Postnatal development of the vasopressinergic system in golden hamsters

DEVELOPMENTAL BRAIN RESEARCH

ELSEVIER

Developmental Brain Research 81 (1994) 230-239

Research Report

Postnatal development of the vasopressinergic system in golden hamsters Yvon Delville *, Karim M. Mansour, Eric W. Quan, Brooke M. Yules, Craig F. Ferris Behavioral Neuroscience Laboratory, Psychiatry Department, University of Massachusetts Medical Centel; 55 Lake Avenue North, Worcester, MA 01655, USA Accepted 19 April 1994

Abstract Adult golden hamsters, as compared to rats, lack several parvicellular vasopressinergic cell groups. We looked at the development of the vasopressinergic system in hamsters to draw comparisons with maturing rats. Arginine-vasopressin-immunoreactive (AVP-ir) neurons, their fibers and associated AVP binding sites were observed at several intervals after birth. Different rates of maturation were observed between different populations of vasopressinergic neurons. Within the suprachiasmatic nucleus (SeN), small AVP-ir neurons, their fibers and related binding sites maturated gradually during the first month after birth. In comparison, large AVP-ir neurons were apparent in newborn animals. Similarly, A VP-ir fibers and AVP binding sites were also present in the brain of newborns within areas not related to small vasopressinergic neurons from the SeN, such as the central amygdala (eeA) or the cerebral cortex. During the following weeks, a heterogenous pattern of development was observed within such areas. As the neurosecretory vasopressinergic system appeared to develop gradually, projections to the brain and their associated binding sites developed rapidly during the first week of life. Transient patterns of maturation were observed within certain sites. Indeed, some of the labelling observed in newborns regressed later. As similar reports were made in rats, our observations draw analogies between the vasopressinergic systems of these two species, beside their apparent dissimilarities in adult animals. Furthermore, our data also reinforce the concept that large vasopressinergic neurons do not constitute a homogenous population.

Key words: Magnocellular; Parvicellular; Arginine-vasopressin immunoreactivity; Autoradiography; Arginine-vasopressin projection; Suprachiasmatic nucleus

1. Introduction

In rats, the vasopressinergic system is composed of two populations of neurons: magnocellular and parvicellular neurons. Magnocellular vasopressinergic neurons are localized in the paraventricular hypothalamic nucleus (PVN), supraoptic nucleus (SON), accessory nuclei and the medial edge of the postero-medial division of the bed nucleus of the stria terminalis (BST) [2,5,20,28,30]. Parvicellular vasopressinergic neurons are localized in the PVN, the suprachiasmatic nucleus (SeN), the centro-lateral part of the medial division of the BST and the posteromedial amygdala [2,7,20,26,30]. Beside their size and location, magnocellular and par-

* Corresponding author. Fax: (1) (508) 856-6426. 0165-3806/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSDl 0165-3806(94)00073-9

vicellular neurons project to separate target sites. While magnocellular neurons project exclusively to the neurohypophysis' [2,28,29], parvicellular neurons project to the median eminence and many neural sites [5,26,30]. In particular, parvicellular neurons in the BST and amygdala project to the lateral septum [12,14]. This innervation is testosterone-dependent and more extensive in males [13,15,36]. Furthermore, the maturation of magnocellular neurons differs from parvicellular neurons. While magnocellular neurons produce arginine-vasopressin (AVP) at birth [3,6,37], parvicellular neurons start expressing vasopressin only a few days after birth [14,32]. In parallel with neuronal development, the vasopressinergic innervation of the lateral septum and other areas innervated by parvicellular neurons start becomes apparent around postnatal day 10-14 [14]. As vasopressinergic neurons mature, so do their target sites. Neural arginine-vasopressin (AVP)

Y. Delville et al./ Developmental Brain Research 81 (1994) 230-239

binding sites also develop during the second week of life, although certain sites contain more receptors during early periods of development [24,33,35]. However, the vasopressinergic system of rats differs from other species. In golden hamsters, small (parvicellular) vasopressinergic neurons are absent from the centro-lateral part of the medial division of the BST and the posteromedial amygdala and rather scarce within the PVN [16,19,20,23]. Consequently, vasopressinergic fibers are nearly absent from the lateral septum and other sites innervated by parvicellular neurons in the BST or the amygdala [11]. Furthermore, large (magnocellular) vasopressinergic neurons do not constitute a homogenous population, as a substantial population of these neurons does not project to the neurohypophysis [19,23]. Because of these differences, we previously classified vasopressinergic neurons in golden hamsters as small (diameter: ca. 10 p,m) or large (diameter: ca. 20 p, m) [20], Although the vasopressinergic systems of these two species differ so much in adult animals, a description of the maturation process of the vasopressinergic system of golden hamsters could reveal common aspects with rats. As magnocellular vasopressinergic neurons develop faster than parvicellular neurons [6,14], it may also be possible to observe vasopressinergic fibers in hamster pups before the maturation of small neurons. Such an observation would support the hypothesis that large vasopressinergic neurons innervate various areas of the brain in hamsters. In the following experiments, vasopressinergic neurons and fibers were observed at several periods of development in golden hamsters. The neural distribution of A VP binding sites was also observed in parallel with AVP-immunoreactivity (AVP-IR).

2. Materials and methods 2.1. Animals and treatment

Golden hamsters were bred in the laboratory and kept on a reverse light/dark cycle (14 h lightjlO h dark, lights on at 19.00 h). The mothers and the pups received food and water ad libitum.

2.2. Immunocytochemistry Immunocytochemistry for AVP was obtained in male and female pups (1, 7, 18 and 28 days old) as previously described [lOJ. In short, the animals were decapitated and the heads were immersed in 10% acrolein (Aldrich Chemical Company, Milwaukee, WI, USA) in 0.1 M potassium phosphate buffer (KPBS, pH 7.2) for 6 h. Then, the brains were transferred in 20% sucrose in KPBS. The next day, the heads were sliced at 40 p.m and the sections were kept in 0.05 M Tris buffered saline (TBS, pH 7.6). Later, the sections were labelled for AVP-IR through the following procedure. First, the sections were pretreated with 1% sodium borohydrite (to eliminate residual aldehyde), followed with 20% normal goat serum, 1% H 2 0 2 , 0.3%

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Triton X-IOO (to reduce non-specific labelling, eliminate endogenous peroxidase and permeabilize the sections, respectively). Later, the sections were incubated in the primary antiserum (Rabbit antiarginine vasopressin, 1/16,000, ICN ImmunoBiologicals, Lisle, IL 60532, USA), containing 2% normal goat serum and 0.3% Triton X-lOO for 1 h at 37°C. After washing in TBS, the sections were successively incubated in the secondary and tertiary antisera (Vectastain ABC Elite kit, Vector, Burlingame, CA), each for 45 min at room temperature, before the immunoreactivity was labelled through incubation in diaminobenzidine (DAB, 0.5 mg/mI). Between treatments, the sections were rinsed in TBS. AU solutions were prepared with TBS. However, the brains of 1- and 7-days-old pups were processed slightly differently to help maintaining the integrity of the sections during immunocytochemical procedure. First, the brains were cut at 60 p.m, second the solutions were prepared with TBS containing 2% normal goat serum and 0.1% gelatin. The specificity of the immunoreactive labelling was tested in adult animals, as either omission of the primary antiserum or addition of AVP (50 /LM) to the primary antiserum blocked the immunoreactivity. Addition of oxytocin (50 j.tM) reduced the intensity of the labelling but did not block the immunoreactivity. Furthermore, sections of I-day-old pups and adult animals were incubated with rabbit anti-oxytocin (VAlO, a gift from Dr. H. Gainer, Bethesda, MD), an antiserum that does not cross react with AVP [1]. Sections labelled for oxytocin showed a different pattern of immunoreactivity than sections labelled for AVP; i.e. lack of oxytocin-immunoreactivity in the SCN and presence of a larger number of oxytocinergic perikarya in the PVN. Immunoreactivity was observed on a Zeiss microscope. For illustration purposes, digital microphotographs were taken with a Kodak digital camera (DCS 200ci). The pictures were then imported on a MacIn tosh computer and edited using Adobe Photos hop ™ (Version 2.5). Editing consisted of small modifications of the brightness and contrast of the pictures, in order to match backgrounds. No attempt was made to modify the content of the pictures.

2.3. Arginine-vasopressin binding sites AVP binding sites were labelled by in vitro autoradiography as previously described [18]. The animals were sacrificed by decapitation, their brains removed, frozen on dry ice, and kept at - 80·C until sectioning. Coronal sections (20 /Lm) were cut in a cryostat set at -10°C and thaw-mounted on gelatin-coated slides and stored at - 80·C, Later, the sections were preincubated at room temperature in 0.05 M Tris-HCI buffer (pH 7.3) containing 100 p.M NaCI and 100 mM guanosine 5' -Triphosphate (Type ll-S #119F-7405, Sigma Chemical, MO) followed by two 5-min washes in Tris buffer. Later, the sections were incubated for 1 h at room temperature in Tris buffer containing 10 mM MgCI 2 , 0.01% bovine serum albumin (Fraction V #128F-00841, Sigma ChemicaJ), 0.05% bacitracin and 40 IU aprotinin and 50 pM 12SI-[d(CH 2)sSar 7]AVP (125I-SAVP) [18,25]. Then, the sections were washed in ice-cold Tris buffer containing 10 mM MgCI 2 • Non-specific binding was obtained by incubations containing 1 p.M unlabelled AVP. Once dried at room temperature, the sections were apposed to Hyperfilm™ 3H (Amersham, IL), in X-ray cassettes for 2-3 weeks at - 80a C, The relative density of SAVP binding was quantified with the Image software (NIMH, Version 1.47). The density of SAVP binding was estimated within standard surfaces (diameter: 0.2 mm) placed inside these areas. The average of 3-5 independent measures was taken for each data point per area and animal. No attempt was made to adapt the results to the increasing size of the areas. Following removal from the X-ray cassettes, the slides were stained with thionin to identify the labelled sites. The specificity of the autoradiography procedure has been previously reported [18,25].

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3. Results 3.1. Vasopressin-immunoreactive neurons 3.1.1. Newborn animals No clear distinction could be made between large and small A VP-ir neurons, as most immunoreactive neurons were rather small and not always darkly labelled. However, A VP-ir neurons were observed in large numbers along the ventral surface of the anterior hypothalamus, spreading laterally from the SON (Fig. 1). Fewer A VP-ir neurons (less than 20 per side and section) were also observed within the PVN, nucleus circularis and BST (Figs. 1 and 2). Few A VP-ir neurons were also observed within the SCN (Fig. 1). 3.1.2. Animals within a week after birth The distinction between large and small A VP-ir neurons was more apparent. Then, large (diameter: ca. 20 .urn) A VP-ir neurons were observed within the

SON, PVN, nucleus circularis and BST (Figs. 1 and 3). At this age, most small (diameter: ca. 10 .urn) A VP-ir neurons were observed within the SeN (about 20 per section) (Fig. 1). In contrast, few (less than 10 per section) small A VP-ir neurons were observed within the PVN and also around large A VP-ir neurons in the BST. Within the SON, large AVP-ir neurons appeared to be reorganized around the developing optic chiasma and optic tract. 3.1.3. Animals by postnatal day 18 The distribution of A VP-ir neurons was similar to adult animals (Fig. 1), as previously described [10]. 3.2. Vasopressin-immunoreactive fibers At all ages, A VP-ir fibers were seen within the forebrain (Figs. 2-4). ~ ..

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Fig. 1. Photomicrographs of AVP-IR within the anterior hypothalamus of developing golden hamsters labelled a four different ages. A; postnatal day 1; B: postnatal day 7; C: postnatal day 18; D: Postnatal day 28. Scale bar: 500 JLm. AH: anterior Hypothalamus; NC: nucleus circularis; PVN: paraventricular hypothalamic nucleus; SCN: suprachiasmatic nucleus; SON: supraoptic nucleus; oc: optic tract.

Y. De/dlle et af. / Developmental Brain Research 81 (] 994) 230-239

3.2.1. Newborn animals A rather small number of A VP-ir fibers were seen coursing to the neurohypophysis across the anterior

hypothalamus. However, A VP-ir fibers were observed in the forebrain within sites unrelated to the neurohypophysis. Fibers apparently originating from the BST

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Y. Delville et al.j Developmental Brain Research 81 (J994) 230-239

234

were seen coursing laterally across the fundus striati towards the cortex as well as rostrally towards the septum. These fibers continued into the corpus callosum, the cortex, and the fimbria of the hippocampus. Fibers were also seen extending laterally along the periphery of the cortex from the lateral parts of the ventral surface of the brain (future SON cells). Fur-

thermore, A VP-ir fibers were observed within many other areas and nuclei, such as the ventral paIlidum, claustrum, dorsal endopiriform nucleus, tenia tecta, central and lateral amygdala, lateral preoptic area, etc. (Figs. 2-4). Interestingly, few fibers were observed coursing along the optic nerve and the exterior surface of the cortex.

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Y. DeldUe el al. / Developmental Brain Research 81 (1994) 230-239

In contrast, no A YP-ir fiber was observed in newborn animals within areas receiving a vasopressinergic input from the SCN [11,22], such as the anterior part of the paraventricular thalamic nucleus (PYA) or the dorsomedial hypothalamic nucleus (DMN) (Figs. 2,4). Furthermore, no AVP-ir fiber was seen projecting from vasopressinergic neurons within the SCN.

235

3.2.2. Animals by postnatal day 7 The distribution of AYP-ir fibers was different from the newborn animals (Fig. 3,4). For instance, many more fibers were seen coursing across the anterior hypothalamus, presumably towards the neurohypophysis, while fewer fibers were seen within the cortex or along its surface. Furthermore, new A YP-ir fibers were

Fig. 4. Darkfield photomicrographs of AVP-ir fibers within the DMN in developing golden hamsters. A: postnatal day 1; B: postnatal day 7; C: postnatal day 1.8; D: postnatal day 28. Scale bar: 200 p.m.

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Y. De/ville et al. / Developmental Brain Research 81 (1994) 230-239

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"<~i,~:(':;. ;:; :'i ",:n~;1:\:" .' Fig. 5. Distribution of [l 25 IJSAVP binding sites at three levels within the forebrain of developing golden hamsters, showing representative autoradiograms of the binding. Animals were sampled at postnatal day 1, 7, 18 and 28. A digitized autoradiographic [!25IJ microscale was added to this figure to represent the gray scale used in all these figures. The numbers presented are expressed as dpm per mg of tissue equivalent.

seen within areas receiving a vasopressinergic input from the SCN in adults [11,22J, although not as extensively as at later ages. The areas include the medial preoptic nucleus, median preoptic nucleus, BST, periventricular hypothalamic nucleus, PVA, DMN and midline thalamic nuclei (Fig. 3). A duster of fibers was also seen within the zona incerta. 3.~.3.

Animals by postnatal days 18 and 28 IThe distribution of AVP-ir fibers was mostly similar to adult animals. Fewer fibers were visible within the cortex, while more fibers were seen within the areas receiving vasopressinergic input from the SCN (Fig. 4). I

the choroid plexus) and the BST (anteromediaI and ventral). A few other sites contained low levels of AVP binding. These sites included the PVN, fundus striati,

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At all ages, specific A VP binding sites were seen within the brain, although fewer sites were observed in newborn animals (Figs. 5 and 6). 3.3.1. Newborn hamsters A VP binding sites were observed mainly within the lateral ventricle (presumably the subfornical organ and

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Fig. 6. Levels of specific [lLSI]SAVP binding within three selected forebrain regions of developing golden hamsters. The levels arc presented as the optical density (mean ± S.E.M.; expressed as dpm per mg of tissue equivalent) of the labelling per standard surface area (diameter: 0.2 mm) analyzed within these sites. Each data point was calculated from the averages of 3-5 measures for two to four animals.

Y. DelL'iIle et al.; Developmental Brain Research 81 (J994) 230-239

central amygdala (CeA), tenia tecta and ventral pallidum (Fig. 5). Binding was apparently absent from most sites receiving SCN vasopressinergic input, such as the PYA or DMN [11,22]. 3.3.2. Animals by postnatal day 7 Many more binding sites were visible in the forebrain. While the density levels of A YP binding within the BST and CeA increased 3-4 times (Fig. 6), A VP binding within the lateral ventricle had almost disappeared (Fig. 5). New sites, however, were visible within the lateral septum, cortex, amygdala, thalamus and hypothalamus, as observed in adult animals [18] (Fig. 5). Interestingly, a high density of binding was observed within the zona incerta. 3.3.3. Animals by postnatal days 18 and 28 The distribution of A YP binding sites was similar to adult animals [18] (Fig. 5). Within areas receiving a vasopressinergic input from the SCN, the density of binding kept increasing, as seen in the PYA [11,22]. In other sites (such as the CeA), the density of binding remained elevated as at postnatal day 7. A similar pattern was obs~rved in the anterior hypothalamus. However, in certain sites (such as the BST) the density of binding decreased after postnatal day 18.

4. Discussion

The present data confirm the existence of different populations of vasopressinergic neurons in hamsters [20]. As in rats [6,14,33], these populations are characterized by different patterns of maturation. In hamsters, small vasopressinergic neurons in the SCN mature gradually after birth, as parvicellular neurons do in rats [14,33]. Indeed, AVP-ir was observed initially within neurons, then later within an increasing number of fibers. Moreover, within SeN target sites [11,22], the maturation of AVP receptors and afferent vasopressinergic fibers occurred simultaneously. In contrast, other vasopressinergic neurons or elements of the vasopressinergic system follow different patterns of maturation. Although some large A VP-ir neurons follow a gradual pattern of maturation, ahead of SCN neurons, elements of the vasopressinergic system undergo transient growths. As an example of gradual growth, large A VP-ir neurons projecting to the neurohypophysis start maturing before birth. At birth, these neurons are present and some already project to the neurohypophysis. Later, these neurons become larger and more projections can be observed coursing across the hypothalamus. Similar observations of early start and gradual maturation have been reported for magnocellular neurons in rats [3,6,37].

237

In comparison, certain elements of the vasopressinergic system experienced transient growth. However, different rates of maturation were observed even within systems undergoing transient growth. As a result, different periods of development are characterized by transient expression of the vasopressinergic system within different parts of the brain. For instance, the presence of vasopressinergic fibers within the cortex and its periphery is only observed during the first days after birth. Interestingly, this transient expression is concomitant with the development of the cortex and the hippocampus. In contrast, the transient expression of A VP receptors within the BST and zona incerta occurs around postnatal day 7. Similar transient expressions have been reported for the vasopressinergic system of rats [24,33,35], although sometimes within different areas. For example, in rats, intense A VP binding has been reported within the cingulate cortex and the facial nucleus only around postnatal day 7 [33,35]. The functional significance of these transient changes is unclear. It is possible that the diminution of binding observed after postnatal day 7 may be related to an increase in the size of the area analyzed, the total number of receptors remaining constant. However, in some cases, such as the zona incerta, the apparent transient expression of SAVP binding correlates with a transient concentration of AVP-ir fibers. Therefore, it is very likely that such transient expression of SAVP binding is more than just apparent. Moreover, the early and transient presence of AVP-ir fibers developing areas, such as the cortex, hippocampus or optic nerve, suggests that A VP may be involved in their maturation. This suggestion is supported by reports of vasopressin promoting the development of cultured hippocampal neurons [4]. Our results also showed the presence of AVP-ir neurons within the BST in newborn animals. Because the landmarks are not fully developed at that age, it is difficult to determine the identity of this neuronal subpopulation. In adults hamsters, most BST neurons are large and located at the proximity of the fornix within the medial edge of the postero-medial division of the nucleus [20]. A similar group of vasopressinergic neurons exist in rats, independently of sexually dimorphic parvicellular neurons located more laterally in the nucleus [20]. As the neurons observed became large by postnatal day 7, it is likely that they belong to the medially located subpopulation of BST cells. The presence of AVP fibers terminating within various parts of the forebrain in newborn animals is an interesting observation. This observation is complemented by the presence of a few AVP binding sites within the brain at that age. Similar observations have been made in newborn rats within the same areas [24,35] (De Vries, personal communication), Interestingly, in newborn rats, AVP binding has also been

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Y. De/ville et a!. / Del'e/opmental Brain Research 81 (1994) 230-239

reported within additional areas, such as the caudate and hippocampus [24], suggesting that A VP affects the development of more brain areas in rats than hamsters. In both species, however, neurons within the SCN do not appear to have vasopressinergic projections at this age [14]. In rats, parvicellular neurons within the BST or MeA start expressing A VP within a few days after birth [14,32]. Therefore, it is not impossible that AVP-ir fibers observed in newborn animals originate from a subpopulation of neurons located within areas generally associated witt- large vasopressinergic neurons projecting to the neurohypophysis. It is possible that this population disappears during development, along with some of these sites and fibers. However, even in nits, many sites containing A VP fibers and receptors are maintained throughout development. For instance, A VP fibers within the tenia tecta and CeA remain throughout development (De Vries, personal communication), Similarly, so do A VP binding sites within the fundus striati and CeA [24,35]. Therefore, it is possible that even in rats, such a subpopulation of vasopressinergic neurons would be maintained during adulthood. Indeed, recent observations made in hamsters suggest the existence of a subpopulation of large vasopressinergic neurons which is located within the PVN and SON and does not project to the neurohypophysis [19,23]. This hypothesis is further supported by the observation of AVP fibers remaining weeks after castration in rats within the CeA, an area not targeted by SCN vasopressinergic terminals [14,15]. Our results also show a close relationship between the development of A VP neurons within the SCN, their vasopressinergic projections to the midline thalamic nuclei (such as the PYA) and A VP binding sites within these nuclei. It is interesting to observe that as SeN vasopressinergic neurons sprout to their target sites, these sites also gain the capacity to respond to A VP. At least, this observation reinforces the concept that A VP binding sites within midline thalamic nuclei are related to the vasopressinergic innervation from the SCN, in golden hamsters [11,22]. Finally, in golden hamsters, one particular AVP binding site is sensitive to testosterone [17]. In this site, the ventrolateral hypothalamus, A VP is involved in the control of aggressive behavior [17]. While no A VP binding site has been found sensitive to gonadal steroid hormones in rats [34], some oxytocin binding sites are sensitive to these hormones [8,9,21,34]. In particular, oxytocin binding within the ventromedial and ventrolateral hypothalamus is sensitive to testosterone and estradiol [8,9,21]. Oxytocin binding within this area is detectable in adult animals, but not in prepuberal rats [27]. As A VP binding within the ventrolateral hypothalamus is testosterone-dependent, it is likely that this binding site also develops during puberty. Interestingly, A VP binding was not detected within the ventrolateral

hypothalamus at postnatal day 7 nor 18. This observation along with a recent report of sexual differences in the numbers of large vasopressinergic neurons within the SON [10] reinforce the concept of heterogeneity within large vasopressinergic neurons.

Acknowledgements These experiments were supported by grants BNS9121097 from the NSF and NS 30199 from the NINDS awarded to Craig Ferris. We are grateful to Geert De Vries, Jude Brewer and Rich Melloni for their insightful discussions and helpful comments on the manuscript.

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