RESUMEN
Neuroimaging and postmortem studies of subjects with major depressive disorder (MDD) reveal smaller hippocampal volume with lengthening duration of illness. Pathology in astrocytes may contribute significantly to this reduced volume and to the involvement of the hippocampus in MDD. Postmortem hippocampal tissues were collected from 17 subjects with MDD and 17 psychiatrically-normal control subjects. Sections from the body of the hippocampus were immunostained for glial fibrillary acidic protein (GFAP), a marker of intermediate filament protein expressed in astrocytes. The density of GFAP-immunoreactive astrocytes was measured in the hippocampus using 3-dimensional cell counting. Hippocampal subfields were also assessed for GFAP-immunoreactive area fraction. In CA1, there was a significant positive correlation between age and either density or area fraction in MDD. The density of astrocytes in the hilus, but not CA1 or CA2/3, was significantly decreased only in depressed subjects not taking an antidepressant drug, but not for depressed subjects taking an antidepressant drug. The area fraction of GFAP-immunoreactivity was significantly decreased in the dentate gyrus in women but not men with depression. In CA2/3, the area fraction of GFAP-immunoreactivity was inversely correlated with the duration of depression in suicide victims. Astrocyte contributions to neuronal function in the hilus may be compromised in depressed subjects not taking antidepressant medication. Due to the cross-sectional nature of the present study of postmortem brain tissue, it remains to be determined whether antidepressant drug treatment prevented a decrease in GFAP-immunoreactive astrocyte density or restored cell density to normal levels.
Asunto(s)
Astrocitos/metabolismo , Trastorno Depresivo Mayor/patología , Lateralidad Funcional/fisiología , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/patología , Adolescente , Adulto , Factores de Edad , Anciano , Femenino , Hipocampo/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Cambios Post Mortem , Estadísticas no Paramétricas , Adulto JovenRESUMEN
The brain serotonergic system has an essential role in the physiological functions of the central nervous system and dysregulation of serotonin (5-HT) homeostasis has been implicated in many neuropsychiatric disorders. The tryptophan hydroxylase-2 (TPH2) gene is the rate-limiting enzyme in brain 5-HT synthesis, and thus is an ideal candidate gene for understanding the role of dysregulation of brain serotonergic homeostasis. Here, we characterized a common, but functional single-nucleotide polymorphism (SNP rs1386493) in the TPH2 gene, which decreases efficiency of normal RNA splicing, resulting in a truncated TPH2 protein (TPH2-TR) by alternative splicing. TPH2-TR, which lacks TPH2 enzyme activity, dominant-negatively affects full-length TPH2 function, causing reduced 5-HT production. The predicted mRNA for TPH2-TR is present in postmortem brain of rs1386493 carriers. The rs13864923 variant does not appear to be overrepresented in either global or multiplex depression cohorts. However, in combination with other gene variants linked to 5-HT homeostasis, this variant may exhibit important epistatic influences.
Asunto(s)
Empalme Alternativo , Depresión/genética , Predisposición Genética a la Enfermedad/genética , Serotonina/biosíntesis , Triptófano Hidroxilasa/genética , Animales , Tronco Encefálico/metabolismo , Línea Celular Transformada , Femenino , Predisposición Genética a la Enfermedad/psicología , Genotipo , Humanos , Masculino , Células PC12 , Linaje , Polimorfismo de Nucleótido Simple/genética , RatasRESUMEN
This study describes cytoarchitectonic criteria to define the prefrontal cortical areas in the mouse brain (C57BL/6 strain). Currently, well-illustrated mouse brain stereotaxic atlases are available, which, however, do not provide a description of the distinctive cytoarchitectonic characteristics of individual prefrontal areas. Such a description is of importance for stereological, neuronal tracing, and physiological, molecular and neuroimaging studies in which a precise parcellation of the prefrontal cortex (PFC) is required. The present study describes and illustrates: the medial prefrontal areas, i.e., the infralimbic, prelimbic, dorsal and ventral anterior cingulate and Fr2 area; areas of the lateral PFC, i.e., the dorsal agranular insular cortical areas and areas of the ventral PFC, i.e., the lateral, ventrolateral, ventral and medial orbital areas. Each cytoarchitectonically defined boundary is corroborated by one or more chemoarchitectonic stainings, i.e., acetylcholine esterase, SMI32, SMI311, dopamine, parvalbumin, calbindin and myelin staining.
Asunto(s)
Mapeo Encefálico , Corteza Prefrontal/anatomía & histología , Corteza Prefrontal/metabolismo , Acetilcolinesterasa/metabolismo , Animales , Calbindinas , Dopamina/metabolismo , Histocitoquímica/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Vaina de Mielina/metabolismo , Vías Nerviosas/anatomía & histología , Vías Nerviosas/metabolismo , Proteínas de Neurofilamentos/metabolismo , Parvalbúminas/metabolismo , Proteína G de Unión al Calcio S100/metabolismoRESUMEN
Recent research has changed the perception of glia from being no more than silent supportive cells of neurons to being dynamic partners participating in brain metabolism and communication between neurons. This discovery of new glial functions coincides with growing evidence of the involvement of glia in the neuropathology of mood disorders. Unanticipated reductions in the density and number of glial cells are reported in fronto-limbic brain regions in major depression and bipolar illness. Moreover, age-dependent decreases in the density of glial fibrillary acidic protein (GFAP) - immunoreactive astrocytes and levels of GFAP protein are observed in the prefrontal cortex of younger depressed subjects. Since astrocytes participate in the uptake, metabolism and recycling of glutamate, we hypothesize that an astrocytic deficit may account for the alterations in glutamate/GABA neurotransmission in depression. Reductions in the density and ultrastructure of oligodendrocytes are also detected in the prefrontal cortex and amygdala in depression. Pathological changes in oligodendrocytes may be relevant to the disruption of white matter tracts in mood disorders reported by diffusion tensor imaging. Factors such as stress, excess of glucocorticoids, altered gene expression of neurotrophic factors and glial transporters, and changes in extracellular levels of neurotransmitters released by neurons may modify glial cell number and affect the neurophysiology of depression. Therefore, we will explore the role of these events in the possible alteration of glial number and activity, and the capacity of glia as a promising new target for therapeutic medications. Finally, we will consider the temporal relationship between glial and neuronal cell pathology in depression.
Asunto(s)
Trastorno Depresivo/patología , Neuroglía/patología , Neuroglía/fisiología , Animales , Astrocitos/patología , Astrocitos/fisiología , Modelos Animales de Enfermedad , Humanos , Microglía/patología , Microglía/fisiología , Neuroglía/clasificación , Neuronas/patología , Neuronas/fisiología , Oligodendroglía/patología , Oligodendroglía/fisiologíaRESUMEN
In human brain imaging studies, it is common practice to use the Talairach stereotaxic reference system for signifying the convergence of brain function and structure. In nearly all neuroimaging reports, the studied cortical areas are specified further with a Brodmann Area (BA) number. This specification is based upon macroscopic extrapolation from Brodmann's projection maps into the Talairach atlas rather than upon a real microscopic cytoarchitectonic study. In this review we argue that such a specification of Brodmann area(s) via the Talairach atlas is not appropriate. Cytoarchitectonic studies reviewed in this paper show large interindividual differences in 3-D location of primary sensory cortical areas (visual cortex) as well as heteromodal associational areas (prefrontal cortical areas), even after correction for differences in brain size and shape. Thus, the simple use of Brodmann cortical areas derived from the Talairach atlas can lead to erroneous results in the specification of pertinent BA. This in turn can further lead to wrong hypotheses on brain system(s) involved in normal functions or in specific brain disorders. In addition, we will briefly discuss the different 'Brodmann' nomenclatures which are in use for the cerebral cortex.
Asunto(s)
Mapeo Encefálico/métodos , Corteza Cerebral/anatomía & histología , Corteza Cerebral/citología , Adulto , Algoritmos , Humanos , Imagenología Tridimensional , Masculino , Ilustración Médica , Persona de Mediana Edad , Técnicas EstereotáxicasRESUMEN
The classification of schizophrenia and bipolar disorder as two separate disease entities has been hotly debated almost from the moment of its inception with Kraepelin's descriptions of "dementia praecox" and "manic-depressive insanity" in 1896. Kraepelin's nosologic distinction was based on clinical observation of symptomatology and outcome, and even today, despite major advances in science and technology, differential diagnosis of psychosis relies on the clinical course of illness. However, new evidence from diverse fields, e.g., genetics, neuropsychology, and brain imaging, have refueled the debate about whether or not schizophrenia and bipolar disorder represent distinct diseases, leading some to postulate that schizophrenia and bipolar disorder represent different manifestations of psychosis along a continuum with schizoaffective disorder representing an intermediate subtype. To this discourse, we add our own recent postmortem anatomic findings indicating that cellular pathology in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder differs not just in magnitude but also in direction, in laminar scope, and in relative involvement of neuronal and glial cell types. Thus, distinct morphometric alterations in the dorsolateral prefrontal cortex underlie what appear on neuroimaging analysis to be similar abnormalities in structural and metabolic function in the prefrontal cortex, and the diverse cellular pathology in the dorsolateral prefrontal cortex in these two disorders may account for the greater deficit in schizophrenia on cognitive tasks involving memory, problem solving and abstraction.
Asunto(s)
Trastorno Bipolar/patología , Corteza Prefrontal/patología , Esquizofrenia/patología , Corteza Cerebral/citología , Corteza Cerebral/patología , Humanos , Neuroglía/patología , Corteza Prefrontal/citologíaRESUMEN
BACKGROUND: Bipolar disorder (BPD) is a mental illness in which depression and mania typically alternate, and both phases can present with psychotic features. The symptomatology of BPD, therefore, resembles major depressive disorder (MDD) and schizophrenia (SCHZ), posing diagnostic dilemmas. Distinct alterations in cellular architecture of the dorsolateral prefrontal cortex distinguish SCHZ and MDD, whereas the cellular neuropathology of BPD has not been studied. METHODS: Dorsolateral prefrontal area 9 was analyzed using a three-dimensional morphometric method in postmortem brains from 10 BPD patients and 11 matched nonpsychiatric control subjects. RESULTS: Area 9 in BPD was characterized by reduced neuronal density in layer III (16%-22%) and reduced pyramidal cell density in layers III and V (17%-30%). A 19% reduction in glial density was found in sublayer IIIc coupled with enlargement and changes in shape of glial nuclei spanning multiple layers. CONCLUSIONS: The morphologic signature of BPD, i.e., decreased neuronal and glial density in association with glial hypertrophy, is distinct from previously described elevations in neuronal density in SCHZ, instead resembling the reductions in cell density found in MDD. Thus, the neuropathologic distinctions between BPD and SCHZ are indicative of separate mental illnesses, each with a unique morphologic disturbance of specific neural circuits.
Asunto(s)
Trastorno Bipolar/patología , Encéfalo/patología , Neuroglía/patología , Adulto , Anciano , Recuento de Células , Técnicas de Cultivo , Femenino , Humanos , Hipertrofia/patología , Masculino , Persona de Mediana Edad , Corteza Prefrontal/patología , Estudios RetrospectivosRESUMEN
Although mood disorders have traditionally been regarded as good prognosis diseases, a growing body of data suggests that the long-term outcome for many patients is often much less favorable than previously thought. Recent morphometric studies have been investigating potential structural brain changes in mood disorders, and there is now evidence from a variety of sources demonstrating significant reductions in regional CNS volume, as well as regional reductions in the numbers and/or sizes of glia and neurons. Furthermore, results from recent clinical and preclinical studies investigating the molecular and cellular targets of mood stabilizers and antidepressants suggest that a reconceptualization about the pathophysiology and optimal long-term treatment of recurrent mood disorders may be warranted. It is proposed that impairments of neuroplasticity and cellular resilience may underlie the pathophysiology of mood disorders, and further that optimal long-term treatment for these severe illnesses may only be achieved by the early and aggressive use of agents with neurotrophic/neuroprotective effects. It is noteworthy that lithium, valproate and antidepressants indirectly regulate a number of factors involved in cell survival pathways including CREB, BDNF, bcl-2 and MAP kinases, and may thus bring about some of their delayed long-term beneficial effects via underappreciated neurotrophic effects. The development of novel treatments which more directly target molecules involved in critical CNS cell survival and cell death pathways have the potential to enhance neuroplasticity and cellular resilience, and thereby modulate the long-term course and trajectory of these devastating illnesses.
Asunto(s)
Trastornos del Humor/fisiopatología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Animales , Encéfalo/citología , Encéfalo/fisiología , Muerte Celular/fisiología , Humanos , Neuronas/citologíaAsunto(s)
Anatomía Artística , Mapeo Encefálico , Imagenología Tridimensional , Ilustración Médica , Corteza Prefrontal/anatomía & histología , Tálamo/anatomía & histología , Adulto , Animales , Variación Genética , Haplorrinos/anatomía & histología , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Corteza Prefrontal/fisiología , Probabilidad , Técnicas Estereotáxicas , Terminología como Asunto , Núcleos Talámicos/anatomía & histología , Núcleos Talámicos/fisiología , Tálamo/fisiologíaAsunto(s)
Trastorno Depresivo Mayor/patología , Dopamina/fisiología , Norepinefrina/fisiología , Corteza Prefrontal/patología , Serotonina/fisiología , Animales , Axones/ultraestructura , Recuento de Células , Tamaño de la Célula , Cognición/fisiología , Trastorno Depresivo Mayor/metabolismo , Emociones/fisiología , Femenino , Ácido Glutámico/fisiología , Haplorrinos , Humanos , Locus Coeruleus/química , Locus Coeruleus/patología , Masculino , Motivación , Factores de Crecimiento Nervioso/fisiología , Proteínas del Tejido Nervioso/análisis , Vías Nerviosas/fisiopatología , Neuroglía/patología , Neuronas/química , Neuronas/patología , Corteza Prefrontal/metabolismo , Núcleos del Rafe/química , Núcleos del Rafe/patología , Receptores Adrenérgicos/efectos de los fármacos , Receptores Adrenérgicos/fisiología , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Dopaminérgicos/fisiología , Receptores de Glutamato/fisiología , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/fisiología , Recompensa , Triptófano Hidroxilasa/análisis , Tirosina 3-Monooxigenasa/análisisRESUMEN
The influence of stress and glucocorticoids on neuronal pathology has been demonstrated in animal and clinical studies. It has been proposed that stress-induced changes in the hippocampus may be central to the development of depression in genetically vulnerable individuals. New evidence implicates the prefrontal cortex (PFC) in addition to the hippocampus as a site of neuropathology in depression. The PFC may be involved in stress-mediated neurotoxicity because stress alters PFC functions and glucocorticoid receptors, the PFC is directly interconnected with the hippocampus, and metabolic alterations are present in the PFC in depressed patients. Postmortem studies in major depression and bipolar disorder provide the first evidence for specific neuronal and glial histopathology in mood disorders. Three patterns of morphometric cellular changes are noted: cell loss (subgenual PFC), cell atrophy (dorsolateral PFC and orbitofrontal cortex), and increased numbers of cells (hypothalamus, dorsal raphe nucleus). The relevance of cellular changes in mood disorders to stress and prolonged PFC development and a role of neurotrophic/neuroprotective factors are suggested, and a link between cellular changes and the action of therapeutic drugs is discussed. The precise anatomic localization of dysfunctional neurons and glia in mood disorders may reveal cortical targets for novel antidepressants and mood stabilizers.
Asunto(s)
Trastornos del Humor/complicaciones , Neuroglía/patología , Neuronas/patología , Atrofia/etiología , Atrofia/metabolismo , Atrofia/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Trastornos del Humor/metabolismo , Neuroglía/metabolismo , Neuronas/metabolismo , Estrés Psicológico/complicacionesRESUMEN
BACKGROUND: Recent postmortem studies in major depressive disorder (MDD) provide evidence for a reduction in the packing density and number of glial cells in different regions of the prefrontal cortex; however, the specific types of glia involved in those morphologic changes are unknown. METHODS: The territory occupied by the astroglial marker glial fibrillary acidic protein (GFAP) was measured as an areal fraction in cortical layers III, IV, and V in sections from the dorsolateral prefrontal cortex (dlPFC) of MDD and control subjects. In addition, the packing density of GFAP-immunoreactive somata was measured by a direct three-dimensional cell counting method. RESULTS: The mean areal fraction and packing density of GFAP-immunoreactive astrocytes in the dlPFC of MDD subjects were not significantly different from those in control subjects; however, in MDD there was a significant strong positive correlation between age and GFAP immunoreactivity. When the MDD group was divided into younger (30-45 years old) and older (46-86) adults, in the five younger MDD adults, areal fraction and packing density were smaller than the smallest values of the control subjects. In contrast, among older MDD subjects these parameters tended to be greater than in the older control subjects. CONCLUSIONS: The present results suggest that the GFAP-immunoreactive astroglia is differentially involved in the pathology of MDD in younger compared with older adults.
Asunto(s)
Trastorno Depresivo Mayor/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Corteza Prefrontal/citología , Corteza Prefrontal/metabolismo , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Envejecimiento , Astrocitos/citología , Astrocitos/metabolismo , Recuento de Células , Técnicas de Cultivo , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana EdadRESUMEN
Increasing evidence suggests that mood disorders are associated with a reduction in regional CNS volume and neuronal and glial cell atrophy or loss. Lithium, a mainstay in the treatment of mood disorders, has recently been demonstrated to robustly increase the levels of the cytoprotective B-cell lymphoma protein-2 (bcl-2) in areas of rodent brain and in cultured cells. In view of bcl-2's antiapoptotic and neurotrophic effects, the present study was undertaken to determine if lithium affects neurogenesis in the adult rodent hippocampus. Mice were chronically treated with lithium, and 5-bromo-2-deoxyuridine (BrdU) labeling of dividing cells was conducted over 12 days. Immunohistochemical analysis was undertaken 1 day after the last injection, and three-dimensional stereological cell counting revealed that lithium produced a significant 25% increase in the BrdU-labeled cells in the dentate gyrus. Double-labeling immunofluorescence studies were undertaken to co-localize BrdU-positive cells with neuron-specific nuclear protein and showed that approximately 65% of the cells were double-labeled. These results add to the growing body of evidence suggesting that mood stabilizers and antidepressants exert neurotrophic effects and may therefore be of use in the long-term treatment of other neuropsychiatric disorders.
Asunto(s)
Hipocampo/efectos de los fármacos , Litio/farmacología , Neuronas/efectos de los fármacos , Animales , Antígenos de Diferenciación/metabolismo , Bromodesoxiuridina , División Celular/efectos de los fármacos , Hipocampo/citología , Hipocampo/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Regeneración Nerviosa/efectos de los fármacos , Neuronas/citología , Neuronas/metabolismo , Fenotipo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
BACKGROUND: The involvement of serotonin in depression and suicide has been proposed, because major depression is successfully treated by medications that specifically block the serotonin transporter, and there is evidence for a decrease in serotonin transporters in major depression and suicide. The midbrain dorsal raphe nucleus (DR) has been implicated as a site for diminished serotonergic activity in that suicide victims with major depression have a significant increase in serotonin-1A autoreceptors in the DR. METHODS: [(3)H]Paroxetine was used to label the serotonin transporter in the subnuclei of the DR at several rostral-to-caudal levels of the midbrain in ten pairs of suicide victims with major depression and age-matched psychiatrically normal control subjects. RESULTS: There was a significant increase in serotonin transporters in the entire DR progressing from rostral-to-caudal levels in both normal control subjects and suicide victims with major depression. At comparable rostral-to-caudal levels, there were no significant differences in [(3)H]paroxetine binding between depressed suicide victims and normal control subjects in either the entire DR or its constituent subnuclei. CONCLUSIONS: The pathophysiology of serotonin mechanisms in suicide victims with major depression does not appear to involve alterations in the binding of [(3)H]paroxetine to the serotonin transporter in the midbrain DR.
Asunto(s)
Proteínas Portadoras/metabolismo , Trastorno Depresivo/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana , Mesencéfalo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Serotonina/metabolismo , Suicidio , Adulto , Anciano , Anciano de 80 o más Años , Autorradiografía , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Paroxetina , Ensayo de Unión Radioligante , Estudios Retrospectivos , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Inhibidores Selectivos de la Recaptación de SerotoninaRESUMEN
Morphometric studies of the cerebral cortex in celloidin sections provide reliable quantitative estimates of cytoarchitectural features in individual brain regions. To increase our knowledge about the morphology and distribution of neuronal and glial cell types using specific cellular markers, we compared two methods of celloidin removal/antigen recovery, and subsequent immunohistochemical staining of free floating sections with specific antibodies. The method based on methanol and NaOH for celloidin removal was the most adequate for optimal recovery of immunoreactivity of the neural markers NF200, MAP2, GFAP, calretinin, parvalbumin, calbindin-D28kD, and synaptophysin. The other method, based on a treatment with ethanol/ether and formic acid, gave good results in the immunostaining of NF200, GFAP and MAP2, but not the other markers named above. The immunostained sections were compared with nearby sections stained with cresyl violet in order to assign the immunoreactive structures to individual layers in the prefrontal cortex. Sections from blocks not embedded in celloidin showed a comparable distribution of all the antigens included in the present study. The present paper provides an antigen recovery technique for celloidin sections that can be applied to optimize studies on the cytoarchitecture and distribution of specific neural elements in the human cerebral cortex.
Asunto(s)
Colodión , Inmunohistoquímica/métodos , Corteza Prefrontal/citología , Adhesivos Tisulares , Adhesión del Tejido/métodos , HumanosRESUMEN
The binding of [125I]p-iodoclonidine to alpha-2, and/or [125I]iodopindolol to beta-1 and beta-2 adrenoceptors was measured in right prefrontal cortex (Brodmann's area 10) and right hippocampus from subjects with DSM-III-R diagnoses of major depression (n = 15) or schizophrenia (n = 8) as well as from control subjects (n = 20). No significant differences between study groups were observed in binding to alpha-2 adrenoceptors in any of the six layers of prefrontal cortex or in any of the hippocampal fields. Likewise, there were no significant differences in beta-1 or beta-2 adrenoceptor binding in any of the hippocampal fields between control and major depressive subjects. In contrast, binding to beta-1 adrenoceptors, but not beta-2 adrenoceptors, was significantly lower (-13 to -27%) in most hippocampal fields of schizophrenic subjects as compared to control subjects or to major depressives. Alterations in beta-1 adrenoceptor binding in the hippocampus of schizophrenics provide further evidence for a role of central noradrenergic neurons in the neurochemical pathology of schizophrenia.
Asunto(s)
Química Encefálica/fisiología , Trastorno Depresivo/metabolismo , Norepinefrina/metabolismo , Receptores Adrenérgicos/metabolismo , Esquizofrenia/metabolismo , Agonistas alfa-Adrenérgicos , Antagonistas Adrenérgicos beta , Adulto , Marcadores de Afinidad , Anciano , Autorradiografía , Clonidina/análogos & derivados , Femenino , Hipocampo/metabolismo , Humanos , Radioisótopos de Yodo , Masculino , Persona de Mediana Edad , Pindolol/análogos & derivados , Corteza Prefrontal/metabolismo , SuicidioRESUMEN
BACKGROUND: This report provides histopathological evidence to support prior neuroimaging findings of decreased volume and altered metabolism in the frontal cortex in major depressive disorder. METHODS: Computer-assisted three-dimensional cell counting was used to reveal abnormal cytoarchitecture in left rostral and caudal orbitofrontal and dorsolateral prefrontal cortical regions in subjects with major depression as compared to psychiatrically normal controls. RESULTS: Depressed subjects had decreases in cortical thickness, neuronal sizes, and neuronal and glial densities in the upper (II-IV) cortical layers of the rostral orbitofrontal region. In the caudal orbitofrontal cortex in depressed subjects, there were prominent reductions in glial densities in the lower (V-VI) cortical layers that were accompanied by small but significant decreases in neuronal sizes. In the dorsolateral prefrontal cortex of depressed subjects marked reductions in the density and size of neurons and glial cells were found in both supra- and infragranular layers. CONCLUSIONS: These results reveal that major depression can be distinguished by specific histopathology of both neurons and glial cells in the prefrontal cortex. Our data will contribute to the interpretation of neuroimaging findings and identification of dysfunctional neuronal circuits in major depression.
Asunto(s)
Depresión/patología , Neuroglía/patología , Neuronas/patología , Corteza Prefrontal/patología , Adulto , Anciano , Tamaño de la Célula , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
For cytoarchitectonic delineation of cortical areas in human brain, the Gallyas staining for somata with its sharp contrast between cell bodies and neuropil is preferable to the classical Nissl staining, the more so when an image analysis system is used. This Gallyas staining, however, does not appear to be appropriate for counting neuron numbers in pertinent brain areas, due to the lack of distinct cytological features between small neurons and glial cells. For cell counting Nissl is preferable. In an optimal design for cell counting at least both the Gallyas and the Nissl staining must be applied, the former staining for cytoarchitectural delineaton of cortical areas and the latter for counting the number of neurons in the pertinent cortical areas.
Asunto(s)
Mapeo Encefálico/métodos , Corteza Cerebral/fisiología , Neuronas/citología , Coloración y Etiquetado/métodos , Adulto , Anciano , Anciano de 80 o más Años , Recuento de Células , Corteza Cerebral/citología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
It has been hypothesized that a deficit in serotonin may be a crucial determinant in the pathophysiology of major depression. Serotonin-1A receptors are located on serotonin cell bodies in the midbrain dorsal raphe (DR) nucleus, and the activation of these receptors inhibits the firing of serotonin neurons and diminishes the release of this neurotransmitter in the prefrontal cortex. Repeated treatment with some antidepressant medications desensitizes serotonin-1A receptors in the rat midbrain. The present study determined whether the binding of [3H]8-hydroxy-2-(di-n-propyl)aminotetralin (8-OH-DPAT), an agonist at serotonin-1A receptors, is altered in the midbrain of suicide victims with major depression. Radiolabeling of the serotonin-1A receptor in the DR varied significantly along the rostral-to-caudal extent of the human midbrain. The binding of [3H]8-OH-DPAT to serotonin-1A receptors was increased significantly in the midbrain DR of suicide victims with major depression as compared with psychiatrically normal control subjects. In suicide victims with major depression, the increase in the binding of [3H]8-OH-DPAT to serotonin-1A receptors was detected in the entire DR and specifically localized to the dorsal and ventrolateral subnuclei. Enhanced radioligand binding of an agonist to inhibitory serotonin-1A autoreceptors in the human DR provides pharmacological evidence to support the hypothesis of diminished activity of serotonin neurons in suicide victims with major depression.
Asunto(s)
Autorreceptores/metabolismo , Depresión/metabolismo , Núcleos del Rafe/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Suicidio , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Autorreceptores/análisis , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Ensayo de Unión Radioligante , Núcleos del Rafe/química , Receptores de Serotonina/análisis , Receptores de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/farmacología , TritioRESUMEN
Neuropsychologic testing in schizophrenic patients has underscored the prominence of dysfunction in cognitive processes associated with the dorsolateral prefrontal cortex. Quantitative cytometric analysis of area 46 was undertaken in brains from schizophrenic patients to determine whether there are morphologic changes underlying these cognitive deficits. Postmortem brain specimens from 9 schizophrenic patients, 10 normal subjects, and 8 Huntington's diseased patients were fixed in formalin and celloidin embedded. A direct, three-dimensional counting method was used to determine cell density and cortical thickness in Nissl-stained sections of area 46. Overall neuronal density was 21% greater in brains from schizophrenic patients in comparison to normal controls. Significant elevations in neuronal density were observed in layers II, III, IV, and VI. The cortical ribbon was slightly (8%) but not significantly thinner. However, layer II exhibited disproportionate thinning compared with all other layers. In brains from Huntington's diseased patients, increases in neuronal (35%) and glial (61%) density with substantial cortical thinning (30%) were observed. The neuropathology of area 46 in schizophrenia is similar in direction and magnitude to that previously described in area 9 (Selemon et al. [1995] Arch. Gen. Psychiatry 52:805-818), except for the abnormalities in layer II, which are specific to area 46. In contrast to Huntington's disease, in which cortical atrophy and gliosis are present, no evidence for cortical cell loss was uncovered in the schizophrenic cohort. The observed elevation in neuronal density suggests that a reduction in interneuronal neuropil may constitute the anatomical substrate for prefrontal cortical dysfunction in schizophrenia.