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Abstract: Stress and environmental enrichment have opposing effects on cerebral cellular plasticity. Stress-induced disturbances in neuronal and glial plasticity have been implicated in the pathophysiology of affective disorders. Patients with depression often show volume reductions in specific brain regions. The mechanisms behind these changes are not well understood, but animal studies have indicated that increased levels of glucocorticoids and stress have negative impact on the neuronal and glial cell populations. On the contrary, enriched environment and physical activity have positive effects. In this study we have examined the effect of corticosterone (CORT), environmental enrichment (EE) and running on angiogenesis in hippocampus and prefrontal cortex (PFC). We demonstrate a dramatic inhibition in endothelial cell proliferation in these brain regions in CORT-treated rats. Environmental enrichment had the opposite effect and stimulated endothelial cell proliferation both in the hippocampus and in the PFC. Running had a stimulatory effect in hippocampus, but not in the PFC. We suggest that the angiostatic effect of CORT demonstrated in this study might be paralleled in human subjects exposed to high levels of stress hormones for prolonged periods of time. Raised cortisol levels in depressed or old patients could, by reducing endothelial cell formation/turnover, lead to rarefaction and aging of the vascular bed, and as a result, neuronal function could be impaired. It is tempting to speculate that a physically and intellectually active life may protect against stress-induced vascular changes. Therapeutic agents also targeting the cerebral vasculature could consequently constitute a new tool in the combat of stress-related disorders. [Copyright &y& Elsevier]

Abstract: Antidepressant drugs and electroconvulsive seizure (ECS)-treatment, an animal model of electroconvulsive therapy, induce neurogenesis in adult rats. Stress and high levels of corticosterone (CORT) on the contrary inhibit neurogenesis. Hippocampal neurogenesis has been described to occur in an angiogenic niche where proliferation of neural progenitors takes place in an environment with active vascular growth. Here we investigate the effect of ECS-treatment on the proliferation of endothelial cells and neuronal precursors in hippocampus of CORT-treated rats. Bromodeoxyuridine (BrdU) was used to identify dividing cells. The number of newborn neuronal precursors and endothelial cells was quantified in the subgranular zone (SGZ) and the molecular layer (ML) of the dentate gyrus. The increase in neuronal precursor proliferation in the SGZ following ECS-treatment was not inhibited by elevated levels of CORT despite CORT strongly inhibiting ECS-induced endothelial cell proliferation. Also in the ML CORT-treatment inhibited the ECS-induced angiogenic response. We conclude that despite common factors regulating neurogenesis and angiogenesis, ECS-induced proliferation of neuronal precursors can take place even if the angiogenic response is blunted. Whether inhibition of angiogenesis affects other steps in the chain of events leading to the formation of fully integrated granule neurons remains to be elucidated. [Copyright &y& Elsevier]

Background: Major depression is often associated with disturbances in basal biological functions regulated by the hypothalamus. Electroconvulsive therapy (ECT), an efficient anti-depressant treatment, alters the activity of hypothalamic neurons. We have previously shown an increased proliferation of endothelial cells in specific areas of the rat hippocampus in response to electroconvulsive seizure (ECS) treatment, an animal model for ECT. Here we examine the effect of ECS treatment on neuronal activation and endothelial cell proliferation in mid-hypothalamus. Methods: Rats received one daily ECS treatment for 5 days and cell proliferation was detected by bromodeoxyuridine (BrdU). The number of cells double-labeled for BrdU and the endothelial cell marker rat endothelial cell antigen-1 was determined. Neuronal activation in response to acute ECS treatment was detected as c-Fos immunoreactivity in an additional experiment. Results: We demonstrate a correlating pattern of increases in neuronal activation and increased endothelial cell proliferation in the paraventricular nucleus, the supraoptic nucleus, and the ventromedial nucleus of the hypothalamus after ECS treatment. Conclusions: Hypothalamic areas with the largest increase in neuronal activation after ECS treatment exhibit increased endothelial cell proliferation. We suggest that similar angiogenic responses to ECT might counteract hypothalamic dysfunction in depressive disorder. [Copyright &y& Elsevier]

Background: Electroconvulsive seizure (ECS)-treatment, a model for electroconvulsive therapy (ECT) has been shown to induce proliferation of endothelial cells in the dentate gyrus (DG) of adult rats. Here we quantified the net angiogenic response after chronic ECS-treatment in the molecular layer (ML) of the dentate gyrus. Patients undergoing ECT are routinely oxygenated to prevent hypoxia, a known inducer of angiogenesis. Therefore we also examined the effect of oxygenation on ECS-induced proliferation of endothelial cells. Methods: Total endothelial cell numbers and vessel length were estimated utilizing design based stereological analysis methods. Endothelial cell proliferation in the DG after ECS with or without oxygenation was assessed using bromodeoxyuridine. Results: The total number of endothelial cells and total vessel length was increased. Oxygenation did not abolish the ECS-induced proliferation of endothelial cells in the DG. Conclusions: ECS-treatment induces a dramatic increase in endothelial cell proliferation leading to a 30% increase in the total number of endothelial cells. The increase in cell number resulted in a 16% increase in vessel length. These findings raise the possibility that similar vascular growth is induced by clinically administered ECT. [Copyright &y& Elsevier]

: BackgroundElectroconvulsive seizures, an animal model for electroconvulsive treatment, induce a strong increase in neurogenesis in the dentate gyrus of adult rats. Hippocampal neurogenesis has previously been described as occurring in an angiogenic niche. This study examines the effect of electroconvulsive seizures on proliferation of vascular cells in rat hippocampus.: MethodsRats were injected with bromodeoxyuridine to label proliferating cells in the dentate gyrus after single/multiple electroconvulsive seizures in a dose-response study and at various time points after single electroconvulsive seizures in a time-course study.: ResultsA dose-response effect on the number of bromodeoxyuridine-labeled endothelial cells located in the granule cell layer, hilus, and molecular layer was noted, as was the case with the number of neural precursors in the subgranular zone. The time-course study revealed that endothelial cell and neural precursor proliferation occurred in concert in response to a single electroconvulsive seizure.: ConclusionsOur data suggest that in response to electroconvulsive seizures, endothelial cell and neural proliferation is coregulated. The increase in endothelial cell proliferation may act to support the increased neural proliferation and neuronal activity or vice versa, possibly leading to structural changes within the hippocampus of importance for the antidepressant effect of electroconvulsive seizures. [Copyright &y& Elsevier]