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Evidence for structural abnormalities of the human habenular complex in affective disorders but not in schizophrenia

Published online by Cambridge University Press:  12 August 2009

K. Ranft ,
H. Dobrowolny ,
D. Krell ,
H. Bielau ,
B. Bogerts  and
H.-G. Bernstein
K. Ranft
Affiliation:
Department of Psychiatry, University of Magdeburg, Magdeburg, Germany Department of Neurology, University of Magdeburg, Magdeburg, Germany
H. Dobrowolny
Affiliation:
Department of Psychiatry, University of Magdeburg, Magdeburg, Germany
D. Krell
Affiliation:
Department of Psychiatry, University of Magdeburg, Magdeburg, Germany
H. Bielau
Affiliation:
Walter-Friedrich-Krankenhaus Olvenstedt, Magdeburg, Germany
B. Bogerts
Affiliation:
Department of Psychiatry, University of Magdeburg, Magdeburg, Germany
H.-G. Bernstein*
Affiliation:
Department of Psychiatry, University of Magdeburg, Magdeburg, Germany
*
*Address for correspondence: Prof. Dr H.-G. Bernstein, Department of Psychiatry, University of Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany. (Email: [email protected])
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Abstract

Background

The habenular complex is composed of important relay nuclei linking the limbic forebrain to the midbrain and brain stem nuclei. Based on clinical observations, experiments with animals and theoretical considerations, it has been speculated that this brain area might be involved in psychiatric diseases (i.e. schizophrenia and depression). However, evidence in favour of this hypothesis is still lacking because the human habenular complex has rarely been studied with regard to mental illness.

Method

We examined habenular volumes in post-mortem brains of 17 schizophrenia patients, 14 patients with depression (six patients with major depression and eight patients with bipolar depression) and 13 matched controls. We further determined the neuronal density, cell number and cell area of the medial habenular nuclei of the same cohorts using a counting box and a computer-assisted instrument.

Results

Significantly reduced habenular volumes of the medial and lateral habenula were estimated in depressive patients in comparison to normal controls and schizophrenia patients. We also found a reduction in neuronal cell number and cell area in depressive patients for the right side compared to controls and schizophrenia patients. No such changes were seen in schizophrenia.

Conclusions

Our anatomical data argue against prominent structural alterations of the habenular nuclei in schizophrenia but demonstrate robust alterations in depressive patients. We are currently applying immunohistochemical markers to better characterize neuronal subpopulations of this brain region in schizophrenia and depression.

Keywords

Affective disorderhabenulahuman brainmorphometryneuronal densityschizophrenia
Type
Original Articles
Information
Psychological Medicine , Volume 40 , Issue 4 , April 2010 , pp. 557 - 567
Copyright
Copyright © Cambridge University Press 2009

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References

Akagi, K, Powell, EW (1968). Differential projections of habenular nuclei. Journal of Comparative Neurology 132, 263–274.CrossRefGoogle ScholarPubMed
Amat, J, Sparks, PD, Matus-Amat, P, Griggs, J, Watkins, LR, Maier, SF (2001). The role of the habenular complex in the elevation of dorsal raphe nucleus serotonin and the changes in the behavioral responses produced by uncontrollable stress. Brain Research 917, 118–126.CrossRefGoogle ScholarPubMed
APA (1987). Diagnostic and Statistical Manual of Mental Disorders, 3rd edn, revised. American Psychiatric Association: Washington, DC.Google Scholar
Andres, KH, von During, M, Veh, RW (1992). Habenula and thalamus cell transplants restore normal sleep behaviors disrupted by denervation of the interpeduncular nucleus. Journal of Neuroscience 12, 3282–3290.Google Scholar
Andres, KH, von During, M, Veh, RW (1999). Subnuclear organization of the rat habenular complexes. Journal of Comparative Neurology 407, 130–150.3.0.CO;2-8>CrossRefGoogle ScholarPubMed
Benabid, AL, Jeaugey, L (1989). Cells of the rat lateral habenula respond to high-threshold somatosensory inputs. Neuroscience Letters 96, 289–294.CrossRefGoogle ScholarPubMed
Bernstein, H-G, Baumann, B, Danos, P, Dieckmann, S, Bogerts, B, Gundelfinger, ED, Braunewell, KH (1999). Regional and cellular distribution of neural visinin-like protein immunoreactivities (VILIP-1 and VILIP-3) in human brain. Journal of Neurocytology 28, 655–662.CrossRefGoogle ScholarPubMed
Bernstein, H-G, Stanarius, A, Baumann, B, Henning, H, Krell, D, Danos, P, Falkai, P, Bogerts, B (1998). Nitric oxide synthase-containing neurons in the human hypothalamus: reduced number of immunoreactive cells in the paraventricular nucleus of depressive patients and schizophrenics. Neuroscience 83, 867–875.CrossRefGoogle ScholarPubMed
Bielau, H, Mawrin, C, Krell, D, Agelink, MW, Trübner, K, Davis, R, Gos, T, Bogerts, B, Bernstein, H-G, Baumann, B (2005). Differences in activation of the dorsal raphe nucleus depending on performance of suicide. Brain Research 1039, 43–52.CrossRefGoogle Scholar
Bogerts, B, Falkai, P, Haupts, M, Greve, B, Ernst, S, Tapernon-Franz, U, Heinzmann, U (1990). Post-mortem volume measurements of limbic system and basal ganglia structures in chronic schizophrenics. Initial results from a new brain collection. Schizophrenia Research 3, 295–301.CrossRefGoogle ScholarPubMed
Caldecott-Hazard, S, Mazziotta, J, Phelps, M (1988). Cerebral correlates of depressed behavior in rats, visualized using 14C-2-deoxyglucose autoradiography. Journal of Neuroscience 8, 1951–1961.CrossRefGoogle ScholarPubMed
Campbell, S, MacQueen, G (2004). The role of the hippocampus in the pathophysiology of major depression. Journal of Psychiatry and Neuroscience 29, 417–426.Google ScholarPubMed
Carlson, J, Armstrong, B, Switzer, RC 3rd, Ellison, G (2000). Selective neurotoxic effects of nicotine on axons in fasciculus retroflexus further support evidence that this a weak link in brain across multiple drugs of abuse. Neuropharmacology 39, 2792–2798.CrossRefGoogle Scholar
Carlson, J, Noguchi, K, Ellison, G (2001). Nicotine produces selective degeneration in the medial habenula and fasciculus retroflexus. Brain Research 906, 127–134.CrossRefGoogle ScholarPubMed
Chastrette, N, Pfaff, DW, Gibbs, RB (1991). Effects of daytime and nighttime stress on Fos-like immunoreactivity in the paraventricular nucleus of the hypothalamus, the habenula, and the posterior paraventricular nucleus of the thalamus. Brain Research 563, 339–344.Google ScholarPubMed
Christoph, GR, Leonzio, RJ, Wilcox, KS (1986). Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmental area of the rat. Journal of Neuroscience 6, 613–619.CrossRefGoogle ScholarPubMed
Contestabile, A, Fonnum, F (1983). Cholinergic and GABAergic forebrain projections to the habenula and nucleus interpeduncularis: surgical and kainic acid lesions. Brain Research 275, 287–297.CrossRefGoogle Scholar
Corodimas, KP, Rosenblatt, JS, Canfield, ME, Morrell, JI (1993). Neurons in the lateral subdivision of the habenular complex mediate the hormonal onset of maternal behavior in rats. Behavioral Neuroscience 107, 827–843.CrossRefGoogle ScholarPubMed
Deutsch, CK, Hobbs, K, Price, SF, Gordon-Vaugh, K (2000). Skewing of the brain midline in schizophrenia. Neuroreport 11, 3985–3988.CrossRefGoogle ScholarPubMed
Dietrich, DE, Bonnenmann, C, Emrich, HM (2007). Cortico-limbic mechanisms of affect regulation in the therapy of depression [in German]. Psychiatrische Praxis 34 (Suppl. 3), 287–291.Google ScholarPubMed
Dorph-Petersen, KA, Pierri, JN, Perel, JM, Sun, Z, Sampson, AR, Lewis, DA (2005). The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and clozapine in macaque monkeys. Neuropsychopharmacology 30, 1649–1661.CrossRefGoogle Scholar
Ellison, G (1994). Stimulant-induced psychosis, the dopamine theory of schizophrenia, and the habenula. Brain Research. Brain Research Reviews 19, 223–239.CrossRefGoogle Scholar
Ellison, G (2002). Neural degeneration following chronic stimulant abuse reveals a weak link in brain, fasciculus retroflexus, implying the loss of forebrain control circuitry. European Neuropsychopharmacology 12, 287–297.CrossRefGoogle ScholarPubMed
Falkai, P, Bogerts, B, Rozumek, M (1988). Limbic pathology in schizophrenia: the entorhinal region – a morphometric study. Biological Psychiatry 24, 515–521.CrossRefGoogle ScholarPubMed
Gallager, DW (1976). Benzodiazepines: potentiation of GABA inhibitor response in the dorsal raphe nucleus. European Journal of Pharmacology 49, 133–143.CrossRefGoogle Scholar
Geisler, S, Andres, KH, Veh, RH (2003). Morphological and cytochemical criteria for the identification and delineation of individual subnuclei within the lateral habenular complex of the rat. Journal of Comparative Neurology 458, 78–97.CrossRefGoogle ScholarPubMed
Geisler, S, Trimble, M (2008). The lateral habenula: no longer neglected. CNS Spectrums 13, 484–489.CrossRefGoogle ScholarPubMed
Goldstein, R (1985). Vasotocin-like activity of cerebrospinal fluid induced by habenular lesions in cats. Neuropeptides 6, 303–310.CrossRefGoogle ScholarPubMed
Gonzalez-Lima, F, Scheich, H (1986). Classical conditioning of tone-signaled bradycardia modifies 2-deoxyglucose uptake patterns in cortex, thalamus, habenula, caudate-putamen and hippocampal formation. Brain Research 363, 339–356.CrossRefGoogle ScholarPubMed
Gottesfeld, Z, Massari, VJ, Muth, EA, Jacobowitz, DM (1977). Stria medullaris: a possible pathway containing GABAergic afferents to the lateral habenula. Brain Research 130, 184–189.CrossRefGoogle ScholarPubMed
Haun, F, Eckenrode, TC, Murray, M (1992). Habenula and thalamus cell transplants restore normal sleep behaviors disrupted by denervation of the interpeduncular nucleus. Journal of Neuroscience 12, 3282–3290.CrossRefGoogle ScholarPubMed
Hauptman, JS, DeSalles, AAF, Espinoza, R, Sedrak, M, Ishida, W (2008). Potential surgical targets for deep brain stimulation in treatment-resistant depression. Neurosurgical Focus 25, E3.CrossRefGoogle ScholarPubMed
Herkenham, M, Nauta, WJ (1977). Afferent connections of the habenular nuclei in the rat. A horseradish peroxidase study, with a note on the fiber-of-passage problem. Journal of Comparative Neurology 173, 123–146.CrossRefGoogle Scholar
Herkenham, M, Nauta, WJ (1979). Efferent connections of the habenular nuclei in the rat. Journal of Comparative Neurology 187, 19–47.CrossRefGoogle ScholarPubMed
Hikosaka, O, Sesack, SR, Lecourtier, L, Shepard, PD (2008). Habenula: crossroad between the basal ganglia and the limbic system. Journal of Neuroscience 28, 11825–11829.CrossRefGoogle ScholarPubMed
Kelly, PH (1998). Defective inhibition of dream event memory formation: a hypothesized mechanism in the onset and progression of symptoms of schizophrenia. Brain Research Bulletin 46, 189–197.CrossRefGoogle ScholarPubMed
Kiss, J, Csaki, A, Bokor, H, Kocsis, K, Kocsis, B (2002). Possible glutamatergic/aspartatergic projections to the supramammillary nucleus and their origins in the rat studied by selective [(3)H]D-aspartate labelling and immunocytochemistry. Neuroscience 111, 671–691.CrossRefGoogle Scholar
Klemm, WR (2004). Habenular and interpeduncularis nuclei: shared components in multiple-function networks. Medical Science Monitor 10, RA261–RA273.Google ScholarPubMed
Lecourtier, L, Neijt, HC, Kelly, PH (2004). Habenula lesions cause impaired cognitive performance in rats: implications for schizophrenia. European Journal of Neuroscience 19, 2551–2560.CrossRefGoogle ScholarPubMed
Lecourtier, L, Saboureau, M, Kelly, CD, Pevet, P, Kelly, PH (2005). Impaired cognitive performance in rats after complete epithalamus lesions, but not after pinealectomy alone. Behavioural Brain Research 161, 276–285.CrossRefGoogle Scholar
Lieberman, JA, Tollefson, GD, Charles, C, Zipursky, R, Sharma, T, Kahn, RS, Keefe, RS, Green, AI, Gur, RE, McEvoy, J, Perkins, D, Hamer, RM, Gu, H, Tohen, M; HGDH Study Group (2005). Antipsychotic drug effects on brain morphology in first-episode psychosis. Archives of General Psychiatry 62, 361–370.CrossRefGoogle ScholarPubMed
Lisoprawski, A, Herve, D, Blanc, G, Glowinski, J, Tassin, JP (1980). Selective activation of the mesocortico-frontal dopaminergic neurons induced by lesion of the habenula in the rat. Brain Research 183, 229–234.CrossRefGoogle ScholarPubMed
London, ED, Waller, SB, Wamsley, JK (1985). Autoradiographic localization of [3H]nicotine binding sites in the rat brain. Neuroscience Letters 53, 179–184.CrossRefGoogle ScholarPubMed
Lucas, LR, Hurley, DL, Krause, JE, Harlan, RE (1992). Localization of the tachykinin neurokinin B precursor peptide in rat brain by immunocytochemistry and in situ hybridization. Neuroscience 51, 317–345.CrossRefGoogle ScholarPubMed
Mahieux, G, Benabid, AL (1987). Naloxone-reversible analgesia induced by electrical stimulation of the habenula in the rat. Brain Research 406, 118–129.CrossRefGoogle ScholarPubMed
Marburg, O (1944). The structure and fiber connections of the human habenula. Journal of Comparative Neurology 80, 211–233.CrossRefGoogle Scholar
Matthews-Felton, T, Corodimas, KP, Rosenblatt, JS, Morrell, JI (1995). Lateral habenula neurons are necessary for the hormonal onset of maternal behavior and for the display of postpartum estrus in naturally parturient female rats. Behavioral Neuroscience 109, 1172–1188.CrossRefGoogle ScholarPubMed
Mayhew, MH (1992). A review of recent advances in stereology for quantifying neural structure. Journal of Neurocytology 21, 313–328.CrossRefGoogle ScholarPubMed
McCulloch, J, Savaki, HE, Sokoloff, L (1980). Influence of dopaminergic systems on the lateral habenular nucleus of the rat. Brain Research 194, 117–124.CrossRefGoogle ScholarPubMed
Möller, HJ (2003). Bipolar disorder and schizophrenia: distinct illnesses or a continuum? Journal of Clinical Psychiatry 64, 23–27.Google ScholarPubMed
Mori, I, Diehl, AD, Chauhan, A, Ljunggren, HG, Kristensson, K (1999). Selective targeting of habenular, thalamic midline and monoaminergic brainstem neurons by neurotropic influenza A virus in mice. Journal of Neurovirology 5, 355–362.CrossRefGoogle ScholarPubMed
Morris, JS, Smith, KA, Cowen, PJ, Friston, KJ, Dolan, RJ (1999). Covariation of activity in habenula and dorsal raphe nuclei following tryptophan depletion. Neuroimage 10, 163–172.CrossRefGoogle ScholarPubMed
Murphy, CA, DiCamillo, AM, Haun, F, Murray, M (1996). Lesion of the habenular efferent pathway produces anxiety and locomotor hyperactivity in rats: a comparison of the effects of neonatal and adult lesions. Behavioural Brain Research 81, 43–52.CrossRefGoogle ScholarPubMed
Nauta, HJ (1974). Evidence of a pallidohabenular pathway in the cat. Journal of Comparative Neurology 156, 19–27.CrossRefGoogle ScholarPubMed
Nauta, WJ (1958). Hippocampal projections and related pathways to the midbrain in the cat. Brain 81, 319–340.CrossRefGoogle Scholar
Pankratov, Y, Lalo, U, Verkhratsky, A, Nort, RA (2006). Vesicular release of ATP at central synapses. Pflügers Archives of Physiology 452, 589–597.CrossRefGoogle ScholarPubMed
Ramon y Cajal, S (1911). Histologie du Systeme Nerveux de l'Homme et des Vertebres, Tome II. Instituto Ramon y Cajal: Madrid.Google Scholar
Reisine, TD, Soubrie, P, Artaud, F, Glowinski, J (1982). Involvement of lateral habenula-dorsal raphe neurons in the differential regulation of striatal and nigral serotonergic transmission cats. Journal of Neuroscience 2, 1062–1071.CrossRefGoogle ScholarPubMed
Ronnekleiv, OK (1988). Distribution in the macaque pineal organ of nerve fibers containing immunoreactive substance P, vasopressin, oxytocin, and neurophysins. Journal of Pineal Research 5, 259–271.CrossRefGoogle ScholarPubMed
Ronnekleiv, OK, Kelly, MJ, Wuttke, W (1980). Single unit recordings in the rat pineal gland: evidence for habenulo-pineal neural connections. Experimental Brain Research 39, 187–192.CrossRefGoogle ScholarPubMed
Sandyk, R (1992). Pineal and habenula calcification in schizophrenia. International Journal of Neuroscience 67, 19–30.CrossRefGoogle ScholarPubMed
Sartorius, A, Henn, FA (2007). Deep brain stimulation of the lateral habenula in treatment resistant major depression. Medical Hypotheses 69, 1305–1308.CrossRefGoogle ScholarPubMed
Scheibel, AB (1997). The thalamus and neuropsychiatric illness. Journal of Neuropsychiatry and Clinical Neuroscience 9, 342–353.Google ScholarPubMed
Schmitt, A, Steyskal, S, Bernstein, H-G, Schneider-Axmann, T, Parlapani, E, Schaeffer, EL, Gattaz, WF, Bogerts, B, Schmitz, C, Falkai, P (2009). Stereologic investigation of the posterior part of the hippocampus in schizophrenia. Acta Neuropathologica 117, 395–407.CrossRefGoogle ScholarPubMed
Shepard, PD, Holcomb, HH, Gold, JM (2006). Schizophrenia in translation: the presence of the absence: habenular regulation of dopamine neurons and the encoding of negative outcomes. Schizophrenia Bulletin 32, 417–412.CrossRefGoogle ScholarPubMed
Shumake, J, Edwards, E, Gonzalez-Lima, F (2003). Opposite metabolic changes in the habenula and ventral tegmental area of a genetic model of helpless behavior. Brain Research 96, 274–281.CrossRefGoogle Scholar
Shumake, J, Conejo-Jimenez, N, Gonzalez-Pardo, H, Gonzalez-Lima, F (2004). Brain differences in newborn rats predisposed to helpless and depressive behavior. Brain Research 1030, 267–276.CrossRefGoogle ScholarPubMed
Spitzer, RL, Endicott, J (1978). Schedule for Affective Disorders and Schizophrenia – Lifetime Version, 3rd edn. New York State Psychiatric Institute, Biometrics Research Division: New York.Google Scholar
Sutherland, RJ (1982). The dorsal diencephalic conduction system: a review of the anatomy and functions of the habenular complex. Neuroscience and Biobehavioral Reviews 6, 1–13.CrossRefGoogle ScholarPubMed
Sutherland, RJ, Nakajima, S (1981). Self-stimulation of the habenular complex in the rat. Journal of Comparative and Physiological Psychology 95, 781–791.CrossRefGoogle ScholarPubMed
Thornton, EW, Evans, JA, Harris, C (1985). Attenuated response to nomifensine in rats during a swim test following lesion of the habenula complex. Psychopharmacology 187, 81–85.CrossRefGoogle Scholar
Thornton, EW, Bradbury, GE (1989). Effort and stress influence the effect of lesion of the habenula complex in one-way active avoidance learning. Physiology and Behavior 45, 929–935.CrossRefGoogle ScholarPubMed
Ullsperger, M, von Cramon, DY (2003). Error monitoring using external feedback: specific roles of the habenular complex, the reward system, and the cingulate motor area revealed by functional magnetic resonance imaging. Journal of Neuroscience 23, 4308–4314.CrossRefGoogle ScholarPubMed
Vale-Martinez, A, Marti-Nicolovius, M, Guillazo-Blanch, G, Coll-Andreu, M, Morgado-Bernal, I (1997). Effects of habenular lesions upon two-way active avoidance conditioning in rats. Neurobiology of Learning and Memory 68, 68–74.CrossRefGoogle ScholarPubMed
Valjakka, A, Vartiainen, J, Tuomisto, L, Tuomisto, JT, Olkkonen, H, Airaksinen, MM (1998). The fasciculus retroflexus controls the integrity of REM sleep by supporting the generation of hippocampal theta rhythm and rapid eye movements in rats. Brain Research Bulletin 47, 171–184.CrossRefGoogle ScholarPubMed
Wang, RY, Aghajanian, GK (1977). Physiological evidence for habenula as major link between forebrain and midbrain raphe. Science 197, 89–91.CrossRefGoogle ScholarPubMed
White, T, Cullen, K, Rohrer, LM, Karatekin, C, Luciana, M, Schmidt, M, Hongwanishkul, D, Kumra, S, Schulz, SC, Lim, KO (2008). Three limbic structures and networks in children and adolescents with schizophrenia. Schizophrenia Bulletin 34, 18–29.CrossRefGoogle Scholar
Wilcox, KS, Christoph, GR, Double, BA, Leonzio, RJ (1986). Kainate and electrolytic lesions of the lateral habenula: effect on avoidance responses. Physiology and Behavior 136, 413–417.CrossRefGoogle Scholar
Wooten, GF, Collins, RC (1981). Metabolic effects of unilateral lesion of the substantia nigra. Journal of Neuroscience 1, 285–291.CrossRefGoogle ScholarPubMed
Yang, LM, Hu, B, Xia, YH, Zhang, BL, Zhao, H (2008). Lateral habenula lesions improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus. Behavioural Brain Research 188, 84–90.CrossRefGoogle ScholarPubMed
Young, KA, Bonkale, WL, Holcomb, LA, Hicks, PB, German, DC (2008). Major depression, 5HTTLPR genotype, suicide and antidepressant influences on thalamic volume. British Journal of Psychiatry 192, 285–292.CrossRefGoogle ScholarPubMed
Zech, M, Roberts, GW, Bogerts, B, Crow, TJ, Polak, JM (1986). Neuropeptides in the amygdala of controls, schizophrenics and patients suffering from Huntington's chorea: an immunohistochemical study. Acta Neuropathologica 71, 259–266.CrossRefGoogle ScholarPubMed