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

Department of Psychiatry, University of Magdeburg, D-39120 Magdeburg, Germany.
Psychological Medicine (Impact Factor: 5.94). 09/2009; 40(4):557-67. DOI: 10.1017/S0033291709990821
Source: PubMed


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.
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.
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.
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.

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    • "From a structural point of view, decreased habenular volume and neuronal loss, at the expense of neuronal bodies and fibres, have been found in a mixed postmortem sample of patients with unipolar and bipolar depression (Ranft et al., 2010). Only one in vivo MRI study of Hb volume has been published to date but it did not replicate all these findings (Savitz et al., 2011). "
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    ABSTRACT: The habenula (Hb) can play an important role in major depressive disorder (MDD) as it is a key node between fronto-limbic areas and midbrain monoaminergic structures. In vivo neuroimaging studies have shown reductions in Hb volume in a post-mortem sample of patients with affective disorders but findings in unipolar MDD are not consistent. The current study aimed to investigate whether the Hb volume differed between patients with different stages of unipolar MDD and healthy subjects. We also explored differences in grey (GM) and white matter (WM) volumes and potential age and gender effects. High-resolution images were acquired using a 3T-scanner from 95 participants (21 with first-episode MDD; 20 with remitted-recurrent MDD; 20 with treatment-resistant/chronic MDD; and 34 healthy controls).Two researchers blinded to clinical data manually delineated habenular nuclei, with excellent inter-rater agreement. Multivariate analysis of covariance revealed a significant group-by-gender interaction (F9,258=2.22; p=0.02). Univariate effects emerged for Hb-WM volumes (F3,86=3.12; p=0.03) but not for total Hb volumes (F3,86=0.59; p=0.62) or Hb-GM volumes (F3,86=2.01; p=0.12). Women with a first-episode MDD had greater Hb-WM volumes than healthy controls and patients with treatment-resistant/chronic MDD (p<0.01). These findings remained unaltered when controlled for total intracranial volume or medication load. Our results do not support decreased total Hb volumes in unipolar MDD, in patients with first-episode or in patients with long-lasting recurrent or chronic depression. However, the increased Hb-WM volume we observed in women with a first-episode suggests involvement of Hb and its projections in early stages of the recovery process and in the course of MDD.
    No preview · Article · Sep 2015 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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    • "The enhanced cell proliferation and increased numbers of nestin+ NPCs in the hypothalamus and habenula in response to chronic FLX treatment represent a potential mechanism whereby FLX could modulate the activity of these structures, an effect that could have important implications for depressionand anxiety-like behaviors. Interestingly, patients with major depression and bipolar disorder have been reported to exhibit smaller habenula volumes than healthy controls (Ranft et al., 2010; Savitz, Nugent, et al., 2011), as well as smaller hypothalamic volumes and/or larger third ventricles (Schindler et al., 2012). In addition, dysregulation of the hypothalamic-pituitary-adrenal "
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    ABSTRACT: Chronic treatment with antidepressants has been shown to enhance neurogenesis in the adult mammalian brain. Although this effect was initially reported to be restricted to the hippocampus, recent work has suggested that fluoxetine, a selective serotonin reuptake inhibitor, also promotes neurogenesis in the cortex. However, whether antidepressants target neural progenitor cells in other brain regions has not been examined. Here, we used BrdU labeling and immunohistochemistry with a transgenic mouse line in which nestin+ neural progenitor cells can be inducibly labeled with the fluorescent protein, Tomato, following tamoxifen administration. We investigated the effects of chronic fluoxetine on cell proliferation and nestin+ progenitor cells in periventricular areas in the medial hypothalamus and medial habenula, two brain areas involved in stress and anxiety responses. Our data provide the first in vivo evidence that fluoxetine promotes cell proliferation and neurogenesis and increases the mRNA levels of BDNF in the hypothalamus and habenula. By identifying novel cellular targets of fluoxetine, our results may provide new insight into the mechanisms underlying antidepressant responses. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    Full-text · Article · Oct 2014 · The International Journal of Neuropsychopharmacology
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    • "GR knockout fish exhibit elevated stress-, anxiety-, and depression-like behavior (Griffiths et al. 2012) SNPs in the P2RX7 gene altered ATP mediated signaling in vitro (Roger et al. 2010) BDNF gene mutation induced manic-like behavior (Einat et al. 2003) Knockout of the neural activity-regulated petaxin gene resulted in freezing and anxiety-like behavior (Ranft et al. 2010; Okamoto et al. 2012a) Pharmacological Reserpine administration (Kyzar et al. 2013) "
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    ABSTRACT: Depression is a serious psychiatric condition affecting millions of patients worldwide. Unipolar depression is characterized by low mood, anhedonia, social withdrawal and other severely debilitating psychiatric symptoms. Bipolar disorder manifests in alternating depressed mood and 'hyperactive' manic/hypomanic states. Animal experimental models are an invaluable tool for research into the pathogenesis of bipolar/unipolar depression, and for the development of potential treatments. Due to their high throughput value, genetic tractability, low cost and quick reproductive cycle, zebrafish (Danio rerio) have emerged as a promising new model species for studying brain disorders. Here, we discuss the developing utility of zebrafish for studying depression disorders, and outline future areas of research in this field. We argue that zebrafish represent a useful model organism for studying depression and its behavioral, genetic and physiological mechanisms, as well as for anti-depressant drug discovery.
    Full-text · Article · Mar 2014 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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