RESUMO
Individuals with clinical disorders associated with elevated plasma glucocorticoids, such as major depressive disorder and Cushing's syndrome, are reported to have smaller hippocampal volume. To understand how the hippocampus responds at the cellular and subcellular levels to glucocorticoids and how such changes are related to volume measures, we have undertaken a comprehensive study of glucocorticoid effects on hippocampal CA3 volume and identified elements in the neuropil including astrocytic volume and cell and synapse number and size. Male Sprague-Dawley rats were injected with corticosterone (40 mg/kg), the primary glucocorticoid in rodents, or vehicle for 60 days. The CA3 was further subdivided so that the two-thirds of CA3 (nearest the dentate gyrus) previously shown to be vulnerable to corticosterone could be analyzed as two separate subfields. Corticosterone had no effect on neuropil volume or glial volume in the proximal subfield but caused a strong tendency for astrocytic processes to make up a larger proportion of the tissue and for volume of tissue made of constituents other than glial cells (primarily neuronal processes) to be smaller in the middle subfield. Within the neuropil, there were no cellular or subcellular profiles that indicated degeneration, suggesting that corticosterone does not cause prolonged damage. Corticosterone did not reduce cell number or cell or nonperforated synapse size but did cause a pronounced loss of synapses. This loss occurred in both subfields and, therefore, was independent of volume loss. Together, the findings suggest that volume measures can underestimate corticosterone effects on neural structure.
Assuntos
Atrofia/fisiopatologia , Glucocorticoides/metabolismo , Hipocampo/patologia , Degeneração Neural/fisiopatologia , Neurônios/patologia , Neurópilo/patologia , Sinapses/patologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Atrofia/induzido quimicamente , Contagem de Células , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Doença Crônica , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/fisiopatologia , Modelos Animais de Doenças , Gliose/induzido quimicamente , Gliose/fisiopatologia , Glucocorticoides/efeitos adversos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Degeneração Neural/induzido quimicamente , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurópilo/efeitos dos fármacos , Neurópilo/metabolismo , Hipersecreção Hipofisária de ACTH/complicações , Hipersecreção Hipofisária de ACTH/fisiopatologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , Ratos , Ratos Sprague-Dawley , Estresse Fisiológico/complicações , Estresse Fisiológico/fisiopatologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Regulação para Cima/fisiologiaRESUMO
Pleiotrophin (PTN) is an extracellular matrix-associated protein with neurotrophic and neuroprotective effects that is involved in a variety of neurodevelopmental processes. Data regarding the cognitive-behavioral and neuroanatomical phenotype of pleiotrophin knockout (KO) mice is limited. The purpose of this study was to more fully characterize this phenotype, with emphasis on the domains of learning and memory, cognitive-behavioral flexibility, exploratory behavior and anxiety, social behavior, and the neuronal and vascular microstructure of the lateral entorhinal cortex (EC). PTN KOs exhibited cognitive rigidity, heightened anxiety, behavioral reticence in novel contexts and novel social interactions suggestive of neophobia, and lamina-specific decreases in neuronal area and increases in neuronal density in the lateral EC. Initial learning of spatial and other associative tasks, as well as vascular density in the lateral EC, was normal in the KOs. These data suggest that the absence of PTN in vivo is associated with disruption of specific cognitive and affective processes, raising the possibility that further study of PTN KOs might have implications for the study of human disorders with similar features.