Evidence for structural abnormalities of the human habenular complex in affective disorders but not in schizophrenia
ABSTRACT 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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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.Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2014; 55. DOI:10.1016/j.pnpbp.2014.03.003 · 4.03 Impact Factor
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ABSTRACT: Substance P (SP) levels are closely related with the pathogenesis of depression. Recent work has focused on the antidepressive effect of substance P receptor antagonist (SPA), however, its action site and mechanism remain largely unresolved. Our previous results showed that the lateral habenula (LHb) plays a key role in the pathogenesis of depression. The current study investigates the effects of SPA microinjected into the LHb on the behavioral responses of two types of rats that exhibit depression-like behavior. To produce adult rats that exhibit depression-like behavior, rats were either exposed to chronic mild stress (CMS), or clomipramine (CLI), a tricyclic antidepressant, was chronically administered to the rats during the neonatal state of life. The forced-swimming test (FST) was used to evaluate the behavioral responses of the rats. Furthermore, we measured serotonin (5-HT) levels in the dorsal raphe nucleus (DRN) using microdialysis. The FST showed that the immobility time decreased and the climbing time increased after SPA injection into the LHb of depression-like behavior rats. In addition, the 5-HT levels in the DRN increased after SPA was microinjected into the LHb of rats that exhibited depression-like behavior. This study demonstrates that the LHb mediates the antidepressive effect of SPA by increasing the 5-HT levels in the DRN, suggesting that the LHb may be a potential target of antidepressant.Brain research bulletin 10/2013; DOI:10.1016/j.brainresbull.2013.10.007 · 2.97 Impact Factor
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ABSTRACT: The habenular complex linking forebrain and midbrain structures is subdivided into the medial (mHb) and the lateral nuclei (lHb). The mHb is characterized by the expression of specific nicotinic acetylcholine receptor isoforms and the release of acetylcholine to the interpeduncular nucleus (IPN), the sole output region of the mHb. The specific function of this circuit, however, is poorly understood. Here we generated transgenic mice in which mHb cells were selectively ablated postnatally. These lesions led to large reductions in acetylcholine levels within the IPN. The mutant mice exhibited abnormalities in a wide range of behavioral domains. They tended to be hyperactive during the early night period and were maladapted when repeatedly exposed to new environments. Mutant mice also showed a high rate of premature responses in the 5-choice serial reaction time task (5-CSRTT), indicating impulsive and compulsive behavior. Additionally, mice also exhibited delay and effort aversion in a decision-making test, deficits in spatial memory, a subtle increase in anxiety levels, and attenuated sensorimotor gating. IntelliCage studies under social housing conditions confirmed hyperactivity, environmental maladaptation, and impulsive/compulsive behavior, delay discounting, deficits in long-term spatial memory, and reduced flexibility in complex learning paradigms. In 5-CSRTT and adaptation tasks, systemic administration of nicotine slowed down nose-poke reaction and enhanced adaptation in control but not mutant mice. These findings demonstrate that the mHb-IPN pathway plays a crucial role in inhibitory control and cognition-dependent executive functions.Frontiers in Behavioral Neuroscience 03/2013; 7:17. DOI:10.3389/fnbeh.2013.00017 · 4.16 Impact Factor