Electroconvulsive Seizures Research Articles

Electroconvulsive seizure treatment increases cell proliferation in rat frontal cortex.

Recent studies have demonstrated increased neurogenesis in adult hippocampus in response to electroconvulsive seizure (ECS) or antidepressant drug treatment. Adult neurogenesis in the subgranular zone of the hippocampus and the subventricular zone is well established, whereas neuronal proliferation outside of these areas under unstimulated conditions is not observed. Since mood disorders are likely to involve brain regions in addition to hippocampus, particularly the frontal cortex, it is likely that antidepressant treatments produce cellular changes in these brain regions as well. In this study, we have investigated the effect of repeated ECS administration on the proliferation of cells in the frontal cortex, and we have examined the phenotype of these cells 4 weeks after labeling with a cell division marker. We found that ECS treatment increases the number of newly divided cells in the frontal cortex and that these new cells express markers of either endothelial cells or oligodendrocytes, but not neurons. It is possible that increased proliferation of these cell types in the frontal cortex could reverse the loss of glial cell number and the reduced volume that has been reported in the frontal cortex of depressed patients.

The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and 5-HIAA levels

The reported increase in brain-derived neurotrophic factor (BDNF) mRNA expression after antidepressant treatment is a cornerstone of the BDNF hypothesis of antidepressant action. However, if this increase becomes manifest on the BDNF protein level is unknown. In the present study we performed parallel measurements of BDNF mRNA and protein expression in the frontal cortex and hippocampus of the rat after chronic treatment with electroconvulsive seizures (ECS), lithium, desipramine or escitalopram. ECS increased BDNF mRNA and protein in the hippocampus and BDNF protein in the frontal cortex. Desipramine moderately increased BDNF mRNA expression in the dentate gyrus but did not change BDNF protein in neither region. Escitalopram did not affect BDNF mRNA expression, but decreased BDNF protein in the frontal cortex and the hippocampus. Lithium increased BDNF protein levels in the hippocampus and frontal cortex, but overall decreased BDNF mRNA expression. Thus, here we report a striking non-correspondence between changes in BDNF mRNA and protein expression induced by the antidepressant treatments and lithium. Further, increased expression of BDNF mRNA or protein was not a common action of the treatments. We also investigated if treatment-induced modulations of the tissue contents of 5-hydroxytryptamine (5-HT) and its metabolite, 5-hydroxy-indoleacetic acid (5-HIAA), were related to changes in BDNF mRNA or protein expression. No correlation was found. However, all treatments increased 5-HT levels in the hippocampus.

Structure-related oxidative damage in rat brain after acute and chronic electroshock.

The role of oxidative stress in electroconvulsive therapy-related effects is not well studied. The purpose of this study was to determine oxidative stress parameters in several brain structures after a single electroconvulsive seizure or multiple electroconvulsive seizures. Rats were given either a single electroconvulsive shock or a series of eight electroconvulsive shocks. Brain regions were isolated, and levels of oxidative stress in the brain tissue (cortex, hippocampus, striatum and cerebellum) were measured. We demonstrated a decrease in lipid peroxidation and protein carbonyls in the hippocampus, cerebellum, and striatum several times after a single electroconvulsive shock or multiple electroconvulsive shocks. In contrast, lipid peroxidation increases both after a single electroconvulsive shock or multiple electroconvulsive shocks in cortex. In conclusion, we demonstrate an increase in oxidative damage in cortex, in contrast to a reduction of oxidative damage in hippocampus, striatum, and cerebellum.

Genetic and phenotypic analysis of seizure susceptibility in PL/J mice.

Epilepsy is one of the most common but genetically complex neurological disorders in humans. Identifying animal models that recapitulate human epilepsies is important for pharmacological studies of anticonvulsants, dissection of molecular and biochemical pathogenesis of epilepsy, and discovery of epilepsy susceptibility genes. We discovered that the PL/J inbred mouse strain is susceptible to handling- and rhythmic tossing-induced seizure. The tonic-clonic and generalized seizures observed after induction were accompanied by abnormal EEGs, similar to seizures observed in EL and SWXL-4 mice. PL/J mice also had an extremely low threshold to electroconvulsive seizures compared to other strains and showed variable sensitivity to pentylenetetrazole-induced seizures. Gross neurostructural abnormalities were not found in PL/J mice. Crosses with the seizure-resistant C57BL/6 J strain revealed semidominant inheritance of the rhythmic tossing seizure trait with low penetrance. F2 progeny indicated that the genetic inheritance of seizure susceptibility in PL/J is non-Mendelian. We crossed DBA/2 J mice, which are resistant to rhythmic tossing seizure but susceptible to audiogenic seizures, to PL/J. We found that seizure penetrance in (DBA/2 J x PL/J)F1 mice was similar to the penetrance in (C57BL/6 J x PL/J)F1 mice but the severity and frequency of seizure were higher in (DBA/2 J x PL/J)F1 mice. The PL/J strain serves as an interesting new model for studying the genetics, neurobiology, and pharmacology of epilepsy.

Regulation of growth factor receptor bound 2 by electroconvulsive seizure

Electroconvulsive seizure (ECS) is a well-established non-chemical antidepressant that is effective in the treatment of severe depression and also in subjects resistant to chemical antidepressant treatment. Although the molecular mechanism governing the antidepressant efficacy of ECS is unknown, recent work suggests that an amplification of growth/neurotrophic signaling might play a role in mediating the therapeutic effects. In this context, we examined the regulation of growth factor receptor bound 2 (Grb2), an important adaptor molecule in several growth factor signaling cascades. In situ hybridization analysis revealed a more than 2-fold induction of Grb2 mRNA in the hippocampal dentate gyrus as well as superficial and deep layers of the cortex with both acute and chronic ECS. Grb2 also exhibited a time-dependent induction 4 and 8 h after acute ECS, returning to basal levels at 24 h. These results provide further evidence of increased growth factor signaling in response to ECS.

Brain-derived neurotrophic factor mRNA and protein are targeted to discrete dendritic laminas by events that trigger epileptogenesis.

Dendritic targeting of mRNA and local protein synthesis are mechanisms that enable neurons to deliver proteins to specific postsynaptic sites. Here, we demonstrate that epileptogenic stimuli induce a dramatic accumulation of BDNF mRNA and protein in the dendrites of hippocampal neurons in vivo. BDNF mRNA and protein accumulate in dendrites in all hippocampal subfields after pilocarpine seizures and in selected subfields after other epileptogenic stimuli (kainate and kindling). BDNF accumulates selectively in discrete dendritic laminas, suggesting targeting to synapses that are active during seizures. Dendritic targeting of BDNF mRNA occurs during the time when the cellular changes that underlie epilepsy are occurring and is not seen after intense stimuli that are non-epileptogenic, including electroconvulsive seizures and high-frequency stimulation. MK801, an NMDA receptor antagonist that can prevent epileptogenesis but not acute seizures, prevents the dendritic accumulation of BDNF mRNA, indicating that dendritic targeting is mediated via NMDA receptor activation. Together, these results suggest that dendritic accumulation of BDNF mRNA and protein plays a critical role in the cellular changes leading to epilepsy.

Myelination in the hippocampus during development and following lesion.

Myelin is crucial for the stabilization of axonal projections in the developing and adult mammalian brain. However, myelin components also act as a non-permissive and repellent substrate for outgrowing axons. Therefore, one major factor which accounts for the lack of axonal regeneration in the mature brain is myelin. Here we report on the appearance of mature, fully myelinated axons during hippocampal development and following entorhinal lesion with the myelin-specific marker Black Gold. Although entorhinal axons enter the hippocampal formation at embryonic day 17, light and ultrastructural analysis revealed that mature myelinated fibers in the hippocampus occur in the second postnatal week. During postnatal development, increasing numbers of myelinated fibers appear and the distribution of myelinated fibers at postnatal day 25 was similar to that found in the adult. After entorhinal cortex lesion, a specific anterograde denervation in the hippocampus takes place, accompanied by a long-lasting loss of myelin. Quantitative analysis of myelin and myelin breakdown products at different time points after lesion revealed a temporally close correlation to the degeneration and reorganization pha-ses in the hippocampus. In contrast, electroconvulsive seizures resulted in brief demyelination and a faster recovery time course. In conclusion, we could show that the appearance of mature axons in the hippocampus is temporally regulated during development. In the adult hippocampus, demyelination was found after anterograde degeneration and also following seizures, suggesting that independent types of insult lead to demyelination. Reappearing mature axons were found in the hippocampus following axonal sprouting. Therefore, our quantitative analysis of mature axons and myelination effectively reflects the readjusted axonal density and possible electrophysiological balance following lesion.

Electroconvulsive seizures regulate gene expression of distinct neurotrophic signaling pathways.

Electroconvulsive therapy (ECT) remains the treatment of choice for drug-resistant patients with depressive disorders, yet the mechanism for its efficacy remains unknown. Gene transcription changes were measured in the frontal cortex and hippocampus of rats subjected to sham seizures or to 1 or 10 electroconvulsive seizures (ECS), a model of ECT. Among the 3500-4400 RNA sequences detected in each sample, ECS increased by 1.5- to 11-fold or decreased by at least 34% the expression of 120 unique genes. The hippocampus produced more than three times the number of gene changes seen in the cortex, and many hippocampal gene changes persisted with chronic ECS, unlike in the cortex. Among the 120 genes, 77 have not been reported in previous studies of ECS or seizure responses, and 39 were confirmed among 59 studied by quantitative real time PCR. Another 19 genes, 10 previously unreported, changed by <1.5-fold but with very high significance. Multiple genes were identified within distinct pathways, including the BDNF-MAP kinase-cAMP-cAMP response element-binding protein pathway (15 genes), the arachidonic acid pathway (5 genes), and more than 10 genes in each of the immediate-early gene, neurogenesis, and exercise response gene groups. Neurogenesis, neurite outgrowth, and neuronal plasticity associated with BDNF, glutamate, and cAMP-protein kinase A signaling pathways may mediate the antidepressant effects of ECT in humans. These genes, and others that increase only with chronic ECS such as neuropeptide Y and thyrotropin-releasing hormone, may provide novel ways to select drugs for the treatment of depression and mimic the rapid effectiveness of ECT.

Inducible cAMP early repressor regulates corticosterone suppression after tricyclic antidepressant treatment.

The cAMP-response element binding protein (CREB) is involved in antidepressant action, but the role of related CRE-binding transcription factors in the behavioral and endocrine responses to antidepressants is unclear. Alternative transcription of the cAMP response element-modulator (CREM) gene yields activator and repressor isoforms, including the strong repressor inducible cAMP early repressor (ICER). ICER is highly expressed in hypothalamic tissues and upregulated after electroconvulsive seizure. Thus, ICER may be a novel mediator of antidepressant action at endocrine and/or behavioral levels. Here we establish that both subchronic and chronic desipramine (DMI) treatments upregulate hypothalamic ICER expression in wild-type mice. Behavioral responses to DMI in the forced swim and tail suspension tests are unchanged in mice lacking ICER. However, the ability of DMI to suppress an acute corticosterone response after swim stress is compromised in ICER-deficient mice, suggesting that increased hypothalamic ICER mRNA after DMI treatment may be required for suppression of corticosterone release. To investigate the mechanism underlying this response, we measured corticotropin releasing factor (CRF), an upstream modulator of corticosterone release. Using real-time quantitative PCR, we establish that hypothalamic CRF expression is significantly reduced after swim exposure in DMI-treated wild-type mice, however DMI is unable to blunt hypothalamic CRF expression in ICER-deficient mice. Furthermore, we demonstrate that ICER is enriched in CRF-expressing neurons in the paraventricular nucleus of the hypothalamus. These data indicate that ICER is required for DMI to reduce stress-induced corticosterone release through regulation of hypothalamic CRF expression, revealing a novel role for ICER in antidepressant regulation of the hypothalamic-pituitary adrenal axis.

Electroconvulsive seizures induce proliferation of NG2-expressing glial cells in adult rat amygdala

BackgroundVolumetric changes and glial pathology have been reported in the amygdala in patients with major depressive disorder. Here we report an analysis of glial cell proliferation in response to electroconvulsive seizures (ECS), clinically used for the treatment of severe depression. MethodsMale Wistar rats were subjected to five ECS-treatments and then injected with bromodeoxyuridine (BrdU) to detect cell proliferation in the amygdala. The animals were transcardially perfused either 12 hours or 3 weeks after the last BrdU injection. Tissue sections were double-stained for BrdU and the cell-type markers NG2, OX-42, RIP, S-100β, Doublecortin, or NeuN. ResultsElectroconvulsive seizures dramatically increased the proliferation of amygdala cells expressing the oligodendrocyte progenitor marker NG2. Bromodeoxyuridine-labeled NG2-expressing cells were still present after 3 weeks of survival, and a small proportion of the proliferating cells had differentiated into mature oligodendrocytes. ConclusionsMajor depression has been associated with a reduction of glial cells. Our results show that ECS, an antidepressant treatment, significantly increases the number of NG2+ glial cells and mature oligodendrocytes in the adult rat amygdala.

Gene Profile of Electroconvulsive Seizures: Induction of Neurotrophic and Angiogenic Factors

Electroconvulsive seizure therapy (ECS) is a clinically proven treatment for depression and is often effective even in patients resistant to chemical antidepressants. However, the molecular mechanisms underlying the therapeutic efficacy of ECS are not fully understood. One theory that has gained attention is that ECS and other antidepressants increase the expression of select neurotrophic factors that could reverse or block the atrophy and cell loss resulting from stress and depression. To further address this topic, we examined the expression of other neurotrophic-growth factors and related signaling pathways in the hippocampus in response to ECS using a custom growth factor microarray chip. We report the regulation of several genes that are involved in growth factor and angiogenic-endothelial signaling, including neuritin, stem cell factor, vascular endothelial growth factor (VEGF), VGF (nonacronymic), cyclooxygenase-2, and tissue inhibitor of matrix metalloproteinase-1. Some of these, as well as other growth factors identified, including VEGF, basic fibroblast growth factor, and brain-derived neurotrophic factor, have roles in mediating neurogenesis and cell proliferation in the adult brain. We also examined gene expression in the choroid plexus and found several growth factors that are enriched in this vascular tissue as well as regulated by ECS. These data suggest that an amplification of growth factor signaling combined with angiogenic mechanisms could have an important role in the molecular action of ECS. This study demonstrates the applicability of custom-focused microarray technology in addressing hypothesis-driven questions regarding the action of antidepressants.

Electroconvulsive seizures induce endothelial cell proliferation in adult rat hippocampus

Background Electroconvulsive 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. Methods Rats 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. Results A 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. Conclusions Our 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.

Electroconvulsive seizures induce proliferation of NG2-expressing glial cells in adult rat hippocampus

Background Analysis of postmortem tissue from patients with major depression and bipolar disorder has revealed structural changes in several brain regions. We have shown that electroconvulsive seizure (ECS), used for the treatment of severe depression, induces proliferation of both neuronal and nonneuronal cells in the adult rat hippocampus. Methods Male Wistar rats were subjected to one or several ECS treatments, then injected with bromodeoxyuridine (BrdU) to detect cell proliferation. Animals were perfused either 1 day or 3 weeks following the last BrdU injection. Cells were double stained for BrdU and the cell type markers chondroitin sulfate proteoglycan (NG2), complement 3-receptor OX-42, 2′, 3′-cyclic nucleotide 3′-phosphodiesterase (CNPase), Ca + binding protein S100-β, or neuron-specific nuclear protein (NeuN). Results We identified NG2-expressing cells as a major cell type proliferating in the rat dentate gyrus in response to ECS. A sharp increase in NG2-positive cell proliferation was seen 2 days after ECS, and a large number of NG2-expressing cells persisted at 3 weeks. Conclusions Our results show that antidepressant treatment can induce a strong proliferation of glial progenitor cells in the adult rat hippocampus. We propose that this may counteract degenerative changes found in depression and be an important neurobiological event underlying the clinical effect of electroconvulsive seizures.

Chronic electroconvulsive seizure up-regulates β-catenin expression in rat hippocampus: role in adult neurogenesis

Background Beta-catenin was discovered as a cytoskeletal protein, constituting a link between the cadherins to the actin cytoskeleton. Aside from this function, β-catenin is a key effector molecule in the Wnt signaling pathway, serving as a downstream transcription factor. Methods In this study, we examined the influence of electroconvulsive seizures (ECS) on the expression of β-catenin, as well as expression of Wnt-2, in rat hippocampus. Repeated administration of generalized seizures increased levels of β-catenin immunoreactivity in the subgranular zone of the hippocampus. To assess the relationship of β-catenin to cell division in the dentate gyrus of the adult rat hippocampus, colocalization of β-catenin with a marker of cell division was examined. Results Beta-catenin immunoreactivity was consistently localized in newborn cells in this region, indicating a possible role in cell division and differentiation in adult hippocampus. We also found that ECS treatment significantly increased levels of Wnt-2, one of the ligands that activates β-catenin signaling. Conclusions These results demonstrate that ECS increases Wnt-β-catenin signaling and suggest that this pathway could mediate in part the neuronal adaptations underlying the therapeutic action of this treatment paradigm.

Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain

Background The antidepressant-like effects of brain-derived neurotrophic factor (BDNF) infusions in brain, and the upregulation of BDNF mRNA and its receptor in rats exposed to electroconvulsive seizure (ECS) and antidepressants, suggested a role for increased BDNF protein. Methods We measured BDNF protein levels with a two-site enzyme-linked immunosorbent assay (ELISA) in six brain regions of adult male rats that received daily ECS or daily injections of antidepressant drugs. Results The BDNF ELISA method was validated by the 50% loss of BDNF protein in the brains of +/− BDNF knockout mice, the 60%–100% recovery of spiked recombinant BDNF, and by the amounts and regional variations of BDNF measured in the six brain regions. Ten consecutive daily exposures to ECS increased BDNF protein in the parietal cortex (219%), entorhinal cortex (153%), hippocampus (132%), frontal cortex (94%), neostriatum (67%), and septum (29%). BDNF increased gradually in the hippocampus and frontal cortex, with a peak response by the fourth day of ECS. Increases peaked at 15 hours after the last ECS and lasted at least 3 days thereafter. Two weeks of daily injections with the monoamine (MAO)-A and -B inhibitor tranylcypromine (8–10 mg/kg, IP) increased BDNF by 15% in the frontal cortex, and 3 weeks treatment increased it by 18% in the frontal cortex and by 29% in the neostriatum. Tranylcypromine, fluoxetine, and desmethylimipramine did not elevate BDNF in the hippocampus. Conclusions Elevations in BDNF protein in brain are consistent with the greater treatment efficacy of ECS and MAO inhibitors in drug-resistant major depressive disorder and may be predictive for the antidepressant action of the more highly efficacious interventions.

Differential regulation of Brain Derived Neurotrophic Factor transcripts by antidepressant treatments in the adult rat brain

Antidepressants are known to increase brain derived neurotrophic factor (BDNF) mRNA in the adult rat brain. The BDNF gene has four differentially regulated promoters that generate four transcript forms, each containing a unique non-coding 5′ exon (exon I–IV) and a common 3′ coding exon. Using in situ hybridization with exon-specific riboprobes, we have examined whether diverse classes of antidepressants recruit a single or multiple BDNF promoters to regulate BDNF mRNAs. The antidepressants tested were electroconvulsive seizure (ECS) and the pharmacological antidepressants tranylcypromine, desipramine and fluoxetine. The effects of both acute and chronic ECS were the most prominent on exon I and II containing BDNF mRNAs in hippocampal and cortical subfields. Chronic ECS enhanced the acute induction of exon I, II and IV mRNAs but did not influence the acute upregulation of exon III mRNAs. Acute pharmacological antidepressants resulted in region-specific decreases in distinct exon-specific BDNF transcripts. In contrast, chronic administration with tranylcypromine and desipramine enhanced exon II and exon III mRNAs, respectively, in discrete hippocampal and cortical subfields. Chronic fluoxetine treatment did not have a significant effect on the exon-specific BDNF transcripts. The results indicate that distinct antidepressants differentially regulate BDNF mRNAs through a region-specific recruitment of the four BDNF promoters and suggest that diverse signaling mechanisms may be recruited to regulate BDNF transcripts.

Accumulation of 7S SNARE complexes in hippocampal synaptosomes from chronically kindled rats.

Kindling is a model of complex partial epilepsy wherein periodic application of an initially subconvulsive stimulus leads to first limbic and then generalized tonic-clonic seizures. Several laboratories have reported that augmented neurotransmitter release of l-glutamate is associated with the chronically kindled state. Neurotransmitter release requires membrane proteins called SNAREs, which form transmembrane complexes that participate in vesicle docking and are required for membrane fusion. We show here that kindling by entorhinal stimulation is associated with an accumulation of 7S SNARE complexes in the ipsilateral hippocampus. This increase of 7S SNARE complexes appears to begin early in the kindling process, achieves a peak with full kindling, and remains at this level for at least a month following cessation of further kindling stimuli. The increase is focal and permanently limited to the ipsilateral hippocampus despite progression to generalized electrographic and behavioral seizures. It is not seen in animals that receive electroconvulsive seizures, suggesting it is related to the kindling process itself. The duration and focality of increased 7S SNARE complexes with entorhinal kindling suggest that this is an altered molecular process associated with epileptogenesis.

Regulation of regulators of G protein signaling mRNA expression in rat brain by acute and chronic electroconvulsive seizures.

G protein-coupled receptor (GPCR) signaling cascades may be key substrates for the antidepressant effects of chronic electroconvulsive seizures (ECS). To better understand changes in these signaling pathways, alterations in levels of mRNA's encoding regulators of G protein signaling (RGS) protein subtypes-2, -4, -7, -8 and -10 were evaluated in rat brain using northern blotting and in situ hybridization. In prefrontal cortex, RGS2 mRNA levels were increased several-fold 2 h following an acute ECS. Increases in RGS8 mRNA were of lesser magnitude (30%), and no changes were evident for the other RGS subtypes. At 24 h following a chronic ECS regimen, RGS4, -7, and -10 mRNA levels were reduced by 20-30%; only RGS10 was significantly reduced 24 h after acute ECS. Levels of RGS2 mRNA were unchanged 24 h following either acute or chronic ECS. In hippocampus, RGS2 mRNA levels were markedly increased 2 h following acute ECS. More modest increases were seen for RGS4 mRNA expression, whereas levels of the other RGS subtypes were unaltered. At 24 h following chronic ECS, RGS7, -8 and -10 mRNA levels were decreased in the granule cell layer, and RGS7 and -8 mRNA levels were decreased in the pyramidal cell layers. Only RGS8 and -10 mRNA levels were significantly reduced in hippocampus 24 h following an acute ECS. Paralleling neocortex, RGS2 mRNA content was unchanged in hippocampus 24 h following either acute or chronic ECS. In ventromedial hypothalamus, RGS4 mRNA content was increased 24 h following chronic ECS, whereas RGS7 mRNA levels were only increased 24 h following an acute ECS. The increased RGS4 mRNA levels in hypothalamus were significant by 2 h following an acute ECS. These studies demonstrate subtype-, time-, and region-specific regulation of RGS proteins by ECS, adaptations that may contribute to the antidepressant effects of this treatment.

Electroconvulsive seizures increase hippocampal neurogenesis after chronic corticosterone treatment

Major depression is often associated with elevated glucocorticoid levels. High levels of glucocorticoids reduce neurogenesis in the adult rat hippocampus. Electroconvulsive seizures (ECS) can enhance neurogenesis, and we investigated the effects of ECS in rats where glucocorticoid levels were elevated in order to mimic conditions seen in depression. Rats given injections of corticosterone or vehicle for 21 days were at the end of this period treated with either a single or five daily ECSs. Proliferating cells were labelled with bromodeoxyuridine (BrdU). After 3 weeks, BrdU-positive cells in the dentate gyrus were quantified and analyzed for co-labelling with the neuronal marker neuron-specific nuclear protein (NeuN). In corticosterone-treated rats, neurogenesis was decreased by 75%. This was counteracted by a single ECS. Multiple ECS further increased neurogenesis and no significant differences in BrdU/NeuN positive cells were detected between corticosterone- and vehicle-treated rats given five ECS. Approximately 80% of the cells within the granule cell layer and 10% of the hilar cells were double-labelled with BrdU and NeuN. We therefore conclude that electroconvulsive seizures can increase hippocampal neurogenesis even in the presence of elevated levels of glucocorticoids. This further supports the hypothesis that induction of neurogenesis is an important event in the action of antidepressant treatment.

Brain-derived-neurotrophic-factor (BDNF) stress response in rats bred for learned helplessness.

Stress-induced elevation of glucocorticoids is accompanied by structural changes and neuronal damage in certain brain areas. This includes reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus which can be prevented by chronic electroconvulsive seizures and antidepressant drug treatment. In the last years we have bred two strains of rats, one which reacts with congenital helplessness to stress (cLH), and one which congenitally does not acquire helplessness when stressed (cNLH). After being selectively bred for more than 40 generations these strains have lost their behavioural plasticity including their sensitivity to antidepressant treatment. We show here that in cLH rats, acute immobilization stress does not induce a reduction of BDNF expression in the hippocampus which is observed in Sprague--Dawley and cNLH rats. All animals tested exhibited elevated corticosterone levels when stressed, an indication, that in cLH rats regulation of BDNF expression in the hippocampal formation is uncoupled from corticosterone increase induced through stress. This may explain the lack of adaptive responses in this strain.