laufende Projekte:
seit 2011: DFG-geförderter Einzelantrag (PIs: Dr. D. Inta / apl. Prof. P. Gass) "Gen-Umwelt Interaktionen und Störungen der postnatalen Hirnentwicklung und Neurogenese in Mausmodellen für Schizophrenie"
Die Ätiologie der Schizophrenie wird durch genetische Faktoren dominiert. Außerdem wurden etliche Umweltrisikofaktoren für die Erkrankung identifiziert. Es ist davon auszugehen, dass Interaktionen zwischen Genen und Umwelt, durch Beeinflussung neuronaler Netzwerke während der Hirnentwicklung, einen wesentlichen Anteil an der Pathogenese der Schizophrenie haben. Trotz der Identifizierung mehrerer vielversprechender Suszeptibilitätsgene für Schizophrenie, wie Disrupted in Schizophrenia 1 (DISC1) oder Neuregulin, sind die zugrunde liegenden neurobiologischen Mechanismen der Interaktion mit Umwelteinflüssen weitgehend unbekannt. Im vorliegenden Antrag soll in Mausmodellen das Zusammenspiel von genetischen Faktoren und Umweltfaktoren während der frühen postnatalen Entwicklung in der Entstehung der Schizophrenie untersucht werden. Dabei wollen wir die Rolle einiger für die Schizophrenie relevanter Risikofaktoren (neonatale Hypoxie, Stress) bei der Entstehung von Schizophrenie-ähnlichen Verhaltensauffälligkeiten sowohl in Wildtyp-Tieren als auch in genetischen (z.B. DISC1 +/-, BDNF+/- Mäusen) Tiermodellen für Schizophrenie untersuchen. Angesichts der bekannten Rolle dieser Gene in der Proliferation und Migration von immaturen Neuronen ist unsere Arbeitshypothese, dass vor allem Störungen der postnatalen Neurogenese in für die Schizophrenie kritischen Hirnregionen (präfrontaler Kortex, Striatum, Nucleus accumbens, Calleja-Inseln, Hippokampus) von Bedeutung sind für den vollen Ausbruch der Erkrankung nach der Pubertät. Deswegen besteht das wesentliche Ziel unseres Projektes in einer umfassenden Untersuchung krankheitsrelevanter, durch Gen-Umwelt Interaktionen induzierten, strukturellen, neuroendokrinen und funktionellen Abnormalitäten dieser spezifischen Areale.
seit 2010: Teilprojekt C8 (PIs: apl. Prof. Dr. B. Vollmayr / apl. Prof. P. Gass) "Analysis of higher cognitive functions in rodent models of schizophrenia and depression" within the Bernstein Center Computational Neuroscience Mannheim/Heidelberg
We will study mice with specific genetic alterations that are also investigated by the in vivo, imaging and computational groups of this consortium (e.g. human COMT polymorphisms, DAT, GRM3 and NR1) and rats bred for congenital learned-helpless as genetic risk models for schizophrenia and depression. Later in the project, we will behaviourally characterize mutant mice and rats generated by the consortium. Behavioral analyses will include disease relevant paradigms in close analogy to human studies, using similar read-outs. Thus, for working memory we will use an eight arm radial maze, for HC-dependent functions we apply aversive trace conditioning, and for cognitive flexibility we use a set shift task. The influence of stress vs. environmental enrichment, as well as the interaction of genetic and environmental factors will be investigated. Moreover, the modification by dopaminergic and glutamatergic drugs will be studied. In addition to behavioural testing in the tasks specified, functional MRI at high fields (9.4T) will be employed in our animal models via resting state fMRI, cerebral blood flow (rCBF) or cerebral blood volume (rCBV) mapping for quantification of signal to noise and functional connectivity of PFC-related networks, PFC-HC interactions in particular. Investigating functional connectivity, CBF and CBV in mutants exposed to stress or other environmental changes and/or treated with specific drugs enables the detection of possible gene x environment x pharmacological challenge interactions. The data generated in this project will be used a) to validate the use of rodent data in constructing computational models aimed at explaining aberrant information processing in humans, or highlight any potential differences that may urge cautious interpretation, and b) to further test behavioural and neuroimaging predictions of the computational models that cannot be addressed in human subjects.
seit 2010: Network of European Funding for Neuroscience Research (PI: apl. Prof. P. Gass) "Rodent models for pre- and postnatal stress, birth complications and maternal care: effects on behaviour, gene expression and epigenetics in adulthood", part of the POSEIDON group (Pre-, peri- and postnatal Stress in human and non-human off-spring: a translational approach to study Epigenetic Impact on DepressiON)
In a multi-disciplinary and translational approach, this project combines several subprojects investigating epigenetic effects of prenatal and postnatal risks, including mother-pup-interaction and weaning in rodents. This approach allows behavioral analysis of the adult phenotype evoked by ELS as well as analyses at the epigenetic and expression level in the brain. Rodent studies allow generating a more detailed picture of the points in time as well as the types of stressors during the perinatal period to impact on the methylome. The effect of interventions as different as chronic prenatal stress, perinatal asphyxia, caesarean section, variations of maternal care, enriched environment and early weaning will be used. Since epigenetic processes may be tissue-specific, the animal experiments will allow an in-depth analysis of tissue- and stressor- and time-specific epigenetic effects.
seit 2010: Network of European Funding for Neuroscience Research (apl. Prof. A. Sartorius together with apl. Prof. Dr. B. Vollmayr) as a part of the SuppHab group (Improvement of treatment resistant depression by Suppression of lateral Habenula activity)
To test the hypothesis that the LHb is a key structure that couples dopaminergic and serotonergic circuits and whose hyperactivation causes depression, we will use a series of translational and transnational synergistic experiments: high-field MRI in depressed patients and in congenitally helpless rats. Effective connections between the LHb and the prefrontal and hippocampal brain regions, as well as metabolic activity (quantified with magnetic resonance spectroscopy, MRS) in humans and congenital helpless rats, will be identified inter alia with resting state fMRI. Additionally, to test the hypothesis that alterations in LHb activity are a reason for neuroadaptive changes of depression we want to use manganese enhanced MRI (MEMRI) to directly trace alterations in neuronal networks in the same animal model (Jerusalem) The hypothesized effect of lesion and DBS of the LHb on behaviour and rCBV, as well as on dopamine and serotonin levels, and their metabolites, will be tested in the animal model.
seit 2008: Fortsetzung Teilprojekt B3 (PI: apl. Prof. P. Gass) "The role of glucocorticoid receptors in specific neuronal systems for emotional behaviour: a combined transgenic and environmental approach" im Sonderforschungsbereich SFB636 "Learning, Memory and Brain Plasticity: Implications for Psychopathology"
Glucocorticoid receptors (GRs) have been postulated to play an important role in affective disorders such as depression. However, it is not known where in the brain increased corticosteroid levels or altered GR functioning may have deleterious effects. These questions can be studied using conditional transgenic techniques in combination with specific mouse models for affective disorders. During the first grant period we have characterized 2 strains of mice underexpressing (GR+/-) and overexpressing (YGR) glucocorticoid receptors throughout the nervous system behaviourally and neuroendocrinologically. We could show that GR+/- mice have a predisposition to develop typical stress-induced depression-like changes, while YGR mice turned out to be stress-resistant. Searching for potential molecular correlates (apart from GR) for this altered behaviour we found a downregulation of BDNF in “depressive” GR+/- mice and an upregulation in YGR animals, which is in agreement with the so-called neurotrophin hypothesis of depression. Since the GR gene is dysregulated during the whole ontogenesis in these strains, it is not clear, when and where (in the brain) a dysbalance of GR is important for affective disorders. Furthermore it is not known which pathophysiological and pathobiochemical alterations occur in these brain regions. These questions should be investigated during the next grant period using conditional mouse strains with specific alterations of GR expression, i.e. in the forebrain, the serotonergic system and the noradrenergic system. To identify/rule out a developmental role of GR expression, we will study strains with a constitutive knockout in these brain regions as well as an inducible knockout. Furthermore we will investigate the effect of early and late environmental manipulations (i.e. maternal care and enriched environment) in GR compromised mice to identify potential gene-environment-interactions inducing alterations of emotional behaviours. As a first line of evidence we will study the behaviour of these mice in specific depression models (e.g. learned helplessness, chronic stress) and tests for emotional behaviours. In a second step we will analyze by biochemical (monoaminergic systems), pathophysiological (electrophysiology) and neuroanatomical (spine morphology) methods changes in neural plasticity that could correlate with the identified behavioural alterations . In an alternative approach we plan to study in which brain areas the GR is activated following environmental and pharmacological manipulations. For this purpose we will generate a “GR-reporter mouse”, using a construct in which a GR response element (GRE) drives the expression of a reporter enzyme whose activity can be measured in vitro and in situ.
abgeschlossene Projekte:
2008-2011: DFG-geförderter Einzelantrag (PI: apl. Prof. P. Gass) "The Role of Glutamate und Glutamate Receptors in Mouse Models for Emotional Behaviors and Mood Disorders" zusammen mit Dr. R. Sprengel, Max-Planck-Institute für Medizinische Forschung, Heidelberg
2009-2010: DAAD Vigoni-Programm Förderung für die deutsch-italienische Zusammenarbeit (PI: apl. Prof. P. Gass) mit Prof. M. Riva, Universität Mailand "Stress-dependent Modulation of Neuronal Plasticity Molecules in Mice Mutant for Glucocorticoid/Mineralocorticoid (GR/MR) Receptors and their Potential Role in Depression "
2008-2010: DFG-geförderter Einzelantrag (PI: apl. Prof. P. Gass) "Brain-derived neurotrophic factor, nerve growth factor und neurotrophin-3 Expression in Mausmodellen für depressive Störungen: Regulation durch Stress und antidepressive Maßnahmen", zusammen mit Prof. R. Hellweg, Klinik für Psychiatrie und Psychotherapie , Charite, Berlin
2006-2007: DAAD Vigoni-Programm Förderung für die deutsch-italienische Zusammenarbeit (PI: apl. Prof. P. Gass) "Glutamaterge Signalwege als neue Zielsysteme für antidepressive Behandlungen" zusammen mit Prof. F. Fumagalli, Universität Mailand
2004-2007: EU Grant "Genome-based therapeutic drugs for depression, animal part (GENDEP)", 6th framework program (PI: apl. Prof. P. Gass)
2004-2007: Teilprojekt B3 (PI: apl. Prof. P. Gass): "Mice with over- and underexpression of glucocorticoid receptors: models for affective and stress disorders?" im Sonderforschungsbereich SFB636 "Learning, Memory and Brain Plasticity: Implications for Psychopathology"
2004-2005: DAAD Vigoni-Programm Förderung (PI: apl. Prof. P. Gass) für die deutsch-italienische Zusammenarbeit mit Prof. M. Riva, Universität Mailand über "Neurotrophine, Stress und Steroid-Rezeptor-transgene Mäuse: Modelle für Affektive Störungen"
2000-2005: DFG-geförderter Einzelantrag (PI: apl. Prof. P. Gass) "Regulation von neurotrophen Faktoren bei transgenen Mäusen in Modellen für depressive Erkrankungen"
abgeschlossene Doktorarbeiten:
Dr. med. Johannes Fuss
Involvement of hippocampal neurogenesis in the development of anxiety in voluntarily exercising mice.
Medizinische Fakultät Mannheim, Ruprecht-Karls-Universität Heidelberg, 2011
" summa cum laude "
Dr. med. Donya Golizadeh
Establishing a new paradigm to detect cognitive bias in rats
Medizinische Fakultät Mannheim, Ruprecht-Karls-Universität Heidelberg, 2010
" magna cum laude "
Dr. med. Johanna Bätzing
Antidepressive Behandlung moduliert die Zellproliferation im präfrontalen Kortex
Medizinische Fakultät Mannheim, Ruprecht-Karls-Universität Heidelberg, 2010
" magna cum laude "
Dr. rer. nat. Miriam A. Vogt
Depression-like behavior of mice with conditional ablation of glucocorticoid signaling: the impact of tamoxifen on the behavioral phenotype.
Naturwissenschaftliche Fakultät, Ruprecht-Karls-Universität Heidelberg, 2010
" magna "
Dr. rer. nat. Sabine Chourbaji
Coping with stress: impact of the hypothalamic pituitary adrenal system and neurotrophic circuits in the learned helplessness modell of depression.
Naturwissenschaftliche Fakultät, Ruprecht-Karls-Universität Heidelberg, 2005
" magna "
Dr. med. Björn Zörner
Verhaltensbiologische und neurochemische Untersuchungen zur Neurotrophin-Hypothese der Depression mit transgenen Mäusen.
Medizinische Fakultät, Ruprecht-Karls-Universität Heidelberg, 2004
" summa cum laude "
abgeschlossene Habilitationsarbeiten
Dr. rer. nat. Sabine Chourbaji
Die Bedeutung von Genetik und Umweltfaktoren in der Pathologie und Behandlung stressinduzierter Erkrankungen: Mausmutanten, Stressoren und Depression.
Naturwissenschaftliche Fakultät, Ruprecht-Karls-Universität Heidelberg, 2010
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