Projekte

The major aim of this project is to unravel neurobiological, cellular, molecular, and epigenetic events that mediate the development of stress resilience versus stress vulnerability in a rat model of early life stress (ELS). The overarching hypothesis is that vulnerable as well as resilient individuals exist and that exposure to ELS (1st hit) induces different or contrasting adaptive plasticity processes in the respective animals. We will test if repeated exposure to stress at different stages of development, ELS as 1st "hit” and swim stress at juvenility as 2nd "hit” will have lasting effects on neuronal networks in the brain, specifically those mediating affect regulation and social approach and reward. More specifically, we will analyze if rats classified as resilient or susceptible following the 1st hit and subsequently exposed to a 2nd hit at juvenility will demonstrate the same phenotype at adulthood, that is, resilient animals will remain resilient throughout the lifespan, whereas susceptible animals may display exacerbation of symptoms following the 2nd hit (cumulative stress concept).

On the mechanistic level we will address two complementary hypotheses of ELS-induced brain plasticity. First, we hypothesize that a) the mPFC-amygdala-NAc circuit is central in understanding vulnerability vs resilience due to its continuous and significant maturation during juvenility ; b) the long-term effect of ELS-induced "stress-inoculation” vs vulnerability is sex-specific and is conferred c) by activity-induced changes in the expression of synaptic plasticity proteins within specific neuronal ensembles, which confer d) structural long-term changes in synaptic connectivity and plasticity. Second, we hypothesize that ELS-induced resilience is conferred e) by changes in CB1 receptors, whose expression f) is epigenetically re-programmed by ELS. Finally, the project will also elucidate if and in which way pharmacological interventions on the endocannabinoid system may be effective in normalizing behavioral pathology and in epigenetic "reprogramming” of ELS-induced brain functions.
This multidisciplinary project is essential in order to disentangle the factors that moderate the long-term effects of ELS, which is crucial for identifying the biological underpinnings of resilience and characterizing neural circuits and molecular pathways involved in (re-)programming mechanisms.

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Experience-driven maturation of neuronal and behavioral functions represents a fundamental principle of functional brain development. During brain development, genetically preprogrammed events interact with environmental and psychological ‘epigenetic’ factors, which results in ‘fine-tuning’ of neuronal networks in order to adapt to an individual´s environment and to generate appropriate responses to environmental challenges. Studies in humans as well as in various animal models have shown that the exposure to one or multiple forms of early-life adversity (ELA), such as childhood stress, abuse and neglect, constitutes a major risk factor for developing somatic and behavioral disorders and in the etiology of a wide range of mental diseases. Increasing evidence, including those from our own studies, demonstrated that negative and positive environmental early-life experiences critically interfere with the maturation of brain structure and function . Hence, synaptic circuitries adapt or maladapt to a given environment, which - in the case of adverse experiences such as socio-emotional neglect, abuse, and trauma - can lead to dysfunctional neuronal circuitries, and thereby contribute to the aetiology of mental and behavioral disorders. Moreover, evidence is emerging that behavioral and brain structural/functional consequences of ELA can be transmitted to the next generations, however, the detailed mechanisms underlying inter- and transgenerational transmission of ELA are still poorly understood.
Based on these findings the aim of this project is to compare the inter- and transgenerational transmission of ELA-induced changes in behavior and in prefrontal and hippocampal Oxytocin-receptor (OxtR) expression, including the underlying epigenetic regulation, in male and female offspring (F1 and F2 generation) of stress-exposed mothers (F0 generation).

We expect that the brain of individuals, which were exposed to ELA, suffers from dysfunctional neuronal circuits in prefrontal and hippocampal areas, which hinders their behavioral flexibility and adaptations to the environment. We will focus on the oxytocinergic system (specifically the expression of the OxtR) based on our previous investigations, where we observed a) depressive-like and ADHD-like behavioral phenotypes in ELA animals, b) impaired maternal care behavior in ELA females (F0 generation) towards their offspring (F1 generation) and c) decreased OxtR gene-expression in the PFC of ELA exposed F0 females. We will address the working hypothesis (a) that the ELA induced decrease in OxtR gene expression in the brain and oocytes of adult female mice (F0 generation) is a) epigenetically regulated and b) transmitted to their F1 and F2 offspring via © maternal behavior and/or (d) via the maternal germline.

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Early life adversity and early life stress (ELS) constitute major risk factors that contribute to the aetiology of various psychiatric disorders which emerge during puberty and adulthood. The vast majority of animal studies on ELA have studied the impact of a single brief or chronic stress episode during defined developmental time windows. However, in "normal” life individuals "collect” many experiences of stress, trauma and neglect throughout life. Using an animal model of consecutive stress exposure (neonatal, periadolescent, adult) in mice we address the following questions: Do consecutive stressors during critical developmental phases accumulate and potentiate their effects and thereby increase the risk for the development of mental disorders? Or can consecutive ELS episodes induce adaptive neuronal and behavioral changes making an individual resilient towards an adverse environment later in life? We hypothesize that ELS can programm the expression of NPY-receptors in limbic and prefrontal brain areas via epigenetic mechanisms and thereby influencing stress response at later life periods. Thus, we will assess epigenetic changes (DNA-methylation, histone-modifications) at the promoter regions of NPY-receptors that may influence gene expression changes in response to single or consecutive stress exposure. Another focus of this project will be on potential sex-specific differences in susceptibility and resilience.

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Early life adversity and early life stress (ELS) constitute major risk factors that contribute to the aetiology of various psychiatric disorders which emerge during puberty and adulthood. The vast majority of animal studies on ELA have studied the impact of a single brief or chronic stress episode during defined developmental time windows. However, in "normal” life individuals "collect” many experiences of stress, trauma and neglect throughout life. Hence, in a "top-down” approach using an animal model of consecutive stress exposure (neonatal and periadolescent) we will address questions including: do consecutive stressors during critical developmental phases accumulate and successively potentiate their effects and thereby increase an individual´s vulnerability, resulting in severely dysfunctional brain and behavior? Or can consecutive ELS episodes entrain brain plasticity and behavior to make an individual resilient and better cope with an adverse environment later in life ("stress inoculation”)? On the mechanistic level we will address two complementary hypotheses of ELS-induced brain plasticity. First, we hypothesize that a) the mPFC-amygdala-n.accumbens circuit is central in understanding vulnerability vs resilience due to its continuous and significant maturation during juvenility (i.e. time point of our 2^nd Hit); b) the long-term effect of ELS-induced "stress-inoculation” vs vulnerability is conferred by activity-induced changes in the expression of synaptic plasticity proteins within specific neuronal ensembles, which confer c) structural long-term changes in synaptic connectivity, neuronal function and plasticity, and d) that sex-specific differences exist. Second, we hypothesize that ELS-induced resilience is conferred e) by changes in endocannabinoid CB1 receptors, whose expression f) is epigenetically re-programmed by ELS. Using Chip sequencing we will screen for novel gene targets, including potential proteins, which are part of CB1-activated downstream signaling cascades. On the therapeutic level we will also elucidate if and in which way pharmacological interventions "normalize” behavioral pathology and ELS-induced changes in neuronal and synaptic function and plasticity brain. Since - despite the fact that many clinical investigations provide ample evidence for a considerable sex bias in the prevalence of ELS-induced mental disorders - the vast majority of research in animal models has focused on the analysis of males, another focus of this project will be laid on sex-specific differences in susceptibility and resilience.

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Suicide is an increasing public health problem, causing almost half of all violent deaths and resulting in almost one million fatalities in the world every year. It is of paramount importance to gain a comprehensive understanding of the brain mechanisms underlying the pathogenesis and pathophysiology of suicidal behavior, as well as to identify potential therapeutically relevant biomarkers in peripheral cells, in order to generate science-based, individually tailored protective and therapeutic interventions. We will address our working hypothesis that suicide may result from reduced neuronal activity and impaired synaptic plasticity, which constricts an individual´s competence to adequately and flexibly adapt to the environment. Besides specific genetic predispositions, evidence emerges that epigenetic mechanisms are also critically involved in the etiology of suicidal behavior. In postmortem human anterior cingulate cortex (from suicide victims and sudden-death controls archived in the Polish Suicide Brain Bank) the following hypotheses will be addressed: 1) is impaired neuronal activity in the suicidal brain associated with reduced rDNA transcriptional activity? 2) Is the reduced rDNA transcriptional activity caused by decreased mTOR expression, due to 3) reduced NMDA receptor expression/activation? 4) Is impaired synaptic plasticity associated with reduced synthesis of the synaptic plasticity protein Arc, as result of reduced mTOR expression? 5) Is the expected reduction in Arc expression related to long-term neuromorphological changes (dendrites, spine synapses)? 6) Is mTOR downregulation regulated via DNA hypermethylation? The added value of this project lies in the interdisciplinary and complementary experimental approaches, where different methodologies (AgNOR histology, mRNA expression/qPCR, DNA methylation analysis, 3D neuromorphology), are applied in tissue of the same individuals and thereby allows to correlate all biological parameters with each other and with the medical history of the individuals, and to create a multifaceted concept of the neurobiological changes in the suicidal brain.

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The impact of two paradigms for early life adversity (ELA are compared, long- (LTSS) and short-term separation stress (STSS) on Oxtr gene expression in cardiac muscle is analyzed including epigenetic regulatory mechanisms.

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Exposure to one or multiple forms of early-life adversity (ELA) constitutes a major risk factor for developing somatic and behavioral disorders and in the etiology of a wide range of mental disorders. On the other hand there is also evidence that ELA exposure may lead to stress resilience. In our animal model for ELA behavioral profiling of offspring of ELA-exposed mothers will identify vulnerable and resilient individuals in which epigenetic and transcriptomic changes will be compared. Evidence is emerging that behavioral and brain structural/functional consequences of ELA can be transmitted to the next generations, however, the detailed mechanisms underlying inter- and transgenerational transmission of ELA are still poorly understood. In our animal model for ELA we will attempt to unveil causal relationships between ELA exposure, behavioral dysfunctions, changes in gene expression and underlying epigenetic modifications in brain and other organs/cells. So far, various genes in particular those integrated in HPA functions, have been identified, whose expression is altered in response to ELA. However, ELA-induced changes in gene transcription are much more complex and most likely affect specific cellular, physiological and biochemical signaling pathways, which are involved in developmental and adult synaptic plasticity. Based on our findings one aim of this project is guided by a hypothesis-driven approach and will assess i) whether changes of OxtR gene expression, which we observed in ELA exposed F0 mothers are transmitted to the next (F1, F2) generations, and ii) if these changes are epigenetically regulated via DNA-methylation. Considering transgenerational epigenetic inheritance via the maternal line in mammals and in particular human populations, we will also identify ELA transmission paths, i.e. if transmission is mediated via behavioral maternal traits or through epigenetic changes in oocytes.
To expand our knowledge on ELA-induced changes in gene expression, another aim of this project is to conduct a whole genome transcriptome analysis to i) further identify ELA-induced changes in genes encoding proteins that are part of OxtR-related intracellular signaling cascades and ii) to detect novel gene targets which are affected by ELA.
Most of what is known about the effects of ELA on brain development arises from experimental studies in male individuals, which is somewhat surprising in view of the considerable sex-bias in the prevalence of ELA-induced disorders. Consequently, another aim of this project is to deepen our knowledge about sex-specific effects of ELA and to characterize sex as vulnerability or resiliency factor.

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Major depressive disorder (MDD) is one of the most disabling and potentially life-threatening diseases. The lifetime prevalence of MDD is 15-20%, and women suffer from MDD about twice more often than men. MDD is a complex multifactorial disorder, with both genetic and environmental factors playing an important role in its development. Despite decades of research and efforts to collect cohorts for genetic studies, we still lack a fundamental understanding of the pathophysiology for any of the classical psychiatric disorders, including MDD. Although heritability is estimated to be approximately 37%, DNA sequence variations cannot fully explain the susceptibility to MDD, exposure to known environmental risk factors, such as early life adversity (ELA), also significantly contribute to the aetiology of MDD. It is widely accepted that early life adversities (ELA) such as stress, trauma, abuse and neglect are critical risk factors contributing to the aetiology various mental disorders including major depressive disorder and suicidal behavior. This project is guided by the hypotheses that
· exposure to early life adversity (ELA) such as early life stress induces - depending on the duration of stress exposure - either stress vulnerability or stress resilience;
· ELA exposure induces epigenetically regulated changes in the expression of genes encoding proteins that are critically involved in synaptic plasticity, and
· resilient individuals display elevated synaptic plasticity, which enables them to better cope with stress challenges and to continuously adapt to environmental changes;
· vulnerable individuals show reduced synaptic plasticity ,which impairs stress coping and the competence to adapt to the environment.
Since in human patients the level of analysis is limited to peripheral cells or to postmortem brain tissue, we have established animal models, in which peripheral and brain tissue can be analyzed in parallel, as well as other body organs, e.g. to unveil potential comorbidities

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Early childhood traumatic experiences, such as disorders of mother-child interaction, are associated with long-term, often even transgenerational behavioral disorders. Epigenetic changes, which influence the gene expression potential of certain genes in interaction with environmental factors and thus control neuronal adaptation processes, are discussed as causal mechanisms for the development of these disorders.
An animal experimental approach is used to investigate which epigenetic mechanisms contribute to the transgenerational transmission of early stress experiences. Repeated maternal separation in mice serves as a model for this. Our working hypothesis postulates that these early trauma experiences lead to region-specific changes in modulatory transmitter receptors that are epigenetically regulated and can be transmitted to the offspring.
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This project investigates the ontogenesis of negative feedback learning and whether early childhood learning experiences influence learning performance in later life. We postulate that, depending on the timing of the early childhood learning experience, there is either a reduction (learning blockade) or an improvement in learning performance in adulthood. The project includes behavioral analyses and functional imaging to analyze learning-specific neuronal networks.
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This project aims to investigate the specific role of the father in the development of his offspring. The project includes behavioral analyses of paternal behavior and functional imaging to measure brain activity in order to identify neural circuits specifically associated with paternal behaviors.
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A number of animal studies throughout the last decades, including ours, which induced chronic or repeated perinatal stress (e.g. maternal separation) to mimic human early childhood trauma and neglect, revealed that the maturation of neuronal pathways and socio-emotional behaviour is altered in these animals . So far, neither the brain functional, nor the epigenetic mechanisms underlying these trauma-induced neuronal and behavioural changes are understood and thus will be one focus of our project. Epigenetics is most commonly defined as the ensemble of heritable alterations in gene functions, that cannot be explained by changes in the DNA sequence itself. At the molecular level, epigenetic mechanisms are modifications of the DNA and histone proteins, the major constituents of chromatin. These mechanisms include direct modifications of the DNA, i.e. through DNA-methylation and specific modifications of histone proteins (i.e. acetylation, phosphorylation, methylation). Depending on the type of modification this can result in actively transcribed or silenced genes, and this strongly influences neuronal and synaptic development in the juvenile brain. There is increasing evidence that these changes affect higher cognitive functions and emotionality and that epigenetic factors mediate the relationship between early life experiences and the long-term behavioural outcome. The first focus of this project is to test the hypothesis that maternal care interferes with the functional maturation of prefronto-limbic-hypothalamic (PLH) pathways. Functionality of PLH pathways of traumatized animals will be assessed using functional imaging techniques (2-FDG, SPECT), which are established in our lab and which allow to monitor brain activity in awake, freely behaving animals. In direct correspondence to clinical projects of this network a modified version of an emotion recognition task used in the clinical studies will be applied as well as an acute stress challenge. Preliminary functional imaging experiments revealed that traumatized infant and preadolescent animals, display significantly reduced activation in prefrontal and limbic brain regions. The second focus will address the hypothesis that the brain functional and structural changes are induced by epigenetic alterations, evoked by changes in maternal care. First, DNA-methylation profiles on the promoters of 5-HTT and GR will be analyzed from samples of oral mucosa, which can be directly compared with the results of the clinical projects. In our lab we will search for histone modifications affecting other targets, including oxytocin, dopamine-receptors (DAR) and dopaminetransporters (DAT), egr-1 and arc/arg3.1.

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A number of animal studies throughout the last decades, including ours, which induced chronic or repeated perinatal stress (e.g. maternal separation) to mimic human early childhood trauma and neglect, revealed that the maturation of neuronal pathways and socio-emotional behaviour is altered in these animals . So far, neither the brain functional, nor the epigenetic mechanisms underlying these trauma-induced neuronal and behavioural changes are understood and thus will be one focus of our project. Epigenetics is most commonly defined as the ensemble of heritable alterations in gene functions, that cannot be explained by changes in the DNA sequence itself. At the molecular level, epigenetic mechanisms are modifications of the DNA and histone proteins, the major constituents of chromatin. These mechanisms include direct modifications of the DNA, i.e. through DNA-methylation and specific modifications of histone proteins (i.e. acetylation, phosphorylation, methylation). Depending on the type of modification this can result in actively transcribed or silenced genes, and this strongly influences neuronal and synaptic development in the juvenile brain. There is increasing evidence that these changes affect higher cognitive functions and emotionality and that epigenetic factors mediate the relationship between early life experiences and the long-term behavioural outcome. The first focus of this project is to test the hypothesis that maternal care interferes with the functional maturation of prefronto-limbic-hypothalamic (PLH) pathways. Functionality of PLH pathways of traumatized animals will be assessed using functional imaging techniques (2-FDG, SPECT), which are established in our lab and which allow to monitor brain activity in awake, freely behaving animals. In direct correspondence to clinical projects of this network a modified version of an emotion recognition task used in the clinical studies will be applied as well as an acute stress challenge. Preliminary functional imaging experiments revealed that traumatized infant and preadolescent animals, display significantly reduced activation in prefrontal and limbic brain regions. The second focus will address the hypothesis that the brain functional and structural changes are induced by epigenetic alterations, evoked by changes in maternal care. First, DNA-methylation profiles on the promoters of 5-HTT and GR will be analyzed from samples of oral mucosa, which can be directly compared with the results of the clinical projects. In our lab we will search for histone modifications affecting other targets, including oxytocin, dopamine-receptors (DAR) and dopaminetransporters (DAT), egr-1 and arc/arg3.1.

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The general aim of this project is to unravel the epigenetic and molecular mechanisms underlying perinatal stress-induced dendritic and synaptic maturational changes in prefrontal and limbic brain regions, which are assumed to represent the neuronal substrate for stress-induced behavioral dysfunctions, including anxiety and depression. We will test the hypothesis that prenatal stress exposure induces chromatin remodeling, including changes in histone acetylation, which are assumed to play a key role in both the etiology and treatment of depression. We will focus on epigenetic modifications, which particularly affect gene expression and the synthesis of synaptic and cytoskeletal proteins, which are likely candidates to mediate the stress-induced dendritic and synaptic changes in the prefrontal cortex, hippocampus and the amygdala. Because many of the mental disorders associated with prenatal stress exhibit a sex bias, the molecular analysis of how sex-specific susceptibility arises will improve our mechanistic insight and lead to the identification of novel targets for protective and therapeutic development. Thus, another aim will be the identification sex-specific differences in chromatin remodeling in response to prenatal stress, which we assume to underlie the previously observed stress-induced sex-specific behavioral, molecular, dendritic and synaptic changes.

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Among the neurodegenerative changes of the central nervous system, Alzheimer's disease is the most common. As the risk of developing the disease increases with advancing age, it can be assumed that increasing life expectancy will lead to a dramatic rise in the number of cases in Europe and other parts of the world in the coming decades. In addition to causing considerable suffering, the disease also causes considerable economic damage due to the high level of care required. Although science favors a central role of Aß peptide overproduction in pathogenesis, initial attempts to exploit this mechanism therapeutically have been disappointing and the molecular biological details of pathogenesis remain unclear. This neural network uses novel mouse models to investigate the role of a chronic deficiency of the neurotrophic factor BDNF previously found in patients in the genesis of Alzheimer's disease, with particular emphasis on memory performance in multiple behavioral tests and considering a potential role of mitochondrial disorders associated with oxidative stress. Once sufficiently characterized, the disease models will later provide the basis for evaluating protective strategies, such as physical or cognitive stimulation, BDNF substitution, receptor agonists or deep brain stimulation.
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Frühe Lern- und Erfahrungsprozesse beeinflussen in Interaktion mit genetisch festgelegten Programmen die funktionelle neuronale Entwicklung. Negativerfahrungen wie z.B. Stress können hierbei zu Fehlentwicklungen führen, eine Ursache für später auftretende Verhaltensdefizite. Chromatin-Remodellierung und Histonmodifikationen sind epigenetische Prozesse, die sowohl für die Etablierung als auch für die Aufrechterhaltung des konstanten Verhältnisses von aktiven und inaktiven Genen verantwortlich sind und somit vermutlich auch einen erheblichen regulatorischen Einfluss auf die neuronale Entwicklung ausüben. Bislang gibt es allerdings keinerlei Hinweise ob und welche epigenetischen Mechanismen durch frühe Stresserfahrungen induziert werden und somit auch keine Hinweise inwieweit diese Mechanismen mit stressinduzierten synaptischen Fehlentwicklungen in Zusammenhang stehen. Wir wollen daher in diesem Projekt der Frage nachgehen, ob frühe prä- und postnatale Stresserfahrungen zu Chromatin-Remodellierung und Histonmodifikationen führen und ob diese mit der funktionellen neuronalen Reifung in limbischen Arealen und der damit zusammenhängenden Entwicklung spezifischer Verhaltensweisen korrelieren.

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