Virtual reality exposure therapy for fear of spiders: an open trial and feasibility study of a new treatment for arachnophobia.

PURPOSE: This analogue pilot study examined the feasibility (i.e. preliminary results, safety, acceptability) of a new single-session treatment for adults with a fear of spiders. MATERIALS: It used state-of-the-art consumer available VR-hardware for therapist-assisted exposure (VRET-AP). The VRET-AP is largely adapted from Öst's one-session treatment for arachnophobia (Öst, 1987), with the aim of addressing shortcomings of previous VRET treatments, such as marked differences in procedures compared to available and evidence based in-vivo treatments. METHOD: Participants (N = 12) were screened for fear of spiders using the Spider Phobia Questionnaire (SPQ), Fear Questionnaire (FQ) and the Behavioral Approach Test (BAT), prior to and directly after treatment in a repeated measures quasi-experimental design. In addition, acceptance and completion rates were measured and participants were interviewed about their experience of the treatment. Mean ratings as well as Reliable Change Index (RCI) for individual trajectories were analyzed. RESULTS: The results from the preliminary data indicates potential for improvements with large effect sizes (d = 0.90-1,384) in all measurements of spider fear at post-treatment. Reliable Change Index (RCI) analysis showed that spider fear diminished in all twelve participants although the change was certain in only two. None deteriorated. All that responded accepted the treatment and all 11 participants completed all levels in the treatment. No concerns or adverse effects were reported in the interviews which largely confirm the quantitative results. CONCLUSION: VRET-AP is a feasible alternative for delivering effective treatment for fear of spiders and the results motivate larger, randomized trials of VRET-AP involving participants diagnosed with arachnophobia.

Racemic Ketamine as an Alternative to Electroconvulsive Therapy for Unipolar Depression: A Randomized, Open-Label, Non-Inferiority Trial (KetECT).

BACKGROUND: Ketamine has emerged as a fast-acting and powerful antidepressant, but no head to head trial has been performed, Here, ketamine is compared with electroconvulsive therapy (ECT), the most effective therapy for depression. METHODS: Hospitalized patients with unipolar depression were randomized (1:1) to thrice-weekly racemic ketamine (0.5 mg/kg) infusions or ECT in a parallel, open-label, non-inferiority study. The primary outcome was remission (Montgomery Åsberg Depression Rating Scale score ≤10). Secondary outcomes included adverse events (AEs), time to remission, and relapse. Treatment sessions (maximum of 12) were administered until remission or maximal effect was achieved. Remitters were followed for 12 months after the final treatment session. RESULTS: In total 186 inpatients were included and received treatment. Among patients receiving ECT, 63% remitted compared with 46% receiving ketamine infusions (P = .026; difference 95% CI 2%, 30%). Both ketamine and ECT required a median of 6 treatment sessions to induce remission. Distinct AEs were associated with each treatment. Serious and long-lasting AEs, including cases of persisting amnesia, were more common with ECT, while treatment-emergent AEs led to more dropouts in the ketamine group. Among remitters, 70% and 63%, with 57 and 61 median days in remission, relapsed within 12 months in the ketamine and ECT groups, respectively (P = .52). CONCLUSION: Remission and cumulative symptom reduction following multiple racemic ketamine infusions in severely ill patients (age 18-85 years) in an authentic clinical setting suggest that ketamine, despite being inferior to ECT, can be a safe and valuable tool in treating unipolar depression.

Monosynaptic retrograde tracing of neurons expressing the G-protein coupled receptor Gpr151 in the mouse brain.

GPR151 is a G-protein coupled receptor for which the endogenous ligand remains unknown. In the nervous system of vertebrates, its expression is enriched in specific diencephalic structures, where the highest levels are observed in the habenular area. The habenula has been implicated in a range of different functions including behavioral flexibility, decision making, inhibitory control, and pain processing, which makes it a promising target for treating psychiatric and neurological disease. This study aimed to further characterize neurons expressing the Gpr151 gene, by tracing the afferent connectivity of this diencephalic cell population. Using pseudotyped rabies virus in a transgenic Gpr151-Cre mouse line, monosynaptic afferents of habenular and thalamic Gpr151-expressing neuronal populations could be visualized. The habenular and thalamic Gpr151 systems displayed both shared and distinct connectivity patterns. The habenular neurons primarily received input from basal forebrain structures, the bed nucleus of stria terminalis, the lateral preoptic area, the entopeduncular nucleus, and the lateral hypothalamic area. The Gpr151-expressing neurons in the paraventricular nucleus of the thalamus was primarily contacted by medial hypothalamic areas as well as the zona incerta and projected to specific forebrain areas such as the prelimbic cortex and the accumbens nucleus. Gpr151 mRNA was also detected at low levels in the lateral posterior thalamic nucleus which received input from areas associated with visual processing, including the superior colliculus, zona incerta, and the visual and retrosplenial cortices. Knowledge about the connectivity of Gpr151-expressing neurons will facilitate the interpretation of future functional studies of this receptor.

Systematic evaluation of skeletal fractures caused by induction of electroconvulsive seizures in rat state a need for attention and refinement of the procedure.

OBJECTIVE: Electroconvulsive therapy (ECT) is one of the most efficient treatments for major depression. Electroconvulsive seizures (ECS), the animal model of ECT, is widely used to study both mechanisms of action and adverse effects of ECT. As the treatment itself serves as an instant anaesthetic and anaesthetic agents may affect memory functions and behaviour, ECS is traditionally administered without muscle relaxation and anaesthesia. A major problem of unmodified ECS, which has only been addressed peripherally in the literature, is that some animals sustain spinal fractures and subsequent hind leg paralysis (paraplegia). This phenomenon leads to a higher degree of suffering and these animals need to be excluded from the studies. To reach sufficient statistical power, the group sizes are therefore often increased and this may lead to a pre-selected study group in risk of skewing the results. Moreover, the study design of the experiments do not comply with the 3R principles, which advocate for both refinement and reduction of animal experiments. The objective of this study is to systematically evaluate injuries caused by ECS. METHODS: We summarise the incidence of spinal fractures from 24 studies conducted during 2009-2015 in six different rat strains and report preliminary findings on scapular fractures following auricular ECS. RESULTS: In total, 12.8% of all tested animals suffered from spinal fractures and we find an increase in spinal fracture incidence over time. Furthermore, X-ray analyses revealed that some animals displayed scapular fractures. CONCLUSION: We discuss consequences of and possible explanations for ECS-induced fractures. Modifications of the method are highly warranted and we furthermore suggest that all animals are thoroughly examined for discrete fractures.

EUDOR-A multi-centre research program: A naturalistic, European Multi-centre Clinical study of EDOR Test in adult patients with primary depression.

BACKGROUND: Electrodermal reactivity has been successfully used as indicator of interest, curiosity as well as depressive states. The measured reactivity depends on the quantity of sweat secreted by those eccrine sweat glands that are located in the hypodermis of palmar and plantar regions. Electrodermal hyporeactive individuals are those who show an unusual rapid habituation to identical non-significant stimuli. Previous findings suggested that electrodermal hyporeactivity has a high sensitivity and a high specificity for suicide. The aims of the present study are to test the effectiveness and the usefulness of the EDOR (ElectroDermal Orienting Reactivity) Test as a support in the suicide risk assessment of depressed patients and to assess the predictive value of electrodermal hyporeactivity, measured through the EDOR Test, for suicide and suicide attempt in adult patients with a primary diagnosis of depression. METHODS AND DESIGN: 1573 patients with a primary diagnosis of depression, whether currently depressed or in remission, have been recruited at 15 centres in 9 different European countries. Depressive symptomatology was evaluated through the Montgomery-Asberg Depression Scale. Previous suicide attempts were registered and the suicide intent of the worst attempt was rated according to the first eight items of the Beck Suicide Intent Scale. The suicide risk was also assessed according to rules and traditions at the centre. The EDOR Test was finally performed. During the EDOR Test, two fingers are put on gold electrodes and direct current of 0.5 V is passed through the epidermis of the fingers according to standards. A moderately strong tone is presented through headphones now and then during the test. The electrodermal responses to the stimuli represent an increase in the conductance due to the increased number of filled sweat ducts that act as conductors through the electrically highly resistant epidermis. Each patient is followed up for one year in order to assess the occurrence of intentional self-harm. DISCUSSION: Based on previous studies, expected results would be that patients realizing a suicide attempt with a strong intent or committing suicide should be electrodermally hyporeactive in most cases and non-hyporeactive patients should show only few indications of death intent or suicides. TRIAL REGISTRATION: The German Clinical Trials Register, DRKS00010082 . Registered May 31st, 2016. Retrospectively registered.

Spatial memory impairment in Morris water maze after electroconvulsive seizures.

OBJECTIVE: Electroconvulsive therapy (ECT) is one of the most efficient treatments for severe major depression, but some patients suffer from retrograde memory loss after treatment. Electroconvulsive seizures (ECS), an animal model of ECT, have repeatedly been shown to increase hippocampal neurogenesis, and multiple ECS treatments cause retrograde amnesia in hippocampus-dependent memory tasks. Since recent studies propose that addition of newborn hippocampal neurons might degrade existing memories, we investigated whether the memory impairment after multiple ECS treatments is a cumulative effect of repeated treatments, or if it is the result of a delayed effect after a single ECS. METHODS: We used the hippocampus-dependent memory task Morris water maze (MWM) to evaluate spatial memory. Rats were exposed to an 8-day training paradigm before receiving either a single ECS or sham treatment and tested in the MWM 24 h, 72 h, or 7 days after this treatment, or multiple (four) ECS or sham treatments and tested 7 days after the first treatment. RESULTS: A single ECS treatment was not sufficient to cause retrograde amnesia whereas multiple ECS treatments strongly disrupted spatial memory in the MWM. CONCLUSION: The retrograde amnesia after multiple ECS is a cumulative effect of repeated treatments rather than a delayed effect after a single ECS.

Effect of electroconvulsive seizures on cognitive flexibility.

Electroconvulsive seizures (ECS), an animal model of electroconvulsive therapy, strongly stimulate hippocampal neurogenesis, but it is not known how this relates to the therapeutic effect or to the unwanted cognitive side effects. Recent findings suggest that neurogenesis might be important for flexible learning in changing environments. We hypothesize that animals receiving ECS treatment, which induces hippocampal neurogenesis, will show enhanced cognitive flexibility compared with controls. We have utilized a touch screen-based cognitive test (location discrimination (LD) task) to assess how five consecutive ECS treatments affect cognitive flexibility (measured as reversal of cognitive strategy) as well as spatial pattern separation ability. ECS-treated animals performed more reversals in the LD task earlier than controls over the 9 experimental weeks irrespective of spatial separation of visual stimuli, indicating an enhanced cognitive flexibility but unaffected pattern separation ability after ECS. We observed no correlation between hippocampal neurogenesis and the number of performed reversals during the last experimental week. This is the first study to elucidate the effect of ECS on cognitive flexibility. Our results indicate that ECS improves cognitive flexibility without affecting spatial pattern separation ability. Whether cognitive flexibility is enhanced via neurogenesis or other ECS-modulated processes, remains unknown. © 2016 Wiley Periodicals, Inc.

Effect of electroconvulsive seizures on pattern separation.

Strategies employing different techniques to inhibit or stimulate neurogenesis have implicated a role for adult-born neurons in the therapeutic effect of antidepressant drugs, as well as a role in memory formation. Electroconvulsive seizures (ECS), an animal model of electroconvulsive therapy, robustly stimulate hippocampal neurogenesis, but it is not known how this relates to either therapeutic efficacy or unwanted cognitive side effects. We hypothesized that the ECS-derived increase in adult-born neurons would manifest in improved pattern separation ability, a memory function that is believed to be both hippocampus-dependent and coupled to neurogenesis. To test this hypothesis, we stimulated neurogenesis in adult rats by treating them with a series of ECS and compared their performances in a trial-unique delayed nonmatching-to-location task (TUNL) to a control group. TUNL performance was analyzed over a 12-week period, during which newly formed neurons differentiate and become functionally integrated in the hippocampal neurocircuitry. Task difficulty was manipulated by modifying the delay between sample and choice, and by varying the spatial similarity between target and distracter location. Although animals learned the task and improved the number of correct responses over time, ECS did not influence spatial pattern separation ability.

Conserved expression of the GPR151 receptor in habenular axonal projections of vertebrates.

The habenula is a phylogenetically conserved brain structure in the epithalamus. It is a major node in the information flow between fronto-limbic brain regions and monoaminergic brainstem nuclei, and is thus anatomically and functionally ideally positioned to regulate emotional, motivational, and cognitive behaviors. Consequently, the habenula may be critically important in the pathophysiology of psychiatric disorders such as addiction and depression. Here we investigated the expression pattern of GPR151, a G protein-coupled receptor (GPCR), whose mRNA has been identified as highly and specifically enriched in habenular neurons by in situ hybridization and translating ribosome affinity purification (TRAP). In the present immunohistochemical study we demonstrate a pronounced and highly specific expression of the GPR151 protein in the medial and lateral habenula of rodent brain. Specific expression was also seen in efferent habenular fibers projecting to the interpeduncular nucleus, the rostromedial tegmental area, the rhabdoid nucleus, the mesencephalic raphe nuclei, and the dorsal tegmental nucleus. Using confocal microscopy and quantitative colocalization analysis, we found that GPR151-expressing axons and terminals overlap with cholinergic, substance P-ergic, and glutamatergic markers. Virtually identical expression patterns were observed in rat, mouse, and zebrafish brains. Our data demonstrate that GPR151 is highly conserved, specific for a subdivision of the habenular neurocircuitry, and constitutes a promising novel target for psychiatric drug development.

Orchestrated regulation of Nogo receptors, LOTUS, AMPA receptors and BDNF in an ECT model suggests opening and closure of a window of synaptic plasticity.

Electroconvulsive therapy (ECT) is an efficient and relatively fast acting treatment for depression. However, one severe side effect of the treatment is retrograde amnesia, which in certain cases can be long-term. The mechanisms behind the antidepressant effect and the amnesia are not well understood. We hypothesized that ECT causes transient downregulation of key molecules needed to stabilize synaptic structure and to prevent Ca2+ influx, and a simultaneous increase in neurotrophic factors, thus providing a short time window of increased structural synaptic plasticity. Here we followed regulation of NgR1, NgR3, LOTUS, BDNF, and AMPA subunits GluR1 and GluR2 flip and flop mRNA levels in hippocampus at 2, 4, 12, 24, and 72 hours after a single episode of induced electroconvulsive seizures (ECS) in rats. NgR1 and LOTUS mRNA levels were transiently downregulated in the dentate gyrus 2, 4, 12 and 4, 12, 24 h after ECS treatment, respectively. GluR2 flip, flop and GluR1 flop were downregulated at 4 h. GluR2 flip remained downregulated at 12 h. In contrast, BDNF, NgR3 and GluR1 flip mRNA levels were upregulated. Thus, ECS treatment induces a transient regulation of factors important for neuronal plasticity. Our data provide correlations between ECS treatment and molecular events compatible with the hypothesis that both effects and side effects of ECT may be caused by structural synaptic rearrangements.

Repeated electroconvulsive seizures increase the number of vessel-associated macrophages in rat hippocampus.

OBJECTIVES: We have previously reported that electroconvulsive seizure (ECS)--an animal model of the antidepressant treatment electroconvulsive therapy--causes glial cell activation in hippocampus and other limbic areas. In the current study, we have investigated whether the cellular response to ECS includes recruitment and infiltration of nonresident macrophages into the hippocampal brain parenchyma. METHODS: Adult rats received 1 ECS daily for 10 consecutive days and were then killed at different time points after the last ECS treatment. Brain sections were immunostained for laminin, a matrix protein expressed in the basal membrane of blood vessels, in combination with anti-CD163, which identifies mature blood-borne macrophages. The number of CD163 cells in the hippocampus was quantified. We also investigated the number of vessel-associated cells expressing CD4 and major histocompatibility complex class II (MHC II). CD4 is mainly expressed by CD4 T cells, but can also be found on macrophages, monocytes, and activated microglia, whereas MHC II is expressed by macrophages, activated microglia, dendritic cells, and B cells. RESULTS: Our results demonstrate increased numbers of CD163 and CD4 cells following ECS. Most CD4 cells within the vasculature had a similar morphology to the CD163 macrophages. No CD163 cells were detected outside the vessels but a subpopulation of CD4 cells was seen in the brain parenchyma, here with a morphology resembling microglia. There was a transient increase in the number of blood vessel-associated MHC II cells following ECS. CONCLUSIONS: Our observations showed that the cellular response to ECS involves recruitment of blood-derived macrophages, but we could not see any infiltration into the brain parenchyma of these cells.

Glial cell activation in response to electroconvulsive seizures.

Electroconvulsive therapy (ECT) is a very efficient treatment for severe depression. However, cognitive side effects have raised concern to whether ECT can cause cellular damage in vulnerable brain regions. A few recent animal studies have reported limited hippocampal cell loss, while a number of other studies have failed to find any signs of cellular damage and some even report that electroconvulsive seizures (ECS; the animal counterpart of ECT) has neuroprotective effects. We previously have described gliogenesis in response to ECS. Loss of glial cells is seen in depression and de novo formation of glial cells may thus have an important therapeutic role. Glial cell proliferation and activation is however also seen in response to neuronal damage. The aim of the present study was to further characterize glial cell activation in response to ECS. Two groups of rats were treated with 10 ECS using different sets of stimulus parameters. ECS-induced changes in the morphology and expression of markers typical for reactive microglia, astrocytes and NG2+ glial cells were analyzed immunohistochemically in prefrontal cortex, hippocampus, amygdala, hypothalamus, piriform cortex and entorhinal cortex. We observed changes in glial cell morphology and an enhanced expression of activation markers 2 h following ECS treatment, regardless of the stimulus parameters used. Four weeks later, few activated glial cells persisted. In conclusion, ECS treatment induced transient glial cell activation in several brain areas. Whether similar processes play a role in the therapeutic effect of clinically administered ECT or contribute to its side effects will require further investigations.

Chronic lithium treatment decreases NG2 cell proliferation in rat dentate hilus, amygdala and corpus callosum.

An increasing number of investigations suggest volumetric changes and glial pathology in several brain regions of patients with bipolar disorder. Lithium, used in the treatment of this disorder, has been reported to be neuroprotective and increase brain volume. Here we investigate the effect of lithium on the proliferation and survival of glial cells positive for the chondroitin sulphate proteoglycan NG2 (NG2 cells); a continuously dividing cell type implicated in remyelination and suggested to be involved in regulation of neuronal signaling and axonal outgrowth. Adult male rats were treated with lithium for four weeks and injected with the proliferation marker bromodeoxyuridine (BrdU) before or at the end of the treatment period. Immunohistochemical analysis of brain sections was performed to estimate the number of newly born (BrdU-labeled) NG2 cells and oligodendrocytes in hippocampus, basolateral nuclei of amygdala and corpus callosum. Lithium significantly decreased the proliferation of NG2 cells in dentate hilus of hippocampus, amygdala and corpus callosum, but not in the molecular layer or the cornu ammonis (CA) regions of hippocampus. The effect was more pronounced in the corpus callosum. No effect of lithium on the survival of newborn cells or the number of newly generated oligodendrocytes could be detected. Our results demonstrate that in both white and gray matter brain regions implicated in the pathophysiology of bipolar disorder, chronic lithium treatment significantly decreases the proliferation rate of NG2 cells; the major proliferating cell type of the adult brain.

Environmental enrichment, exercise and corticosterone affect endothelial cell proliferation in adult rat hippocampus and prefrontal cortex.

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.

Differential inhibition of neurogenesis and angiogenesis by corticosterone in rats stimulated with electroconvulsive seizures.

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.

Region specific hypothalamic neuronal activation and endothelial cell proliferation in response to electroconvulsive seizures.

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.

Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression.

From clinical studies it is known that recurrent depressive episodes associate with a reduced hippocampal volume. Conversely, preclinical studies have shown that chronic antidepressant treatment increases hippocampal neurogenesis. Consequently, it has been suggested that a deficit in hippocampal neurogenesis is implicated in the pathophysiology of depression. To study a potential correlation between recovery and hippocampal cytogenesis, we established the chronic mild stress (CMS) rat model of depression. When rats are subjected to CMS, several depressive symptoms develop, including the major symptom anhedonia. Rats were exposed to stress for 2 weeks and subsequently to stress in combination with antidepressant treatment for 4 consecutive weeks. The behavioral deficit measured in anhedonic animals is a reduced intake of a sucrose solution. Prior to perfusion animals were injected with bromodeoxyuridine (BrdU), a marker of proliferating cells. Brains were sectioned horizontally and newborn cells positive for BrdU were counted in the dentate gyrus and tracked in a dorsoventral direction.CMS significantly decreased sucrose consumption and cytogenesis in the ventral part of the hippocampal formation. During exposure to the antidepressant escitalopram, given as intraperitoneally dosages of either 5 or 10 mg/kg/day, animals distributed in a bimodal fashion into a group, which recovered (increase in sucrose consumption), and a subgroup, which refracted treatment (no increase in sucrose consumption). Chronic treatment with escitalopram reversed the CMS-induced decrease in cytogenesis in the dentate gyrus of the ventral hippocampal formation, but in recovered animals only. Our data show a correlation between recovery from anhedonia, as measured by cessation of behavioral deficits in the CMS model, and an increase in cytogenesis in the dentate gyrus of the ventral hippocampal formation.

Corticosterone-induced inhibition of gliogenesis in rat hippocampus is counteracted by electroconvulsive seizures.

BACKGROUND: Volumetric changes and glial pathology have been reported in the central nervous system (CNS) of patients with depressive disorder, an illness often associated with elevated glucocorticoid levels. Glucocorticoids reduce gliogenesis in the adult rat CNS. Electroconvulsive seizure (ECS)-treatment, an animal model for the antidepressant treatment electroconvulsive therapy, can enhance proliferation of glial cells. This study examined glial cell proliferation in response to ECS in rats whose glucocorticoid levels were elevated to mimic the conditions seen in depression. METHODS: Rats were injected daily for seven days with either corticosterone or vehicle. ECS- or sham- treatment was given once daily during the first five days. Proliferating cells in the hippocampus were labeled with bromodeoxyuridine and analyzed for co-labeling with the glial cell markers NG2, Ox42, S-100beta and Rip. RESULTS: ECS counteracted the glucocorticoid-induced inhibition of NG2+, Ox42+ and Rip+ cell proliferation, and the gliogenesis rate was restored to baseline levels. Volumetric changes in rats treated with ECS were detected. CONCLUSIONS: Our results show that ECS-treatment affects the proliferation of glial cells even in the presence of elevated levels of glucocorticoids. This result adds to an increasing number of studies suggesting that antidepressant treatment can counteract degenerative processes associated with major depression.

Electroconvulsive seizures induce angiogenesis in adult rat hippocampus.

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.