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Cited by 667Stress Responses and CortisolNeuropeptides and Animal PhysiologyNeuroendocrine regulation and behavior

Increased Numbers of Corticotropin-Releasing Hormone Expressing Neurons in the Hypothalamic Paraventricular Nucleus of Depressed Patients

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Raadsheer, Frederik C., Hoogendijk, Witte J.G., Stam, Frans C., Tilders, Fred J.H., Swaab, Dick F.·2008·Neuroendocrinology
DOI 10.1159/000126778
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Abstract

The hypothalamo-pituitary-adrenal (HPA) axis is known to be activated in depressed patients. Although direct evidence is lacking, this activation is hypothesized to be due to hyperactivity of corticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus (PVN). Recent immunocytochemical studies in experimental animals and in humans showed that the number of CRH-expressing neurons correlated with the activity of these neurons. In addition, colocalization of AVP in CRH neurons has been shown to be an index for the secretory activity. Therefore, we estimated the total number of CRH-immunoreactive neurons and their fraction showing colocalization with AVP in the PVN of 10 control subjects and of 6 depressed patients who were diagnosed to be suffering from a major depression or a bipolar disorder. The mean total number of CRH-expressing neurons of the 6 depressed patients was four times higher, and the number of CRH neurons co-expressing AVP was almost three times higher than those in the control group. We also determined the two activity parameters of CRH neurons in the PVN of 2 subjects with a depressive organic mood syndrome or a depressive disorder not otherwise specified. In these two ‘non-major depressed’ subjects, the activity parameters of CRH neurons were comparable to those of control subjects. Our observations strongly support the hypothesis that CRH neurons in the PVN are hyperactivated in major depressed patients. This hyperactivity might be causally related to at least part of the symptomatology of depression.

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  1. 1 Vale W, Rivier C, Brown MV, Spiess J, Koob G, Swanson L, Bilezikjian L, Bloom F, Rivier J: Chemical and biological characterization of corticotropin-releasing factor. Recent Prog Horm Res 1983;39:245–270.
  2. 2 Vale W, Spiess J, Rivier C, Rivier J: Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and β-endorphin. Science 1981;213:13941397.
  3. 3Gillies GE, Linton L, Lowry PJ: Corticotropinreleasing activity of the new CRF is potentiated several times by vasopressin. Nature 1982;299: 355-357.
  4. 4 Rivier C, Vale W: Interaction of corticotropinreleasing factor and arginine-vasopressin on adrenocorticotropin secretion in vivo. Endocrinology 1983;113:939–942.
  5. 5 Bissette G: Central nervous system CRF in stress: radioimmunossay studies; in De Souza EB, Nemeroff CB (eds): Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide. Boca Raton, CRC Press, 1990, pp 21-28.
  6. 6 Chrousos GP, Gold PW: The concepts of stress and stress system disorders. JAMA 1993;267: 1244-1252.
  7. 7 Holsboer F, Spengler D, Heuser I: The role of corticotropin-releasing hormone in the pathogenesis of Cushing's disease, anorexia nervosa, alcoholism, affective disorders and dementia; in Swaab DF, Hofman MA, Mirmiran M, Ravid R, Van Leeuwen FW (eds): The Human Hypothalamus in Health and Disease. Prog Brain Res 1992;93:385-417.
  8. 8 Sacher EJ, Hellman L, Roffwarg HP, Halpern F, Fukishima D, Gallagher T: Disrupted 24hour patterns of cortisol secretion in psychiatric depression. Arch Gen Psychiatry 1973;28: 19-24.
  9. 9 Carroll BJ, Feinberg M, Greden JF, Tarika J, Albala AA, Hasket RF, James NM, Kronfol Z, Lohr N, Steiner M, Vigne JP, Young E: A specific laboratorium test for the diagnosis of melancholia. Arch Gen Psychiatry 1981;38:1522.
  10. 10 Amsterdam JD, Maislin G, Winokur A, Berwish N, Kling M, Gold P: The oCRH stimulation test before and after clinical recovery from depression. J. Affect Dis 1987;14:213-222.
  11. 11 Gold PW, Chrousos G, Kellner C, Post R, Roy A, Avgerinos P, Schulte H, Oldfield H, Loriaux DL: Psychiatric implications of basic and clinical studies with corticotropin-releasing factor. Am J Psychiatry 1984;141:619-627.
  12. 12 Gold PW, Loriaux DL, Roy A, Kling MA, Calabrese JR, Kellner LK, Nieman LK, Post RM, Pickar D, Gallucci WT, Avgerinos PC, Paul S, Oldfield EH, Cutler GB Jr, Chrousos GP: Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease. Pathophysiological and diagnostic implications. N Engl J Med 1986;314:1329– 1335.
  13. 13 Holsboer F: Prediction of clinical course by dexamethasone suppression test (DST) response in depressed patients: Physiological and clinical construct validity of the DST. Pharmacopsychiatry 1983;16:186-191.
  14. 14 Holsboer F, Müller OA, Doerr HG, Sippel WG, Stalla GK, Gerken A, Steiger A, Boll E, Benkert O: ACTH and multisteroid responses to corticotropin-releasing factor in depressive illness: Relationship to multisteroid responses after ACTH stimulation and dexamethasone suppression. Psychoneuroendocrinology 1984; 9:147-160.
  15. 15 Holsboer F, Gerken A, Stalla GK, Müller OA: ACTH, cortisol and corticosterone output after ovine corticotropin-releasing factor challenge during depression and after recovery. Biol Psychiatry 1985;20:276–286.
  16. 16 Holsboer F, Von Bardeleben U, Gerken A, Stalla GK, Müller OA: Blunted corticotropin and normal cortisol response to human corticotropin-releasing factor (h-CRF) in depression. N Engl J Med 1984;311:1127.
  17. 17 Holsboer F, Gerken A, Von Bardeleben U, Grimm W, Beyer H, Müller OA, Stalla GK: Human corticotropin-releasing hormone in depression. Biol Psychiatry 1986;21:229–231.
  18. 18 HolsboerF, Gerken A, Stalla GK and Müller OA: Blunted aldosterone and ACTH release after human CRH administration in depressed patients. Am J Psychiatry 1987;144:229-231.
  19. 19 Aguilera G, Flores M, Carvallo P, Harwood JP, Millan M, Catt KJ: Receptors for corticotropin-releasing factor; in De Souza EB, Nemeroff CB (eds): Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide. Boca Raton, CRC Press, 1990, pp 153–174.
  20. 20Arato M, Banki CM, Nemeroff CB, Bissette G: Hypothalamic-pituitary-adrenal axis and suicide. Ann NY Acad Sci 1986;487:263–270.
  21. 21 Banki CM, Bissette G, Arato M, O'Connor M, Nemeroff CB: Cerebrospinal fluid corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia. Am J Psychiatry 1987;144:873-877.
  22. 22 France RD, Urban B, Krishnan RR, Bissette G, Banki CM, Nemeroff CB, Spielman FJ: CSF corticotropin-releasing factor-like immunoreactivity in chronic pain patients with and without depression. Biol Psychiatry 1988;23:8688.
  23. 23 Kurlan R, Shoulson I, Caine E, Rubin A, Nemeroff CB, Bissette G, Zaczek R, Coyle J, Spielman FJ: Cerebrospinal fluid correlates of depression in Huntington's disease. Soc Neurosci Abstr 1987;13:1473.
  24. 24 Nemeroff CB, Widerlöv E, Bissette G, Wallcus H, Karlsson I, Kilts CS, Loosen PT, Vale W: Elevated concentration of CSF corticotropinreleasing factor-like immunoreactivity in depressed patients. Science 1984;226:13421344.
  25. 25 Sawchenko PE, Swanson LW: Organization of CRF immunoreactive cells and fibers in the rat brain; immunohistochemical studies; in De Souza EB, Nemeroff CB (eds): CorticotropinReleasing Factor: Basic and Clinical Studies of a Neuropeptide. Boca Raton, CRC Press, 1990, pp 29-51.
  26. 26 Pelletier G, Désy L, Côté J, Vaudry H: Immunocytochemical localization of corticotropinreleasing factor-like immunoreactivity in the human hypothalamus. Neurosci Lett 1983;41: 259-263.
  27. 27 Mouri T, Suda T, Sasano N, Andoh Y, Takei M, Takase M, Sasaki A, Murakami O, Yoshinaga K: Immunocytochemical identification of CRF in the human hypothalamus. Tohoku J Exp Med 1984;142:423-426.
  28. 28 Ohtani H, Mouri T, Sasaki A, Sasano N: Immunoelectron microscopic study of corticotropin-releasing factor in the human hypothalamus and pituitary gland. Neuroendocrinology 1987;45:104-108.
  29. 29 Takahashi K, Mouri T, Yamamoto T, Itoi K, Murakami O, Yoshinaga K, Sasano N: Corticotropin-releasing hormone in the human hypothalamus. Free-floating immunostaining method. Endocr Jpn 1989;36:272–280.
  30. 30 Raadsheer FC, Sluiter AA, Ravid R, Tilders FJH, Swaab DF: Localization of corticotropinreleasing hormone (CRH) neurons in the paraventricular nucleus of the human hypothalamus: Age-dependent colocalization with vasopressin. Brain Res 1993;615:50–62.
  31. 31 Raadsheer FC, Oorschot DE, Verwer RWH, Tilders FJH, Swaab DF: Age related increase in the total number of corticotropin-releasing hormone neurons in the human paraventricular nucleus in controls and Alzheimer's disease: Comparison of the disector with an unfolding method. J Comp Neurol 1994;339:447-457.
  32. 32 Bartanusz V, Jezova D, Bertini LT, Tilders FJH, Aubry JM, Kiss JZ: Stress-induced increase in vasopressin and corticotropin-releasing factor expression in hypophysiotropic paraventricular neurons. Endocrinology 1993;132: 895-902.
  33. 33 de Goeij DCE, Jezova D, Tilders FJH: Repeated stress enhances vasopressin synthesis in corticotropin-releasing factor neurons in the paraventricular nucleus. Brain Res 1992;577: 165-168.
  34. 34 de Goeij DCE, Kvetnansky R, Whitnall MH, Jezova D, Berkenbosch F, Tilders FJH: Repeated stress induced activation of corticotropin-releasing factor (CRF) neurons enhances vasopressin stores and colocalization with CRF in the median eminence of rats. Neuroendocrinology 1991;53:150–159.
  35. 35 Tilders FJH, Schmidt ED, de Goeij DCE: Phenotypic plasticity of CRH neurons during stress. Ann N Y Acad Sci 1993;697:39–52.
  36. 36 Whitnall MH, Kiss A, Aguilera G: Contrasting effects of central alpha-1-adrenoreceptor activation on stress-responsive and stress-nonresponsive subpopulations of corticotropin-releasing hormone neurosecretory cells in the rat. Neuroendocrinology 1993;58:42-48.
  37. 37 Raadsheer FC, Tilders FJH, Swaab DF: Similar age related increase of vasopressin colocalization in paraventricular corticotropin-releasing hormone neurons in controls and Alzheimer patients. J Neuroendocrinol 1994;6:131133.
  38. 39 van de Nes JAP, Kamphorst W, Ravid R, Swaab DF: The distribution of Alz-50 immunoreactivity in the hypothalamus and adjoining areas of Alzheimer's disease patients. Brain 1993;116:103-115.
  39. 40 van Oers JWAM, Tilders FJH, Berkenbosch F: Characterization and biological activity of a monoclonal antibody to rat/human corticotropin-releasing factor. Endocrinology 1989;124: 1239-1246.
  40. 41 van der Sluis PJ, Pool CW, Sluiter AA: Immunocytochemical detection of peptides and proteins on press-blots after direct tissue gel isoelectric focussing. Electrophoresis 1988;9:654– 661.
  41. 42 Pool CW, Madlener S, Diegenbach PC, Sluiter AA, van der Sluis PJ: Quantification of antiserum reactivity in immunocytochemistry. J Histochem Cytochem 1984;32:921-928.
  42. 43 Sterio DC: The unbiased estimation of number and size of arbitrary particles using the disector. J Microsc 1984;134:127–136.
  43. 44 Gundersen HJG, Jensen EB: The efficiency of sampling in stereology and its prediction. J Microsc 1987;147:229–263.
  44. 45 Gundersen HJG, Bagger P, Bendsten TF, Evans SM, Korbo L, Marcusen N, Møller A, Nielsen K, Nyengaard JR, Pakkenberg B, Sørenson FB, Vesterby A, West MJ: The new stereological tools: Disector, fractionator, nucleator and point-sampled intercepts and their use in pathological research and diagnosis. Acta Pathol Microbiol Immunol Scand 1988;96: 857-881.
  45. 46 Braendgaard H, Gundersen HJG: The impact of the recent stereological advances on quantitative studies of the nervous system. J Neurosci Meth 1986;18:39-78.
  46. 47 Pakkenberg B, Gundersen HJG: Total number of neurons and glial cells in human brain nuclei estimated by the disector and fractionator. J Microsc 1988;150:1–20.
  47. 48 Krahn DD, Gosnell BA, Levine AS, Morley JE: Behavioral effects of cortiotropin-releasing factor: Localization and characterization of central effects. Brain Res 1988;443:63–69.
  48. 49 Shibasaki T, Kim SK, Yamauchi N, Masuda A, Imaki T, Hotta M, Demura H, Wakabayashi I, Ling N, Shizume K: Antagonistic effect of somatostatin on corticotropin-releasing factor-induced anorexia in the rat. Life Sci 1988;42: 329-334.
  49. 50 Glowa JR, Gold PW: Corticotropin releasing hormone produces profound anorexigenic effects in the rhesus monkey. Neuropeptides 1991;18:55-61.
  50. 51 Sirinathsinghji DJS, Rees LH, Rivier J, Vale W: Corticotropin-releasing factor is a potent inhibitor of sexual receptivity in the female rat. Nature 1983;305:232-235.
  51. 52 Smith MA, Kling MA, Whitefield HJ, Brand HA, Demitrack MA, Geracioti TD, Chrousos GP, Gold PW: Corticotropin-releasing hormone: From endocrinology to psychobiology. Horm Res 1989;31:66–71.
  52. 53 Matsuzaki I, Takamatsu Y, Moroji T: The effects of intracerebroventricularly injected corticotropin-releasing factor (CRF) on the central nervous system: Behavioural and biochemical studies. Neuropeptides 1989;13:147– 155.
  53. 54 Sawchenko PE: Evidence for differential regulation of corticotropin-releasing factor and vasopressin immunoreactivities in parvocellular neurosecretory and autonomic related projections of the paraventricular nucleus. Brain Res 1987;437:253-263.
  54. 55 Delbende C, Contesse V, Mocaër E, Kamoun A, Vaudry H: The novel antidepressant, tianeptine, reduces stress-evoked stimulation of the hypothalamo-pituitary-adrenal axis. Eur J Pharmacol 1991;202:391-396.
  55. 57 Brady LS, Gold PW, Herkenham M, Lynn AB, Whitfield HJ JR: The antidepressants fluoxetine, idazoxan and phenylzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: Therapeutic implications. Brain Res 1992;572:117-125.
  56. 56 Reul MHM, Stec I, Söder M, Holsboer F: Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamo-pituitary-adrenocortical system. Endocrinology1993;133:312-320.
  57. 58 Brady LS, Whitfield HJ Jr, Fox RJ, Gold PW, Herkenham M: Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. J Clin Invest 1991;87:831-837.
  58. 59 Veith RC, Lewis N, Langohr JI, Murberg M, Ashleigh EA, Castillo S, Peskind ER, Pascualy M, Bissette G, Nemeroff CB, Raskind MA: Effect of desipramine on cerebrospinal fluid concentrations of corticotropin-releasing factor in human subjects. Psychiatry Res 1993;46:1– 6.
  59. 61 Whitnall MH, Smyth D, Gainer H: Vasopressin coexists in half of the corticotropin-releasing factor axons present in the external zone of the median eminence in normal rats. Neuroendocrinology 1987;45:420–424.
  60. 60 Whitnall MH, Key S, Gainer H: Vasopressincontaining and vasopressin deficient subpopulations of corticotropin-releasing factor axons are differentially affected by adrenalectomy. Endocrinology 1987;120:2180-2182.
  61. 62 Whitnall MH: Distributions of pro-vasopressin expressing and pro-vasopressin deficient CRH neurons in the paraventricular hypothalamic nucleus of colchicine treated normal and adrenalectomized rats. J Comp Neurol 1988;275: 13-28.
  62. 63 Whitnall MH: Subpopulations of corticotropin-releasing hormone neurosecretory cells distinguished by the presence or absence of vasopressin: confirmation with multiple corticotropin-releasing hormone antisera. Neuroscience 1990;36:201-205.
  63. 64 Von Bardeleben U, Holsboer F: Cortisol response to a combined dexamethasone-human corticotrophin-releasing hormone challenge in patients with depression. J Neuroendocrinol 1989;1:485-488.
  64. 65Sapolsky RM, Krey LC, McEwen BS: The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis. Endocr Rev 1986;7:284-301.
  65. 66 Herman JP, Schäfer MKH, Young EA, Thompson R, Douglass J, Akil H, Watson SJ: Evidence for hippocampal regulation of neuroendocrine neurons of the hypothalamo-pituitary-adrenocortical axis. J Neurosci 1989;9: 3072-3082.
  66. 67 De Leon MJ, McRae T, Tsai JR, George AE, Marcus DL, Freedman M, Wolf AP, McEwen B: Abnormal cortisol response in Alzheimer's disease linked to hippocampal atrophy. Lancet 1988;13:391-392.
  67. 68 Gurevich D, Siegel B, Dumlao M, Perl E, Chaitin P, Bagne C, Oxenkrug G: HPA axis responsivity to dexamethasone and cognitive impairment in dementia. Prog Neuro-Psychopharmacol Biol Psychiatry1990;14:297–308.

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Authors
Raadsheer, F. C., Hoogendijk, W. J. G., Stam, F. C., Tilders, F. J. H., & Swaab, D. F.
Affiliations
  • Netherlands Brain Bank (NL)
  • Vrije Universiteit Amsterdam (NL)
ORCID
Venue
Neuroendocrinology
Publisher
S. Karger AG
Published
2008-04-09
Volume
60
Issue
4
Pages
436-444
ISSN
  • 0028-3835 (ISSN-L)
  • 1423-0194
DOI
10.1159/000126778
OpenAlex
W1973994559
Cited by
667
References
0
Citations by year
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FWCI
18.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuroendocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
Keywords
corticotropin-releasing factor, hypothalamic paraventricular nucleus, depression, major depressive disorder, bipolar disorder, hypothalamic-pituitary-adrenal axis, vasopressin, neuroendocrine activity
MeSH terms
Adult, Aged, Aged, 80 and over, Arginine Vasopressin, Bipolar Disorder, Corticotropin-Releasing Hormone, Depressive Disorder, Female, Humans, Immunohistochemistry, Male, Middle Aged, Neurons, Paraventricular Hypothalamic Nucleus

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