RESUMEN
BACKGROUND: Growing evidence indicates the role of the thalamus in schizophrenia. The ventral part of the thalamus has been investigated in a few post-mortem studies, suggesting a possible neurodevelopmental etiology of the reduced neuron number. METHODS: Here we adapt a neurodevelopmental animal model, the neonatal excitotoxic brain lesion, to the ventral thalamus (VT) of Sprague-Dawley rats. At postnatal day (PD) 7 male pups were bilaterally infused into the VT using ibotenic acid (IBA) or artificial cerebrospinal fluid. Repeated measurements of prepulse inhibition (PPI) of the acoustic startle response, reviewed as a measure of sensorimotor gating deficits in neuropsychiatric disorders such as schizophrenia, were performed during puberty and adulthood. RESULTS: IBA animals showed lower PPI (p<0.001) compared to controls. The extent of VT lesions correlated negatively with PPI levels (p<0.001). PPI deficits in IBA animals were observed at PD 43 and PPI levels increased significantly after puberty without reaching control levels. Acute or subchronic clozapine treatment did not significantly restore low PPI in IBA rats. CONCLUSION: The present data suggest that the VT may be involved in the PPI deficits observed in schizophrenia.
Asunto(s)
Agonistas de Aminoácidos Excitadores/farmacología , Ácido Iboténico/farmacología , Filtrado Sensorial/efectos de los fármacos , Tálamo/fisiopatología , Factores de Edad , Envejecimiento , Animales , Animales Recién Nacidos , Antipsicóticos/farmacología , Clozapina/farmacología , Modelos Animales de Enfermedad , Masculino , Ratas , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Esquizofrenia/fisiopatología , Filtrado Sensorial/fisiología , Tálamo/efectos de los fármacosRESUMEN
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
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
OBJECTIVES: Catatonia is a psychomotor syndrome with concomittant akinesia and anxiety which both respond almost immediately to benzodiazepines such as lorazepam. The benzodiazepine receptor distribution was therefore investigated in akinetic catatonia with single photon emission tomography (SPECT) using iodine-123-iomazenil ((123) I Iomazenil). METHODS: Ten akinetic catatonic patients, 10 psychiatric controls (similar age, sex, medication, and underlying psychiatric diagnosis but without catatonic syndrome), and 20 healthy controls were investigated with SPECT 2 hours after injection of (123) I Iomazenil. To exclude potential effects of cerebral perfusion (r-CBF) r-CBF was additionally investigated with Tc-99mECD SPECT. RESULTS: Catatonic patients showed significantly lower iomazenil binding and altered right-left relations in the left sensorimotor cortex compared with psychiatric (p<0.001) and healthy (p<0.001) controls. In addition, there was significantly lower r-CBF in the right lower prefrontal and parietal cortex in catatonia whereas in the left sensorimotor cortex no differences in r-CBF between groups were found. Catatonic motor and affective symptoms showed significant correlations (p<0.05) with benzodiazepine binding in the left sensorimotor cortex as well as with right parietal r-CBF. CONCLUSIONS: Reduced iomazenil binding suggests decreased density of GABA-A receptors in the left sensorimotor cortex in akinetic catatonia. In addition to reduced GABA-A receptor density in the left sensorimotor cortex the parietal cortex seems to be involved in pathophysiology of catatonic symptoms. It is concluded that, considering results from correlation analyses, both emotional and motor symptoms in catatonia seem to be closely related to left sensorimotor and right parietal alterations.
Asunto(s)
Catatonia/diagnóstico por imagen , Corteza Motora/diagnóstico por imagen , Receptores de GABA-A/metabolismo , Adulto , Análisis de Varianza , Unión Competitiva , Catatonia/metabolismo , Catatonia/psicología , Femenino , Flumazenil/análogos & derivados , Flumazenil/metabolismo , Humanos , Masculino , Corteza Motora/metabolismo , Escalas de Valoración Psiquiátrica , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Brain imaging studies have shown superior temporal gyrus (STG) volume loss and abnormal patterns of asymmetry in schizophrenia; however, these are not consistent findings. Post-mortem volumetry of three different STG regions (defined by external landmarks) was used to compare 17 schizophrenics to 20 age- and sex-matched controls. Total STG volumes did not differ. A significant gray-matter volume reduction in schizophrenics was observed in the middle compartment (reaching from the mamillary body to the lateral geniculate body). This may have been related to reduced length of this region, particularly in schizophrenic females. These results reflect the problematic issue of defining boundaries of macroscopic brain structures.
Asunto(s)
Esquizofrenia/patología , Lóbulo Temporal/patología , Análisis de Varianza , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Tubérculos Mamilares , Persona de Mediana Edad , Vías Nerviosas/patología , Factores Sexuales , TálamoRESUMEN
Several recent studies have reported an association between midline cerebral malformations (e.g., corpus callosum, cavum septum pellucidum) and schizophrenia. The authors investigated whether absence of the adhesio interthalamica (AI), a midline structure that develops in concert with prominent features of the ventricular system soon after the bridge from the late embryonic stages to early fetal life, might constitute a marker of early developmental neuropathologic changes in schizophrenia. Eighty-two patients (54 men, 28 women) with a diagnosis of first-episode schizophrenia (FES) were recruited from consecutive admissions to a psychiatric inpatient service. Fifty-two healthy control subjects (30 men, 22 women) were recruited and matched to the patient sample on distributions of sex and age. Magnetic resonance imaging studies were performed, and the presence versus absence of the AI was determined for each subject. The length and volume of the third ventricle were measured for each subject. The AI was found to be absent more often among patients with FES compared with control subjects, and patients without an observable AI also had larger third-ventricle volumes. These differences in presence or absence of the AI observed in vivo (but not in a comparable postmortem sample of histologically fixed and prepared brain slices), which are likely related to third-ventricle enlargement, may represent yet another early developmental marker of cerebral malformation among patients with FES.
Asunto(s)
Imagen por Resonancia Magnética , Trastornos Neurocognitivos/diagnóstico , Esquizofrenia/diagnóstico , Tálamo/anomalías , Adulto , Ventrículos Cerebrales/patología , Dominancia Cerebral/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Red Nerviosa/anomalías , Red Nerviosa/patología , Trastornos Neurocognitivos/patología , Valores de Referencia , Esquizofrenia/patología , Tálamo/patologíaRESUMEN
The neuroanatomical distribution of nitric oxide synthase-immunoreactive neurons was investigated in post mortem hypothalami of 10 patients suffering from schizophrenia, eight patients with depression and 13 matched control cases. Neuronal nitric oxide synthase containing nerve cells were detected in several hypothalamic nuclei including the medial preoptic region, the ventromedial, infundibular and suprachiasmatic nuclei and the lateral hypothalamus. The vast majority of hypothalamic nitric oxide synthase-immunoreactive neurons was found to be located in the paraventricular nucleus. Both magno and parvocellular paraventricular neurons contained the enzyme. A small subset of immunoreactive parvocellular paraventricular neurons co-expresses corticotropin-releasing hormone. The supraoptic nucleus did not contain nitric oxide synthase-immunoreactive neurons. Cell counts of paraventricular nitric oxide synthase-positive neurons in controls, schizophrenics and depressed patients revealed a statistically significant reduction of cell density in the right paraventricular nucleus of depressed patients and schizophrenics as compared to controls. The total amount of nitric oxide synthase-immunoreactive paraventricular neurons was smaller in depressive and schizophrenic patients than in normal cases. The putative pathophysiologic significance of the reduced expression of paraventricular nitric oxide synthase in depressive patients might be related to the supposed regulatory function of nitric oxide in the release of corticotropin-releasing hormone and arginine-vasopressin and/or oxytocin, which have been reported to be over-expressed in the so-called endogenous psychoses, especially in depression.
Asunto(s)
Depresión/enzimología , Hipotálamo/enzimología , Neuronas/enzimología , Óxido Nítrico Sintasa/metabolismo , Núcleo Hipotalámico Paraventricular/enzimología , Esquizofrenia/enzimología , Adulto , Anciano , Recuento de Células , Depresión/patología , Femenino , Humanos , Hipotálamo/citología , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Núcleo Hipotalámico Paraventricular/patología , Valores de Referencia , Esquizofrenia/patologíaRESUMEN
The gas nitric oxide (NO) is an important messenger in brain signaling. Along with many other functions, NO is thought to influence the expression and/or release of various hypothalamic hormones (corticotropin-releasing hormone (CRH), gonadotropin-releasing hormone (GnRH) and vasopressin). To learn more about the role of NO in neuroendocrine mechanisms, we studied in mutant mice lacking neuronal isoform of NO synthase (nNOS) the cellular expression of CRH, neurophysin (the carrier protein of vasopressin/oxytocin) and pro-opiomelanocortin (POMC), as well as of the POMC-derived peptides beta-endorphin (beta-END), alpha-melanocyte-stimulating hormone (alpha-MSH) and corticotropin (ACTH) by use of immunohistochemistry and in situ hybridization. Additionally, the remaining NO-generating capacities of the nNOS minus mice were investigated by NADPH-diaphorase histochemistry and citrulline immunohistochemistry as well as by immunohistochemical localization and Western blot analysis of endothelial NOS (eNOS) and nNOS isoforms. Amongst all hypothalamic peptides under investigation, only beta-END was found to be altered in mutant mice. A morphometric analysis of beta-END producing neurons of the arcuate nucleus revealed that significantly less cells were immunoreactive in mutant mice, whereas the expression of the precursor POMC as well as of other POMC-derived peptides was found to be unchanged. In addition to that, fewer beta-END-immunoreactive fibers were found in the paraventricular nucleus of nNOS minus mice in comparison to wild-type animals. Hence, the reduction of hypothalamic beta-END is probably a posttranslational event that might reflect a disturbed endorphinergic innervation of those hypothalamic neurons which normally express nNOS.
Asunto(s)
Núcleo Arqueado del Hipotálamo/metabolismo , Hipotálamo/fisiología , Neuropéptidos/biosíntesis , Óxido Nítrico Sintasa/deficiencia , betaendorfina/metabolismo , Animales , Inmunohistoquímica , Hibridación in Situ , Ratones , Ratones Noqueados , Mutación , Proteínas del Tejido Nervioso/genética , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo I , Proopiomelanocortina/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genéticaRESUMEN
To find out whether ventricular enlargement in schizophrenia, as demonstrated by neuroradiological methods, is caused by an atrophy of ventricle surrounding diencephalic structures, volume measurements and linear measurements of the whole thalamus, all large thalamic subnuclei and some extrathalamic brain parts were carried out on serial sections of post mortem brains belonging to the Vogt collection. The only significantly diminished parameter of this study was the thickness of the periventricular grey matter surrounding the third ventricle, while the volume and linear measurements of the whole thalamus and all large thalamic subnuclei were not significantly changed. The findings are discussed with respect to current hypotheses of diencephalic dysfunction in schizophrenia.