RESUMEN
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.
Asunto(s)
Habénula/anomalías , Habénula/patología , Trastornos del Humor/patología , Trastornos del Humor/psicología , Esquizofrenia , Adulto , Anciano , Recuento de Células , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Humor/diagnóstico , Red Nerviosa/patología , Esquizofrenia/diagnóstico , Índice de Severidad de la EnfermedadRESUMEN
Depressive disorders belong to the most frequent diseases worldwide showing a lifetime prevalence of up to 20%. Moreover they are one of the leading causes for the amount of years lived with disability. Increasing knowledge about the pathological mechanisms underlying depressive syndromes is obtained by using modern neurobiological research-techniques. Thereby some older theories that have been the basis of emotion-research for decades--like the monoamine hypothesis--have been strengthened. In addition new aspects of the pathological processes underlying depressive disturbances have been unraveled. In this review established models and recent findings will be discussed, to bridge various research-fields, ranging from genetics, epigenetics and morphological changes to the functional consequences of depression. Finally therapeutic implications that could be derived from these results will be presented, showing up putative possibilities for diagnosis and treatment of depressive syndromes.
Asunto(s)
Trastorno Depresivo/fisiopatología , Encéfalo/patología , Encéfalo/fisiopatología , Trastorno Depresivo/genética , Trastorno Depresivo/patología , Trastorno Depresivo/psicología , Emociones/fisiología , Epigénesis Genética , Humanos , Sistema Hipotálamo-Hipofisario/patología , Sistema Hipotálamo-Hipofisario/fisiopatología , Neuronas/patología , Neuronas/fisiología , Sistema Hipófiso-Suprarrenal/patología , Sistema Hipófiso-Suprarrenal/fisiopatología , Factores de Riesgo , SíndromeRESUMEN
OBJECTIVE: To assess levels of glial fibrillar acidic protein (GFAP), myelin basic protein (MBP), neurone-specific enolase (NSE) and S100B in patients with first-onset schizophrenia. METHOD: We investigated CSF and serum samples from 12 patients with first-onset schizophrenia and from 17 control subjects by ELISA (GFAP, MBP) or immunoluminometric sandwich assays (NSE, S100B). RESULTS: Patients with schizophrenia had significantly higher levels of S100B in CSF (p = 0.004; 2.73 (SD 0.80) v 1.92 (0.58) microg/l) and serum (p = 0.032; 0.09 (0.03) v 0.08 (0.02) microg/l) in comparison with those in the matched control group. No diagnosis-dependent differences of protein concentration were seen for GFAP, MBP and NSE. DISCUSSION: Our finding of increased levels of S100B in patients with schizophrenia without an indication for significant glial (GFAP, MBP) or neuronal (NSE) damage may be interpreted as indirect evidence for increased active secretion of S100B during acute psychosis.
Asunto(s)
Factores de Crecimiento Nervioso/sangre , Factores de Crecimiento Nervioso/líquido cefalorraquídeo , Proteínas S100/sangre , Proteínas S100/líquido cefalorraquídeo , Esquizofrenia/fisiopatología , Adolescente , Adulto , Ensayo de Inmunoadsorción Enzimática , Femenino , Proteína Ácida Fibrilar de la Glía/sangre , Proteína Ácida Fibrilar de la Glía/líquido cefalorraquídeo , Humanos , Masculino , Proteína Básica de Mielina/sangre , Proteína Básica de Mielina/líquido cefalorraquídeo , Neuroglía/metabolismo , Neuronas/metabolismo , Fosfopiruvato Hidratasa/sangre , Fosfopiruvato Hidratasa/líquido cefalorraquídeo , Subunidad beta de la Proteína de Unión al Calcio S100RESUMEN
Depression is frequently associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which leads to repeated episodes of hypercortisolemia. Hypothalamic paraventricular neurons are believed to trigger these processes by aberrant generation and/or release of corticotropin releasing hormone, oxytocin, vasopressin, and nitric oxide (NO). Recent findings from two independent laboratories have demonstrated that the suprachiasmatic nucleus, which in part controls the cellular activity of paraventricular neurons (PVN), is also involved in affective disorder. The aim of the present study was to elucidate by stereological analysis, whether suprachiasmatic nucleus (SCN) nitric oxide synthase and neurophysin generating neurons are affected in neuropsychiatric disorders. We show that compared to controls the number of nitric oxide synthase immunoreactive neurons is greatly reduced both in depression and in schizophrenia. In subjects with affective disorder there was a correlation between the number of NOS-expressing cells and duration of treatment with antidepressants. The number of neurophysin-expressing SCN neurons was also fewer in cases with mood disorder. It is concluded that SCN-derived NO may be a relevant pathophysiological factor in neuropsychiatric disorders.
Asunto(s)
Hipotálamo/enzimología , Trastornos del Humor/enzimología , Neuronas/enzimología , Neurofisinas/metabolismo , Óxido Nítrico Sintasa/metabolismo , Núcleo Supraquiasmático/enzimología , Adulto , Depresión/enzimología , Depresión/metabolismo , Depresión/patología , Femenino , Humanos , Sistema Hipotálamo-Hipofisario/patología , Sistema Hipotálamo-Hipofisario/fisiopatología , Hipotálamo/metabolismo , Hipotálamo/patología , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Trastornos del Humor/metabolismo , Trastornos del Humor/patología , Neuronas/metabolismo , Neuronas/patología , Óxido Nítrico Sintasa/biosíntesis , Esquizofrenia/enzimología , Esquizofrenia/metabolismo , Esquizofrenia/patología , Núcleo Supraquiasmático/química , Núcleo Supraquiasmático/metabolismo , Núcleo Supraquiasmático/fisiopatologíaRESUMEN
BACKGROUND: Since long-term treatment is a need in many patients with mood disorders, knowledge on mechanisms of action in the prevention of recurrence is of major relevance. METHODS: Follow-up studies, which are best suited to prove the linkage of causal factors and mechanisms with the clinical course of the disorders, are rare. Another approach to search for preventive mechanisms is to address actions of pharmacological agents, which are effective in prophylactic treatment of mood disorders. Studies over the past several years have indicated that intracellular signaling cascades mediate long-term pharmacological effects via modulation of transcription factors and gene expression of neurotrophic and neuroprotective factors which may interfere with recurrence of affective illness. RESULTS: The impact of treatment on stress responsive systems varies with different therapeutic strategies and the relevance of a treatment-related modification of stress reliability for the course of the disease is not clear. Functional and structural actions of mood stabilizers and of antidepressants on mood-relevant anatomical circuits and modulation of chronobiological alterations also appear to be involved in preventive mechanisms in mood disorders. Moreover, cognitive mediators of prophylactic effects have been described. CONCLUSION: Combined clinical and biological studies should assess the relevance of those modes of action for the long-term course of mood disorders.
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Antidepresivos/uso terapéutico , Trastornos del Humor/prevención & control , Encéfalo/citología , Ritmo Circadiano/fisiología , Cognición/fisiología , Estudios de Seguimiento , Humanos , Modelos Biológicos , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiopatología , Neuronas/metabolismo , Prevención Secundaria , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Medio SocialRESUMEN
The neurobiology of bipolar affective illness can be described in a model with structural and functional components, which also address the role of stressors, coping mechanisms, and psychophysical disposition. More data exist on depressive than on manic patients or on patients switching from one clinical pole to the other. Structural and functional chronobiological alterations appear to play a major role in the pathophysiology of bipolar illness. From an anatomical view, neurobiological abnormalities are primarily confined to limbic-striatal-pallidal-thalamocortical circuits. The whole cascade of neural signaling is changed starting from neurotransmitters and neuromodulators to receptor-mediated intracellular signal transduction targeting nuclear gene expression. Transnosological factors such as suicidal tendency appear to essentially modulate those changes. Replicated data on decisive neurobiological differences between bipolar and unipolar affective disorders are currently not yet available.
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Trastorno Bipolar/fisiopatología , Trastorno Bipolar/genética , Trastorno Bipolar/psicología , Encéfalo/fisiopatología , Predisposición Genética a la Enfermedad/genética , Humanos , Red Nerviosa/fisiopatología , Plasticidad Neuronal/fisiología , Neurotransmisores/fisiología , Factores de Riesgo , Transducción de Señal/fisiología , Estrés Psicológico/complicacionesRESUMEN
The cellular expression of nitric oxide synthase (NOS) was studied in neurons of the Nuc. suprachiasmaticus (SCN) of depressed patients and matched controls. The number of NOS-immunoreactive SCN neurons was significantly reduced in depression. We conclude that affective disorders are accompanied by impaired hypothalamic NO signaling.
Asunto(s)
Trastorno Depresivo/fisiopatología , Hipotálamo/enzimología , Óxido Nítrico Sintasa/genética , Óxido Nítrico/fisiología , Transducción de Señal/fisiología , Núcleo Supraquiasmático/enzimología , Trastorno Depresivo/genética , Trastorno Depresivo/patología , Regulación Enzimológica de la Expresión Génica , Humanos , Hipotálamo/patología , Inmunohistoquímica , Óxido Nítrico Sintasa/análisis , Óxido Nítrico Sintasa de Tipo I , Valores de Referencia , Núcleo Supraquiasmático/patologíaRESUMEN
BACKGROUND: Neurocircuits comprising limbic, striato-pallidal and thalamo cortical brain areas are assumed to be involved in the pathophysiology of mood disorders. All these brain regions receive serotonergic afferents arising from the rostral raphe, mainly the dorsal raphe. Although serotonergic systems appear to be involved in the pathology of mood disorders, there is uncertainty as to whether structural alterations in raphe nuclei exist alongside a functional dysregulation of the serotonergic system. METHODS: In the brains of 12 patients with mood disorders (major depressive disorder N= 6, bipolar disorder N = 6) and 12 normal subjects we performed a morphometric post-mortem study on neuronal morphology in all subnuclei of the dorsal raphe nucleus using Nissl stained 20 microm axial serial sections of the brainstem. RESULTS: The number of neurones of the ventrolateral subnucleus of the dorsal raphe was reduced by 31 % in patients with mood disorders compared with non-psychiatric control subjects. Ventrally located subnuclei of the rostral dorsal raphe (ventrolateral, ventral, interfascicular) taken together also showed a smaller number of neurones. Neurone numbers of the dorsal and the caudal subnucleus and volumes of all single subnuclei appeared to be unchanged. Analysis of morphological neuronal types revealed a smaller number of triangular neurones in the ventrolateral subnucleus. Numbers of ovoid and round neurones in the ventrolateral subnucleus also showed a trend to reduction. No correlation was found between neurone numbers in any subnucleus of the dorsal raphe and duration of illness. Neurone numbers did not differ in any subnucleus between patients with unipolar and those with bipolar affective disorder. CONCLUSIONS: Results indicate that patients with primary mood disorders have a circumscribed numerical neuronal deficiency in the dorsal raphe. This structural deviation may contribute to impaired serotonergic innervation of brain regions which are involved in the pathology of mood disorders.
Asunto(s)
Trastornos del Humor/patología , Núcleos del Rafe/patología , Adulto , Anciano , Análisis de Varianza , Causas de Muerte , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuronas/patologíaRESUMEN
Noradrenergic neurons of the locus coeruleus (LC) have been implicated in the neurobiology of depression and suicidal behavior. The current postmortem study determined numbers of noradrenergic neurons by immunostaining the synthesizing enzyme tyrosine hydroxylase in the LC of 12 non-elderly depressed patients with a mood disorder as compared to 12 age- and sex-matched normal controls. Six patients were suicide victims, the other six patients died of natural causes. Non-suicidal patients had fewer neurons immunoreactive for tyrosine hydroxylase (TH-ir) than suicide victims or controls. No difference appeared between the number of TH-ir neurons in suicide patients and controls. Numbers of pigmented LC neurons were equal in patients and controls. The differences of TH-immunoreactivity could neither be attributed to drug influences nor to polarity of depressive disorder (i.e., unipolar/bipolar). Numbers of TH-ir neurons correlated positively with mean doses of tri- or tetracyclic antidepressants. Results of this study suggest a presynaptic noradrenergic deficit of the LC in depressed non-suicidal patients. Indirect evidence is provided that suicide is not related to decreased noradrenergic function and that traditional antidepressants may enhance noradrenergic activity of the LC in depressed patients.
Asunto(s)
Encéfalo/enzimología , Locus Coeruleus/enzimología , Trastornos del Humor/enzimología , Trastornos del Humor/patología , Suicidio , Tirosina 3-Monooxigenasa/metabolismo , Adulto , Western Blotting , Encéfalo/patología , Femenino , Humanos , Inmunoquímica , Locus Coeruleus/ultraestructura , Masculino , Trastornos del Humor/complicaciones , Tirosina 3-Monooxigenasa/inmunologíaRESUMEN
BACKGROUND: The biological basis of unipolar-bipolar dichotomy of mood disorders was investigated in this postmortem study by morphological comparison of the locus coeruleus (LC) as the main source of noradrenergic transmission in the brain. METHODS: Numbers and the rostro-caudal as well as ventro-dorsal distribution of neuromelanin-containing neurones in the LC were determined in brainstem of 12 patients with bipolar disorder (n = 6) or major depression (n = 6), and 12 normal comparison subjects. RESULTS: Bipolar patients had significantly more neurones on both sides of the LC as a whole than patients with major depression. Topographical analysis revealed that this difference was restricted to the rostral two thirds and the dorsal part of the LC, in which bipolar patients showed at least a trend to higher neurone numbers as compared to unipolar patients or to controls. LIMITATIONS: Small case numbers. CONCLUSIONS: Results suggest differences of innervation arising from the LC of bipolar patients as compared to patients with major depression. These first data of brainstem transmitter system morphology in unipolar and bipolar disorder are in line with neuroanatomical studies of other brain regions indicating a biological basis of the unipolar-bipolar dichotomy of mood disorders.