Gabriele Flügge

German Primate Center

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Eberhard Fuchs

German Primate Center

Boldizsár Czéh

University of Pecs

Nashat Abumaria

Fudan University

Ursula Havemann‐Reinecke

Universitätsmedizin Göttingen

Christina Schlumbohm

Charles River Laboratories (Netherlands)

Marja van Kampen

Bayer (Germany)

Christoph Hiemke

Johannes Gutenberg University Mainz

Rafał Ryguła

Polish Academy of Sciences

Eckart Rüther

Ludwig-Maximilians-Universität München

Lutz Walter

German Primate Center

Cooperative Institutions

German Primate Center

University of Göttingen

Universitätsmedizin Göttingen

Nanoscale Microscopy and Molecular Physiology of the Brain Cluster of Excellence 171 — DFG Research Center 103

Consejo Nacional de Investigaciones Científicas y Técnicas

Max Planck Society

Johannes Gutenberg University Mainz

McGill University

National Institutes of Health

University of Lübeck

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Preclinical approaches to examine novel concepts of the pathophysiology of depressive disorders: lessons learned from tree shrews

Drug Development Research (2005)

Eberhard Fuchs Boldizsár Czéh Gabriele Flügge

Abstract Recent studies have provided evidence that mood disorders such as major depression not only have a neurochemical basis but are also associated with alterations in neuronal and glial structures. Antidepressants may act by restoring structure as well as function of neural networks meaning that they may, as a fundamental principle, affect neural plasticity underlying normal brain functioning. To examine this novel concept of the pathophysiology of depression and antidepressant medication, we have carried out a series of experiments using the social stress paradigm in tree shrews, an animal model with a high validity for the pathophysiology of major depression. We found that 1 month of stress reduced the proliferation rate of newly born neurons in the dentate gyrus and decreased hippocampal volume. Notably, the suppressive effects of social conflict stress on hippocampal structure could be counteracted by treatments with different antidepressants such as clomipramine, tianeptine, and the selective NK1 receptor antagonists L‐760735. In addition, the stress‐induced decrease in number of parvalbumin‐containing cells in the hippocampal formation, presumably GABAergic interneurons, was prevented by concomitant treatment with fluoxetine. These studies show that different classes of antidepressants can reverse the structural alterations of the hippocampal formation induced by stress. Drug Dev. Res. 65:309–317, 2005. © 2005 Wiley‐Liss, Inc.

Tianeptine

Neurochemical

Clomipramine

10.1002/ddr.20032

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Citations (4)

Blockade of glucocorticoid receptors with ORG 34116 does not normalize stress-induced symptoms in male tree shrews

European Journal of Pharmacology (2002)

Marja van Kampen E. R. de Kloet Gabriele Flügge Eberhard Fuchs

Antiglucocorticoid

Chronic Stress

10.1016/s0014-2999(02)02664-x

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Citations (3)

The stress-regulated protein M6a is a key modulator for neurite outgrowth and filopodium/spine formation

Proceedings of the National Academy of Sciences (2005)

Julieta Alfonso María E. Fernández Benjamin H. Cooper Gabriele Flügge Alberto C.C. Frasch

Neuronal remodeling is a fundamental process by which the brain responds to environmental influences, e.g., during stress. In the hippocampus, chronic stress causes retraction of dendrites in CA3 pyramidal neurons. We have recently identified the glycoprotein M6a as a stress-responsive gene in the hippocampal formation. This gene is down-regulated in the hippocampus of both socially and physically stressed animals, and this effect can be reversed by antidepressant treatment. In the present work, we analyzed the biological function of the M6a protein. Immunohistochemistry showed that the M6a protein is abundant in all hippocampal subregions, and subcellular analysis in primary hippocampal neurons revealed its presence in membrane protrusions (filopodia/spines). Transfection experiments revealed that M6a overexpression induces neurite formation and increases filopodia density in hippocampal neurons. M6a knockdown with small interference RNA methodology showed that M6a low-expressing neurons display decreased filopodia number and a lower density of synaptophysin clusters. Taken together, our findings indicate that M6a plays an important role in neurite/filopodium outgrowth and synapse formation. Therefore, reduced M6a expression might be responsible for the morphological alterations found in the hippocampus of chronically stressed animals. Potential mechanisms that might explain the biological effects of M6a are discussed.

Filopodia

Neurite

Synaptophysin

10.1073/pnas.0504262102

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Citations (110)

Immunocytochemical localization of estrogen-binding neurons in the songbird brain

Brain Research (1987)

Manfred Gahr Gabriele Flügge Hans‐Rudolf Güttinger

Songbird

Preoptic area

10.1016/0006-8993(87)91063-8

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Citations (164)

Identification of genes regulated by chronic psychosocial stress and antidepressant treatment in the hippocampus

European Journal of Neuroscience (2004)

Julieta Alfonso Guido D. Pollevick Marieke G. Van Der Hart Gabriele Flügge Eberhard Fuchs

Abstract Analysis of differentially expressed genes in the brain is a promising tool for elucidating pathological mechanisms that lead to central nervous disorders. Stress is known to be involved in the development of psychopathologies such as depression. In the present study, we searched for differentially expressed genes in the hippocampal formation after chronic psychosocial stress and after treatment with the antidepressant clomipramine. Experiments were conducted in male tree shrews, a valid psychosocial stress model in which antidepressant drugs prevent diverse effects of stress. Because many effects of stress have been attributed to the stress‐induced elevation in glucocorticoids, we screened two subtractive hippocampal cDNA libraries generated from RNA of chronic cortisol‐treated animals. Using real‐time PCR to measure mRNA amounts, we identified five sequences whose expression levels differed between stressed animals and controls. Transcript levels of four of them, nerve growth factor (NGF), membrane glycoprotein 6a (M6a), CDC‐like kinase 1 (CLK‐1) and G‐protein alpha q (GNAQ) were reduced by chronic psychosocial stress. Reduced amounts of these genes, which are all related to processes of cell differentiation, is in agreement with previous findings showing a retraction of dendrites and an impairment of neurogenesis in the hippocampal formation after chronic stress. An additional expressed sequence that was also regulated by stress could not be assigned to any known gene. Treatment with the antidepressant clomipramine prevented stress effects on expression of M6a, CLK‐1, GNAQ and the novel sequence, but showed no effect on NGF stress‐induced down‐regulation. These findings support the concept that depressive disorders are accompanied by processes of neuronal dedifferentiation, at least in the hippocampal formation, and that antidepressants prevent these processes.

Clomipramine

Chronic Stress

10.1111/j.1460-9568.2004.03178.x

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Citations (118)

Perturbations in brain monoamine systems during stress

Cell and Tissue Research (2003)

Gabriele Flügge Marja van Kampen M. Janneke Mijnster

Monoaminergic

Neurotransmitter Systems

Chronic Stress

Homeostasis

10.1007/s00441-003-0807-0

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Citations (80)

Chronic psychosocial stress reduces the density of dopamine transporters

European Journal of Neuroscience (2000)

Eleonora Isovich M. Janneke Mijnster Gabriele Flügge Eberhard Fuchs

Abstract The effect of different types of physical stress on brain dopaminergic function has been well established in rodents; however, the role of the dopaminergic system in more naturalistic stress situations is poorly understood. Therefore, the aim of the current study was to investigate the effect of chronic psychosocial stress on the dopamine transporter, which is an important component in the regulation of dopaminergic neurotransmission. For this purpose, we used the well‐characterized paradigm of subordination stress in male tree shrews (Tupaia belangeri). In the present study, the animals were subjected to psychosocial stress for 28 days. Animals were daily videotaped and locomotor activity was quantified. In subordinate animals, urinary cortisol and noradrenaline, as well as adrenal weight, were increased, whereas body weight, locomotor activity and testicular function were decreased. Brain dopamine transporter binding sites were quantified by in vitro autoradiography using [ 3 H] WIN 35,428 as ligand. Chronic stress reduced the number of binding sites (B max ) in the caudate nucleus and the putamen without affecting the affinity (K d ). Stress did not influence the binding parameters in the nucleus accumbens, the substantia nigra or the ventral tegmental area. Furthermore, we found a positive correlation between locomotor activity and the B max values for [ 3 H] WIN 35,428 binding in the caudate nucleus, the putamen and the nucleus accumbens. The present study shows that a naturalistic stressor, such as chronic psychosocial conflict, decreases dopamine transporter binding sites in motor‐related brain areas, suggesting that the reduction in locomotor activity in subordinate tree shrews is related to the downregulation of dopamine transporter binding sites.

Putamen

Caudate nucleus

Chronic Stress

10.1046/j.1460-9568.2000.00969.x

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Citations (77)

CRE/CREB-Driven Up-Regulation of Gene Expression by Chronic Social Stress in CRE-Luciferase Transgenic Mice: Reversal by Antidepressant Treatment

PLoS ONE (2007)

Ulrike Böer Tahseen Alejel Stephan Beimesche Irmgard Cierny Doris Krause

It has been suggested that stress provokes neuropathological changes and may thus contribute to the precipitation of affective disorders such as depression. Likewise, the pharmacological therapy of depression requires chronic treatment and is thought to induce a positive neuronal adaptation, presumably based on changes in gene transcription. The transcription factor cAMP-responsive element binding protein (CREB) and its binding site (CRE) have been suggested to play a major role in both the development of depression and antidepressive therapy.To investigate the impact of stress and antidepressant treatment on CRE/CREB transcriptional activity, we generated a transgenic mouse line in which expression of the luciferase reporter gene is controlled by four copies of CRE. In this transgene, luciferase enzyme activity and protein were detected throughout the brain, e.g., in the hippocampal formation. Chronic social stress significantly increased (by 45 to 120%) CRE/CREB-driven gene expression measured as luciferase activity in several brain regions. This was also reflected by increased CREB-phosphorylation determined by immunoblotting. Treatment of the stressed mice with the antidepressant imipramine normalized luciferase expression to control levels in all brain regions and likewise reduced CREB-phosphorylation. In non-stressed animals, chronic (21 d) but not acute (24 h) treatment with imipramine (2x10 mg/kg/d) reduced luciferase expression in the hippocampus by 40-50%.Our results emphasize a role of CREB in stress-regulated gene expression and support the view that the therapeutic actions of antidepressants are mediated via CRE/CREB-directed transcription.

10.1371/journal.pone.0000431

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Citations (56)

Regulation of α2A-adrenoceptor expression by chronic stress in neurons of the brain stem

Brain Research (2000)

Heiko Meyer Monika Palchaudhuri Mika Scheinin Gabriele Flügge

Locus coeruleus

Solitary tract

Rostral ventrolateral medulla

10.1016/s0006-8993(00)02787-6

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Citations (59)

Reporter gene expression in CRE-Luc mice.

Ulrike Böer Tahseen Alejel Stephan Beimesche Irmgard Cierny Doris Krause

10.1371/journal.pone.0000431.g003

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Citations (0)