Boldizsár Czéh

Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine

Stress-induced structural remodeling in the adult hippocampus, involving debranching and shortening of dendrites and suppression of neurogenesis, provides a cellular basis for understanding the impairment of neural plasticity in the human hippocampus in depressive illness. Accordingly, reversal of structural remodeling may be a desirable goal for antidepressant therapy. The present study investigated the effect of tianeptine, a modified tricyclic antidepressant, in the chronic psychosocial stress model of adult male tree shrews (Tupaia belangeri), a model with high validity for research on the pathophysiology of major depression. Animals were subjected to a 7-day period of psychosocial stress to elicit stress-induced endocrine and central nervous alterations before the onset of daily oral administration of tianeptine (50 mg/kg). The psychosocial stress continued throughout the treatment period of 28 days. Brain metabolite concentrations were determined in vivo by proton magnetic resonance spectroscopy, cell proliferation in the dentate gyrus was quantified by using BrdUrd immunohistochemistry, and hippocampal volume was measured post mortem. Chronic psychosocial stress significantly decreased in vivo concentrations of N-acetyl-aspartate (−13%), creatine and phosphocreatine (−15%), and choline-containing compounds (−13%). The proliferation rate of the granule precursor cells in the dentate gyrus was reduced (−33%). These stress effects were prevented by the simultaneous administration of tianeptine yielding normal values. In stressed animals treated with tianeptine, hippocampal volume increased above the small decrease produced by stress alone. These findings provide a cellular and neurochemical basis for evaluating antidepressant treatments with regard to possible reversal of structural changes in brain that have been reported in depressive disorders.

Prenatal stress diminishes neurogenesis in the dentate gyrus of juvenile Rhesus monkeys

BACKGROUND Early life stress, including during fetal development, has been hypothesized to predispose individuals to several illnesses and psychiatric disorders later in adulthood. METHODS To determine whether prenatal stress alters neural, hormonal, and behavioral processes in nonhuman primates, pregnant rhesus monkeys were acutely stressed on a daily basis for 25% of their 24-week gestation with an acoustical startle protocol. At 2 to 3 years of age, hippocampal volume, neurogenesis in the dentate gyrus, and cortisol levels were evaluated in the offspring generated from stressed and control pregnancies. RESULTS Prenatal stress, both early and late in pregnancy, resulted in a reduced hippocampal volume and an inhibition of neurogenesis in the dentate gyrus. These changes were associated with increased pituitary-adrenal activity, as reflected by higher cortisol levels after a dexamethasone suppression test, and also with behavioral profiles indicative of greater emotionality. CONCLUSIONS These findings indicate that the prenatal environment can alter behavior, dysregulate neuroendocrine systems, and affect the hippocampal structure of primates in a persistent manner.

What causes the hippocampal volume decrease in depression? : Are neurogenesis, glial changes and apoptosis implicated?

Even though in vivo imaging studies document significant reductions of hippocampal volume in depressed patients, the exact underlying cellular mechanisms are unclear. Since stressful life events are associated with an increased risk of developing depression, preclinical studies in which animals are exposed to chronic stress have been used to understand the hippocampal shrinkage in depressed patients. Based on morphometrical studies in these models, parameters like dendritic retraction, suppressed adult neurogenesis and neuronal death, all due to elevated levels of glucocorticoids, have been suggested as major causative factors in hippocampal shrinkage. However, histopathological studies examining hippocampi of depressed individuals have so far failed to confirm either a massive neuronal loss or a suppression of dentate neurogenesis, an event that is notably very rare in adult or elderly humans. In fact, many of the structural changes and the volume reduction appear to be reversible. Clearly, more histopathological studies are needed; especially ones that (a) employ stereological quantification, (b) focus on specific cellular elements and populations, and (c) are performed in nonmedicated depressed patients. We conclude that mainly other factors, like alterations in the somatodendritic, axonal, and synaptic components and putative glial changes are most likely to explain the hippocampal shrinkage in depression, while shifts in fluid balance or changes in the extracellular space cannot be excluded either.

Chronic psychosocial stress and concomitant repetitive transcranial magnetic stimulation: effects on stress hormone levels and adult hippocampal neurogenesis

BACKGROUND Repetitive transcranial magnetic stimulation is increasingly used as a therapeutic tool in psychiatry and has been demonstrated to attenuate the activity of the stress hormone system. Stress-induced structural remodeling in the adult hippocampus may provide a cellular basis for understanding the impairment of neural plasticity in depressive illness. Accordingly, reversal of structural remodeling might be a desirable goal for antidepressant therapy. The present study investigated the effect of chronic psychosocial stress and concomitant repetitive transcranial magnetic stimulation treatment on stress hormone regulation and hippocampal neurogenesis. METHODS Adult male rats were submitted to daily psychosocial stress and repetitive transcranial magnetic stimulation (20 Hz) for 18 days. Cell proliferation in the dentate gyrus was quantified by using BrdU immunohistochemistry, and both the proliferation rate of progenitors and the survival rate of BrdU-labeled cells were evaluated. To characterize the activity of the hypothalamic-pituitary-adrenocortical system, plasma corticotropin and corticosterone concentrations were measured. RESULTS Chronic psychosocial stress resulted in a significant increase of stress hormone levels and potently suppressed the proliferation rate and survival of the newly generated hippocampal granule cells. Concomitant repetitive transcranial magnetic stimulation treatment normalized the stress-induced elevation of stress hormones; however, despite the normalized activity of the hypothalamic-pituitary-adrenocortical system, the decrement of hippocampal cell proliferation was only mildly attenuated by repetitive transcranial magnetic stimulation, while the survival rate of BrdU-labeled cells was further suppressed by the treatment. CONCLUSIONS These results support the notion that attenuation of the hypothalamic-pituitary-adrenocortical system is an important mechanism underlying the clinically observed antidepressant effect of repetitive transcranial magnetic stimulation, whereas this experimental design did not reveal beneficial effects of repetitive transcranial magnetic stimulation on adult hippocampal neurogenesis.

Astroglial Plasticity in the Hippocampus is Affected by Chronic Psychosocial Stress and Concomitant Fluoxetine Treatment

Analysis of post-mortem tissue from patients with affective disorders has revealed a decreased number of glial cells in several brain areas. Here, we examined whether long-term psychosocial stress influences the number and morphology of hippocampal astrocytes in an animal model with high validity for research on the pathophysiology of major depression. Adult male tree shrews were submitted to 5 weeks of psychosocial stress, after which immunocytochemical and quantitative stereological techniques were used to estimate the total number and somal volume of glial fibrillary acidic protein-positive astrocytes in the hippocampal formation. Stress significantly decreased both the number (−25%) and somal volume (−25%) of astroglia, effects that correlated notably with the stress-induced hippocampal volume reduction. Additionally, we examined whether antidepressant treatment with fluoxetine, a selective serotonin reuptake inhibitor, offered protection from these stress-induced effects. Animals were subjected to 7 days of psychosocial stress before the onset of daily oral administration of fluoxetine (15 mg/kg per day), with stress continued throughout the 28-day treatment period. Fluoxetine treatment prevented the stress-induced numerical decrease of astrocytes, but had no counteracting effect on somal volume shrinkage. In nonstressed animals, fluoxetine treatment had no effect on the number of astrocytes, but stress exposure significantly reduced their somal volumes (−20%). These notable changes of astroglial structural plasticity in response to stress and antidepressant treatment support the notion that glial changes may contribute to the pathophysiology of affective disorders as well as to the cellular actions of antidepressants.

Chronic Social Stress Inhibits Cell Proliferation in the Adult Medial Prefrontal Cortex: Hemispheric Asymmetry and Reversal by Fluoxetine Treatment

Profound neuroplastic changes have been demonstrated in various limbic structures after chronic stress exposure and antidepressant treatment in animal models of mood disorders. Here, we examined in rats the effect of chronic social stress and concomitant antidepressant treatment on cell proliferation in the medial prefrontal cortex (mPFC). We also examined possible hemispheric differences. Animals were subjected to 5 weeks of daily social defeat by an aggressive conspecific and received concomitant, daily, oral fluoxetine (10 mg/kg) during the last 4 weeks. Bromodeoxyuridine (BrdU) labeling and quantitative stereological techniques were used to evaluate the treatment effects on proliferation and survival of newborn cells in limbic structures such as the mPFC and the hippocampal dentate gyrus, in comparison with nonlimbic structures such as the primary motor cortex and the subventricular zone. Phenotypic analysis showed that neurogenesis dominated the dentate gyrus, whereas in the mPFC most newborn cells were glia, with smaller numbers of endothelial cells. Chronic stress significantly suppressed cytogenesis in the mPFC and neurogenesis in the dentate gyrus, but had minor effect in nonlimbic structures. Fluoxetine treatment counteracted the inhibitory effect of stress. Hemispheric comparison revealed that the rate of cytogenesis was significantly higher in the left mPFC of control animals, whereas stress inverted this asymmetry, yielding a significantly higher incidence of newborn cells in the right mPFC. Fluoxetine treatment abolished hemispheric asymmetry in both control and stressed animals. These pronounced changes in gliogenesis after chronic stress exposure may relate to the abnormalities of glial cell numbers reported in the frontolimbic areas of depressed patients.

Alterations of neuroplasticity in depression: the hippocampus and beyond

Early hypotheses on the pathophysiology of major depression were based on aberrant intrasynaptic concentrations of mainly the neurotransmitters serotonin and norepinephrine. However, recent neuroimaging studies have demonstrated selective structural changes across various limbic and nonlimbic circuits in the brains of depressed patients. In addition, postmortem morphometric studies revealed decreased glial and neuron densities in selected brain structures supporting the idea that major depression may be related to impairments of structural plasticity. Stressful life events are among the major predisposing risk factors for developing depression. Using the chronic psychosocial stress paradigm in male tree shrews, an animal model with a high validity for the pathophysiology of depressive disorders, we found that 1 month of stress reduced the in vivo concentrations of the brain metabolites N-acetyl-aspartate, choline-containing compounds, and (phospho)-creatine, as well as the proliferation rate in the dentate gyrus and the hippocampal volume. Even though long-lasting social conflict does not lead to a loss of principal cells, the hippocampal changes were accompanied by modifications in the incidence of apoptosis. Notably, these suppressive effects of social conflict on hippocampal structure could be counteracted by treatment with the antidepressant tianeptine. These findings support current theories proposing that major depressive disorders may be associated with impairment of structural plasticity and neural cellular resilience, and that antidepressants may act by correcting this dysfunction.

Antidepressant treatment with tianeptine reduces apoptosis in the hippocampal dentate gyrus and temporal cortex

BACKGROUND Recent clinical and preclinical studies suggest that major depression may be related to impairments of structural plasticity. Consequently, antidepressants may act by restoring altered rates of cell birth or death. Here, we investigated whether the antidepressant tianeptine would affect apoptosis in an animal model of depression, the psychosocially stressed tree shrew. METHODS Animals were subjected to a 7-day period of psychosocial stress before the onset of daily administration of tianeptine. Stress continued throughout the 28-day treatment period. In situ end labeling was used to detect apoptosis in hippocampus and adjacent temporal cortex. RESULTS Both stress and tianeptine treatment had a region-specific effect. Stress increased apoptosis in the temporal cortex, while it reduced it in the Ammons Horn. No significant effect was observed in the dentate gyrus. Interestingly, tianeptine treatment significantly reduced apoptosis in the temporal cortex and dentate gyrus, both in control and stressed animals, but had no effect in the Ammons Horn. Parallel Fluoro-Jade staining indicated that this apoptosis most likely represents non-neuronal cells. CONCLUSIONS This is the first report showing an anti-apoptotic effect of tianeptine in hippocampal subfields and temporal cortex. These findings are consistent with current theories that ascribe enhanced general cell survival to antidepressant action.

Stress, Depression and Hippocampal Apoptosis.

In this review, we summarize and discuss recent studies on structural plasticity changes, particularly apoptosis, in the mammalian hippocampus in relation to stress and depression. Apoptosis continues to occur, yet with very low numbers, in the adult hippocampal dentate gyrus (DG) of various species. Stress and steroid exposure modulate the rate of apoptosis in the DG. Contrary to earlier studies, the impact of chronic stress on structural parameters of the hippocampus like cell number and volume, is rather modest, and requires prolonged and severe stress exposure before only small reductions (< 10 %) become detectable. This does not exclude other structural parameters, like synaptic terminal structure, or dendritic arborization from being significantly altered in critical hippocampal subregions like the DG and/or CA3. Neither does it imply that the functional implications of the changes after stress are also modest. Of interest, most of the structural plasticity changes appear transient and are generally reversible after appropiate recovery periods, or following cessation or blockade of the stress or corticosteroid exposure. The temporary slowing down of both apoptosis and adult proliferation, i.e. the DG turnover, after chronic stress will affect the overall composition, average age and identity of DG cells, and will have considerable consequences for the connectivity, input and properties of the hippocampal circuit and thus for memory function. Modulation of apoptosis and neurogenesis, by drugs interfering with stress components like MR and/or GR, and/or mediators of the cell death cascade, may therefore provide important drug targets for the modulation of mood and memory.

Neuropathology of stress

Environmental challenges are part of daily life for any individual. In fact, stress appears to be increasingly present in our modern, and demanding, industrialized society. Virtually every aspect of our body and brain can be influenced by stress and although its effects are partly mediated by powerful corticosteroid hormones that target the nervous system, relatively little is known about when, and how, the effects of stress shift from being beneficial and protective to becoming deleterious. Decades of stress research have provided valuable insights into whether stress can directly induce dysfunction and/or pathological alterations, which elements of stress exposure are responsible, and which structural substrates are involved. Using a broad definition of pathology, we here review the “neuropathology of stress” and focus on structural consequences of stress exposure for different regions of the rodent, primate and human brain. We discuss cytoarchitectural, neuropathological and structural plasticity measures as well as more recent neuroimaging techniques that allow direct monitoring of the spatiotemporal effects of stress and the role of different CNS structures in the regulation of the hypothalamic–pituitary–adrenal axis in human brain. We focus on the hypothalamus, hippocampus, amygdala, nucleus accumbens, prefrontal and orbitofrontal cortex, key brain regions that not only modulate emotions and cognition but also the response to stress itself, and discuss disorders like depression, post-traumatic stress disorder, Cushing syndrome and dementia.