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Cited by 319Neuroendocrine regulation and behaviorCircadian rhythm and melatoninHypothalamic control of reproductive hormones

Ontogeny of the vasopressinergic neurons of the suprachiasmatic nucleus and their extrahypothalamic projections in the rat brain–presence of a sex difference in the lateral septum

Open access
De Vries, Geert J., Buds, Ruud M., Swaab, Dick F.·1981·Brain Research
DOI 10.1016/0006-8993(81)90989-6
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Abstract

Immunocytochemical studies have revealed the presence of extensive vasopressinergic projections from the suprachiasmatic nucleus to the limbic system and other brain areas. Vibratome sections and the unlabeled antibody enzyme method were used to investigate the ontogeny of the vasopressinergic neurons of the suprachiasmatic nucleus and their exohypothalamic fibers in the rat brain. The first immunopositive neurons of this nucleus were revealed on the 2nd postnatal day. An adult appearance of the suprachiasmatic nucleus was detected on day 14. Although fibers appeared on the periventricular nucleus already on the 7th postnatal day, such fibers were visible in the lateral septum and lateral habenular nucleus only on day 10. From the 12th postnatal day onwards a marked sex difference developed with respect to the density of the vasopressin fibers in the lateral septum and, to a lesser extent, in the lateral habenular nucleus. In male rats the fiber density was higher in both areas. This sex difference persisted in adulthood.

AI snapshot

Written from the paper’s full text.

TL;DR

Using immunocytochemistry on vibratome sections, this study traced the postnatal development of vasopressinergic (AVP) neurons in the rat suprachiasmatic nucleus (SCN) and their extrahypothalamic projections, finding the first AVP-positive SCN cells on postnatal day 2 and an adult-like nucleus by day 14. From postnatal day 12 onward a marked sex difference emerged, with male rats showing denser AVP fiber networks in the lateral septum and, less strikingly, the lateral habenular nucleus, persisting into adulthood.

Key findings

  • No AVP-positive cells were seen in the SCN on postnatal day 1; a few were detected in 1 of 3 two-day-old rats, in 6 of 8 rats on day 3, and in all animals from days 4–6. An adult appearance of the SCN was reached on day 14.
  • Fibers appeared in the periventricular nucleus by day 7, but were visible in the lateral septum and lateral habenular nucleus only on day 10.
  • From day 12 onward a sex difference developed in the density of AVP fibers in the lateral septum: in males density increased dramatically from day 12 to 17, whereas no such change occurred in females. In 55-day-old females the fiber number was still moderate, comparable to that of 12–14-day-old males; the difference persisted in adulthood but was less striking than between days 17 and 35.
  • A similar but weaker sex difference was seen in the lateral habenular nucleus (adult-like appearance in males by day 14, females by day 17), with considerable overlap between the sexes. No sex difference was noted in the SCN or periventricular nucleus.

Methods

  • Infant Wistar rats of either sex: first series studied on days 1–8, 10, 12, 14, 17 and 21 (3 rats per age group); second series sacrificed on days 3, 10, 12, 14, 17, 21, 27, 35 and 55 (2–6 rats of each sex per age group). Adults were 3 male and 3 female rats weighing 230–250 g.
  • Brains were perfused with glutaraldehyde/paraformaldehyde, sectioned with a vibratome, and stained for AVP using the unlabeled antibody enzyme (PAP) method; antibody specificity was tested by immunofluorescence and adsorption controls, including Brattleboro rats.
  • Fiber density in the lateral septum and lateral habenular nucleus was estimated semi-quantitatively in a blind study using 4 categories (+, ++, +++, ++++).

Limitations

  • The paper states that its procedure "was not suited to a quantitative approach," so a sex difference in the number of AVP-containing cells cannot be excluded; it also notes that how the observed sex differences relate to functional differences remains speculative.
  • Evident from the text: fiber density was scored only semi-quantitatively on an ordinal scale, group sizes were small (2–6 rats per sex per age), and large individual variation was noted, particularly in the lateral habenular nucleus where overlap between sexes was considerable.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/0006-8993(81)90989-6

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 8 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Extrahypothalamic areas · p. 6

    The sex difference in the density of the fiber network in the lateral septum was more striking between days 17 and 35 than in adulthood.

    “this difference was not as striking as between days 17 and 35.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The stage of the estrous cycle does not affect the density of AVP-containing fibers in the lateral septum of female rats.
  • Findingown data
    § SUMMARY · p. 2

    The first immunopositive neurons of the suprachiasmatic nucleus are revealed on the 2nd postnatal day.

    “The first immunopositive neurons of this nucleus were revealed on the 2nd postnatal day.”
    • Also stated in: § DISCUSSION · p. 8 · plain
      “In the present study the first AVP-containing cells in the SCN were found on the 2nd postnatal day”
    Quote in the paperSubstantial claim
  • Findingown data
    § Extrahypothalamic areas · p. 8

    AVP-containing fibers are visible in the lateral habenular nucleus on the 10th postnatal day.

    “On the 10th postnatal day the first AVP-containing fibers were visible in this area”
    • Also stated in: § SUMMARY · p. 2 · plain
      “such fibers were visible in the lateral septum and lateral habenular nucleus only on day 10.”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Extrahypothalamic areas · p. 8

    As soon as fibers were visible in the lateral habenular nucleus and the lateral septum, branching of fibers and punctate perineuronal structures could also be detected.

    “As soon as fibers were visible in the lateral habenular nucleus and the lateral septum, branching of fibers and punctate perineuronal structures could also be detected.”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Extrahypothalamic areas · p. 6

    In male and female rats generally only very few AVP-containing fibers were found in the lateral septum on days 10 and 12.

    “In male and female rats generally only very few AVP-containing fibers were found in the lateral septum on days 10 and 12.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 15
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Findingown data
    § Suprachiasmatic nucleus · p. 6

    The immunopositive cells were scattered over the entire SCN but the highest concentration was found at the medial and mediodorsal border of the SCN.

    “The immunopositive cells were scattered over the entire SCN but the highest concentration was found at the medial and mediodorsal border of the SCN.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § SUMMARY · p. 2

    In male rats the fiber density is higher in both the lateral septum and the lateral habenular nucleus.

    “In male rats the fiber density was higher in both areas.”
    • Also stated in: § DISCUSSION · p. 9 · plain
      “higher in male rats than in female rats from the 12th day onwards.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The stage of the estrous cycle does not affect the density of AVP-containing fibers in the lateral septum of female rats.

  • May combine two claims.

    Findingown data
    § Suprachiasmatic nucleus · p. 6

    No sex difference was noted in the development of AVP-containing cells and in the density of fibers in the immediate vicinity of the SCN.

    “No sex difference was noted in the development of the AVP-containing cells and in the density of fibers in the immediate vicinity of the SCN.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Suprachiasmatic nucleus · p. 6

    On postnatal day 3, in 6 out of 8 rats and from the 4th to 6th day in all animals, immunopositive cells were visible in the SCN, revealing only very few or no fibers.

    “On postnatal day 3, in 6 out of 8 rats and from the 4th to 6th day in all animals, immunopositive cells were visible in the SCN, revealing only very few or no fibers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Extrahypothalamic areas · p. 8

    Although generally female rats showed a smaller density of fibers in the lateral habenular nucleus than male rats of the same age, the overlap was considerable.

    “Although generally female rats showed a smaller density of fibers in the lateral habenular nucleus than male rats of the same age, the overlap was considerable.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Suprachiasmatic nucleus · p. 6

    AVP-containing fibers and cells were spread all over the SCN area on the 7th and 8th days, while only very few fibers left the SCN running into rostral or dorsorostral directions.

    “AVP-containing fibers and cells were spread all over the SCN area on the 7th and 8th days (Fig. 2), while only very few fibers left the SCN running into rostral or dorsorostral directions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Extrahypothalamic areas · p. 6

    In adult female rats, the fibers in the lateral septum form a network, but not as dense as in the male rat.

    “while in the adult female rats the fibers had formed a network”
    • Also stated in: § DISCUSSION · p. 10 · plain
      “Female rat. The fibers form a network (arrows), but not as dense as in the male rat.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The stage of the estrous cycle does not affect the density of AVP-containing fibers in the lateral septum of female rats.

  • May combine two claims.

    Findingown data
    § Suprachiasmatic nucleus · p. 6

    On the 10th day the number of cells and the density of fibers fanning out the SCN were dramatically increased.

    “On the 10th day the number of cells and the density of fibers fanning out the SCN were dramatically increased”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Suprachiasmatic nucleus · p. 6

    Numerous fine caliber fibers were homogeneously distributed over the SCN while vast projections fanned out in rostral, rostrodorsal and dorsocaudal directions.

    “Numerous fine caliber fibers were homogeneously distributed over the SCN while vast projections fanned out in rostral, rostrodorsal and dorsocaudal directions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Extrahypothalamic areas · p. 8

    In the lateral habenular nucleus, a practically adult appearance was found in male rats on the 14th day and in female rats on the 17th day.

    “while a practically adult appearance was found in male rats on the 14th day and in female rats on the 17th day.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data
    § SUMMARY · p. 2

    From the 12th postnatal day onwards a sex difference develops in the density of vasopressin fibers in the lateral habenular nucleus, to a lesser extent than in the lateral septum.

    “and, to a lesser extent, in the lateral habenular nucleus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Extrahypothalamic areas · p. 6

    In male rats the fiber density in the lateral septum increased dramatically from the 12th to 17th day, while no such change was seen in female rats.

    “While in male rats the fiber density increased dramatically from the 12th to 17th day, no such change was seen in female rats”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The stage of the estrous cycle does not affect the density of AVP-containing fibers in the lateral septum of female rats.

  • May combine two claims.

    Findingown data
    § Extrahypothalamic areas · p. 6

    Some more fibers, already forming a network, were visible in 3 out of 6 male rats of day 14 and in all male rats of days 17, 21, 27, 35 and 55.

    “Some more fibers, already forming a network, were visible in 3 out of 6 male rats of day 14 (Fig. 5) and in all male rats of days 17, 21, 27, 35 and 55 (Fig. 7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Extrahypothalamic areas · p. 6

    Only on the 55th day was a discernibly larger, but still moderate number of fibers found in female rats, comparable to the number of fibers in the lateral septum of male rats of 12-14 days of age.

    “Only on the 55th day was a discernibly larger, but still moderate number of fibers found, comparable to the number of fibers in the lateral septum of male rats of 12–14 days of age”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning
    § DISCUSSION · p. 10

    The AVP-containing SCN fibers might be associated with the regulation of certain circadian rhythms.

    “The AVPcontaining SCN fibers might thus be associated with the regulation of certain circadian rhythms.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Interpretationcitation
    § DISCUSSION · p. 11

    The AVP-containing fibers of the SCN projecting to the lateral septum might influence neurohypophyseal function via pathways from the lateral septum to the medial septum and PVN/SON.

    “The AVP-containing fibers of the SCN projecting to the lateral septum might influence neurohypophyseal function via these pathways.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation
    § DISCUSSION · p. 10

    AVP fibers in the lateral septum might play a role in the physiology of temperature regulation.

    “AVP fibers in the lateral septum might, in addition, play a role in the physiology of temperature regulation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning
    § DISCUSSION · p. 11

    Another function of AVP fibers of the SCN might be an involvement in the regulation of water balance.

    “Another function of AVP fibers of the SCN might be an involvement in the regulation of water balance.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data
    § MATERIALSANDMETHODS · p. 5

    The density of AVP fibers in the lateral septum and lateral habenular nucleus was estimated in a semi-quantitative manner in a blind study distinguishing 4 categories.

    “nucleus was estimated in a semi-quantitative manner in a blind study distinguishing 4 categories: +, very few fibers; + +, a moderate number of fibers; + + +, fibers form a network; +++ +, fibers form a very dense network”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § DISCUSSION · p. 11

    The sex difference in the density of AVP fibers in the lateral septum became noticeable on the 12th postnatal day, the same day from which higher levels of serotonin in the female brain are measurable.

    “This is consistent with the higher levels of serotonin in the female brain, a sex difference which is only measureable from the 12th postnatal day2⁵, on which day the sex difference in the density of AVP fibers in our study also became noticeable.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Ladosky, 1970, Brain serotonin and sexual differentiation of the nervous system, Neuroendocrinology source
    • Rests on an assumption: The stage of the estrous cycle does not affect the density of AVP-containing fibers in the lateral septum of female rats.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning
    § DISCUSSION · p. 9

    The formation of synaptic contacts might trigger AVP synthesis.

    “The formation of the synaptic contacts might thus trigger AVPsynthesis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning
    § DISCUSSION · p. 9

    The procedure used in this study was not suited to a quantitative approach and for this reason a sex difference in the number of AVP-containing cells can certainly not be excluded.

    “However, the procedure used in this study was not suited to a quantitative approach and for this reason a sex difference in the number of AVP-containing cells can certainly not be excluded.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning
    § DISCUSSION · p. 11

    Serotonin fibers might balance out the paucity of AVP fibers in female rats.

    “serotonin fibers might balance out the paucity of AVP fibers in female rats.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The stage of the estrous cycle does not affect the density of AVP-containing fibers in the lateral septum of female rats.
23 of 23

  • The paper relies on this without support.

    The stage of the estrous cycle does not affect the density of AVP-containing fibers in the lateral septum of female rats.

    “The stages of the estrous cycle of the female rats were proestrus, estrus and metestrus.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Males have more AVP-expressing cells in the bed nucleus of the stria terminalis and medial amygdala and denser AVP-axonal projections to limbic brain regions, especially to the lateral septum.

    “For example, males have more AVP-expressing cells in the bed nucleus of the stria terminalis and medial amygdala and denser AVP-axonal projections to limbic brain regions, especially to the lateral septum (De Vries et al., 1981; Van Leeuwen et al., 1985; Szot and Dorsa, 1993).”

    From Sex-specific modulation of juvenile social play behavior by vasopressin and oxytocin depends on social context (2014) · cites this paper as De Vries et al., 1981

    The Discussion (p. 9) reports denser AVP-containing fibers in male rats in the lateral septum and, to a lesser extent, the lateral habenular nucleus. It does not establish that males have more AVP-expressing cells in the bed nucleus of the stria terminalis or medial amygdala; the cells studied were in the suprachiasmatic nucleus. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Compared to females, males have more AVP-expressing cells in the BNST and MeA and denser AVP-axonal projections to limbic brain regions, especially the lateral septum.

    “For example, compared to females, males have more AVP-expressing cells in the bed nucleus of the stria terminalis (BNST) and medial amygdala (MeA) and denser AVP-axonal projections to limbic brain regions, especially to the lateral septum (LS) (De Vries et al 1981; van Leeuwen et al., 1985; Szot & Dorsa, 1993).”

    From Sex-specific modulation of juvenile social play by vasopressin (2013) · cites this paper as De Vries et al 1981

    The Discussion (p. 9) reports denser AVP-containing fibers in male rats’ lateral septum and, to a lesser extent, lateral habenular nucleus; the Extrahypothalamic areas results (p. 6) show the septal difference persists into adulthood. Our copy does not report that males have more AVP-expressing cells in the BNST or MeA, so it supports the projection-density part of the sentence but not the cell-count part. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Sex differences in AVP immunostaining in the lateral septum are extreme at the end of the third week of life.

    “Likewise sex differences in AVP immunostaining in the lateral septum are similarly extreme at this age (De Vries et al., 1981).”

    From Sexually dimorphic role for vasopressin in the development of social play (2014) · cites this paper as De Vries et al., 1981

  • The sex difference in AVP projections is found in many mammalian species and already exists in juveniles.

    “This sex difference is found in many mammalian species (De Vries & Panzica, 2006) and already exists in juveniles (De Vries et al., 1981).”

    From Sex-specific modulation of juvenile social play by vasopressin (2013) · cites this paper as De Vries et al., 1981

  • The lateral septum shows denser AVP fibers in males than females and abundant expression of V1aR in male and female juvenile rats.

    “To test the hypothesis that the sexually dimorphic effects of ICV injections of V1aR blockade were mediated by the sexually dimorphic projections of the BST and MeA, we specifically targeted the LS, which shows denser AVP fibers in males than in females (De Vries et al., 1981) and abundant expression of V1aR in male and female juvenile rats (Veenema et al., 2012).”

    From Sex-specific modulation of juvenile social play by vasopressin (2013) · cites this paper as De Vries et al., 1981

Cites

Flagged first, then by citations

3 of the 46 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Boer, 1980, Neuropeptides in brain development, Vol. 54
  2. Moore, 1978, Central neural control of circadian rhythms, Front. Neuroendocr., 5, 185

Cited by

Sorted by citations

Related

Authors
De Vries, G. J., Buds, R. M., & Swaab, D. F.
ORCID
Swaab, Dick F.
Venue
Brain Research
Publisher
Elsevier BV
Published
1981-08
Volume
218
Issue
1-2
Pages
67-78
ISSN
0006-8993 (ISSN-L)
DOI
10.1016/0006-8993(81)90989-6
OpenAlex
W2002833231
Semantic Scholar
f6169fc782bda126e0ab5cb93b47a550a41455e3
Cited by
319
References
46
Citations by year
2026: 5 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 8 · 2021: 10 · 2020: 1 · 2019: 7 · 2018: 14 · 2017: 9 · 2016: 7 · 2015: 5 · 2014: 11 · 2013: 4 · 2012: 4
FWCI
21.77
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Brain Research (publishedVersion)
  • PubMed (publishedVersion)
  • KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords
vasopressin, suprachiasmatic nucleus, ontogeny, sex differences, lateral septum, lateral habenula, limbic system, postnatal development, rat brain
MeSH terms
Animals, Female, Hypothalamus, Immunoenzyme Techniques, Male, Neurons, Sex Characteristics, Vasopressins, Rats

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