, transverse fibers of
the pons; TM, tuberomammillary nucleus; ts, tectospinal tract; Tu,
olfactory tubercle; tz, trapezoid body; VCA, ventral cochlear nucleus,
anterior part; VEn, ventral endopiriform nucleus; VL, ventrolateral
thalamic nucleus; VLO, ventrolateral orbital cortex; VMH, ventromedial
nucleus of the hypothalamus; VP, ventral pallidum; VPM, ventral
posteromedial thalamic nucleus; VTA, ventral tegmental nucleus (Tsai);
VTg, ventral tegmental nucleus (Gudden); ZI, zona incerta.
