DFG - Deutsche Forschungsgemeinschaft SFB636: SFB 636: Learning, memory, and brain plasticity: Implications for psychopathology (Collaborative Research Center). 01/2004-12/2015.
Collaborative Research Centers (SFB) are long-term research institutions granted to universities for interdisciplinary programs. SFB 636 focusses on learning and memory mechanisms and resulting plastic brain changes that are involved in psychopathology with an emphasis on disorders of emotion and motivation such as anxiety disorders, addiction, affective disorders and disorders of affect regulation. SFB 636 has 22 subprojects grouped in the four areas: A: Molecular and cellular mechanisms of learning and plasticity, B: Behavioral and physiological mechanisms of learning and plasticity, C: Experimental psychopathology, D: Intervention-related brain plasticity. For these projects the Deutsche Forschungsgemeinschaft (DFG) provides funds up to 11.3 million euro for a period for up to twelve years. They are located at the Central Institute of Mental Health, the Medical Faculties Heidelberg and Mannheim of Heidelberg University, the German Cancer Research Center, the Interdisciplinary Center for Neuroscience as well as the Max-Planck-Institute for Medical Research. The overall aim is a mechanism- rather than disease-oriented analysis of pathophysiological states and the translation of these findings into the development of new behavioral and pharmacological treatments of mental disorders. SFB 636 includes researchers from molecular and cell biology, psychopharmacology, neuroimaging, neurophysiology, neurology, experimental psychology, biological psychiatry, psychotherapy and genetics. The first two funding periods (2004-2011) concentrated on the acquisition and extinction of maladaptive associative memories, the role of appetitive learning, the involvement of the hypothalamus-pituitary-adrenal axis as well as glutamatergic mechanisms. In the third funding period (2012-2015) SFB 636 extends its research to comparative studies across disorders to delineate commonalities and differences with respect to appetitive and aversive associative learning processes. In addition, SFB 636 emphasizes structural remodeling of the involved neural networks and employs optogenetic tools and computational modeling to examine brain mechanisms of associative learning. We investigate mechanisms of extinction and reconsolidation processes across animals and humans with a focus on glutamatergic, dopaminergic and glucocorticoid mechanisms. Finally, SFB 636 works on the development of new interventions that combine behavioral and pharmacological tools and elucidates mechanisms underlying effective behavioral and pharmacological interventions. Furthermore, in April 2008 SFB 636 started its international Graduate Program “Translational Neuroscience” to promote young scientists.
Durstewitz D. BMBF - Bundesministerium für Bildung und Forschung 01GQ1003B: BCCN: Bernstein Center for Computational Neuroscience: Implications of genetic variations for neural information processing in psychiatric conditions. 05/2010-04/2015.
The Bernstein Center Heidelberg-Mannheim investigates implications of genetic variations for neural information processing in psychiatric conditions. Recent years have seen a tremendous progress in identifying risk genes for a number of psychiatric conditions, but we mostly lack a mechanistic understanding of the causal and dynamical links between genetically determined neuronal properties, their implications for cortical network dynamics, and their impact in turn on behavior and cognition. However, such knowledge would be of tremendous clinical relevance. Computational models of neuronal systems are an excellent tool to study such causal links. The ultimate goal of the Bernstein Center Heidelberg-Mannheim is to derive an explanatory and theoretical framework for linking genetic conditions to higher cognitive function and its aberrations in schizophrenia, depression, and age-related mental decline. To these ends, biologically detailed models of relevant brain structures as well as their connection to intracellular processes on the one hand and to macroscopic brain dynamics (fMRI, EEG) on the other hand, will be developed. In close exchange with experimental studies on different levels (genes, intracellular processes, network physiology, fMRI/EEG-measurements, behavior) these models will be parameterized, validated, and their predictions tested. Translation into clinical application is sought through novel diagnostic predictors and a computational platform for an "in-silico psychopharmacology". In Heidelberg the more cellular and network-physiological aspects of the proposal will be pursued, while work at the Central Institute of Mental Health in Mannheim will focus more on the psychiatric, human, and applicational aspects. The BCCN Heidelberg-Mannheim integrates projects at the following research institutions: Heidelberg University Central Institute of Mental Health Mannheim
Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01GS08152: NGFN Plus GENALC: Genetics of Alcohol Addiction. 06/2008-05/2011.
The overall theme of the present application focuses on the genetics of alcohol addiction, with the aim of identifying and validating candidate genes and molecular networks involved in the aetiology of this pathology. Importantly, this genetic and molecular information will guide us in the development of new medication strategies for alcohol-dependent patients. Two research strategies are implemented into our IG: First, we are using genetic information derived from our previous NGFN studies along with genetic information from a previous EU-funded project (TARGALC) and several genome wide association (GWA) studies to extend our research projects into a systematic approach to identify more genes and molecular networks involved in excessive alcohol consumption and addiction (project areas 1 & 2). Second, we are taking a hypothesis-driven strategy, in which the involvement of the glutamatergic system in addictive behaviour is studied in great detail (project areas 3 and 4).
Sommer WH. BMBF - Bundesministerium für Bildung und Forschung 01EW1112: ERA-Net NEURON TRANSALC: Dysfunctional neuronal networks in alcoholism: Utilizing translational neuroimaging to identify altered brain connectivity and treatment efficacy predictors. 03/2011-02/2014.
Alcoholism is a common psychiatric disorder with largely unmet treatment needs. Excellent animal models for this disorder have put forward a number of promising molecular targets for medication development. Yet, clinical trials aimed at exploiting this potential often fall short of expectations. We aim to improve the predictive validity of animal tests by means of functional connectivity analysis using magnetic resonance imaging (MRI) to identify brain response patterns to pharmacotherapy that are comparable between patients and animal models of alcoholism. To this end we have formed an international consortium with highly complementary expertise in the field of alcoholism and neuroimaging research. This project will reveal alcoholism specific connectivity maps and knowledge of their modification by clinical reference compounds, i.e. acamprosate and naltrexone, in humans and animals. Based on this information we expect to predict better the effects of experimental drugs proposed for treatment of alcoholism in human patients.
Deuschle M. BMBF - Bundesministerium für Bildung und Forschung 01EW1109: ERA-Net NEURON POSEIDON: Pre-, peri- and postnatal Stress in human and non-human off-spring: a translational approach to study Epigenetic Impact on DepressiON. 03/2011-02/2014.
Exposure to early life adversities is associated with a prospectively increased risk for psychiatric disease, especially depression, in adulthood. Animal models implicate epigenetic regulation of gene expression to mediate this effect. So far, vulnerable time windows, candidate stressors, specific methylation profiles, time course and persistence of the effects of early life adversity on the methylome are not clear. Also, it is unclear whether blood or saliva are adequate “peripheral markers” of central nervous methylation patterns. The functional significance of gene methylation needs to be clarified by gene expression studies and, from a system biology point of view, methylation patterns could be analyzed using biological pathways in order to gain novel hypothesis how early adversities translate in later disease. The POSEIDON study will focus on these questions in an integrated cross-species (rodent, non-human primate, humans) approach that covers different tissues (neuron, T-cells, buccal cells, saliva), stressors as well as time points of adversities (pre-, peri-, postnatal) and follow-up (infancy, adulthood). From a methodological point of view, we will study the methylation of candidate genes as well as do methylome analysis. The functional relevance of methylation profiles will be analyzed in expression studies as well as using discovery-based systems biology approaches. The relevance of animal findings can immediately be tested for significance in humans. From a work-flow perspective, the rodent studies (project 3a/3b) will give informations on type and time point of stressors (prenatal stress, perinatal asphyxia, good vs. bad maternal care) leading to effects on adult behavioural and neuroendocrine phenotype, glucocorticoid receptor (GR) and BDNF expression as well as methylome analyses in Moshe Szyf’s laboratory. The non-human primate study (project 2) will study maternal vs. nursery reared rhesus monkey phenotpyed at the lab of Dr. Suomi (NICHD). Using a whole genome methylation strategy, expression studies and system biology approaches, candidate genes and functional gene pathways will be identified in T-cells and neurons, which will allow to test whether T-cells could serve as “peripheral markers” in future studies. The human study (project 1) will prospectively analyze early life stressors and their relation to methylation patterns at birth and 6 month follow-up using a candidate approach (GR / BDNF) as well as, together with Moshe Szyf, a methylome approach. Using co-funding, candidate genes and stressors identified in the animal studies will be analyzed in humans. Therefore, POSEIDON might identify DNA methylation signatures that could serve as predictive and diagnostic markers as well as guidance for prevention and intervention of psychiatric disorders in adulthood.
Sartorius A. BMBF - Bundesministerium für Bildung und Forschung 01EW1110: ERA-Net NEURON SuppHab: Improvement of treatment resistant depression by suppression of lateral. 03/2011-02/2014.
About 15% of patients suffering from major depression do not respond to any antidepressant treatment. Recently, deep brain stimulation (DBS) was tested as a new therapeutic approach for these severely ill patients. Here we propose a well controlled study, in an animal model of depression, to test the therapeutic benefits of DBS of the lateral habenula (LHb). We believe that hyperactivity of this structure plays a central role in depression by inhibiting dopaminergic and serotonergic transmission. This hypothesis will be tested by means of magnetic resonance imaging and microdialysis in a well-known animal model of depression and additionally, in depressed patients. Breeding and testing of all animals from the congenital Learned Helpless model will take place in Mannheim and animals will be distributed to partners from here. A subgroup of animals will be investigated by means of cerebral blood volume measurements, functional connectivity analysis and MR-spectroscopy at our 9.4 T scanner. In a final experimental step we will test if helpless behavior can be reversed by DBS and if alterations that have been detected by MR investigation can also be normalised. There is no plan for any business or economic outlook or connectivity. Scientific outlook are excellent publications and improvement and refinement of existing theories of depression. The scientific outlook will be the initiation of a clinical DBS study that takes advantage of the LHb as a new stimulation target to treat therapy refractory depression.
Bohus M. DFG - Deutsche Forschungsgemeinschaft KFO 256: Mechanisms of Disturbed Emotion Processing in Borderline Personality Disorder. 01/2012-12/2014.
Borderline personality disorder (BPD) is a highly prevalent and complex mental disorder that often takes a chronic and severely debilitating course if left untreated. Current theories view dysfunctions in emotion processing, social interaction, and mpulsivity as core mechanism of BPD. This often leads to prototypical behavioral patterns such as suicide attempts, non-suicidal self-injury, high-risk behavior, and impulsive aggression. Most of these patterns can typically be traced back to mid-adolescence. Recent research on psychological and neural mechanisms of BPD points towards an interplay between dysfunctional information processing, structural and functional impairments of fronto-limbic circuits, and learned maladaptive behavior. However, compared to other mental disorders of this importance, scientific knowledge on BPD is relatively sparse. Reasons include study samples that are small, heterogeneous, and often medicated; and a paucity of studies that include clinical controls. Also lacking are experimental data on remitted BPD patients, which might allow for the identification of state-independent psychobiological characteristics that could be accounted for by endophenotypes. These limitations impede both the identification of genetic markers and the development of more specific pharmacologic and psychotherapeutic treatment strategies. The Clinical Research Unit (CRU) at Heidelberg University will join the competences of their members which include clinical and psychopathological competence in both adult and adolescent BPD, expertise in neuropsychology, neuroimaging, genetics, and translational neuroscience. The aim is to further characterize subcomponents of dysfunctional emotion processing and social interaction in BPD and to elucidate their neural underpinnings. This should facilitate the development of specifically tailored psychotherapeutic interventions on one level, and provide the basis for further research on a molecular level on another. To this end, the CRU´s central project will carefully characterize and define the phenotypes of a total of 270 unmedicated patients with BPD, including current, remitted, and adolescent populations. The central project will recruit the patients needed in 6 closely related individual projects (IP1-IP6) that will focus on the following psychological and neural mechanisms: i) rejection hypersensitivity and its consequences for social cooperation, ii) dysfunctional responses to pro-social and aversive social stimuli, iii) deficient capability in trust and coaxing, iv) insufficient sensory integration and its impact on dissociation, v) dysfunctional processing of emotional stimuli and neurofeedback training, vi) self-injurious behavior as a form of dysfunctional emotion regulation, and vii) functional and structural connectivity related to disturbed emotion processing. These 6 projects, will be complemented by 3 associated projects. These associated projects (AP1-AP3) will focus on impulsivity, development of a new treatment, and development of an animal model.