Projekte: Psychopharmakologie

Köhr G, Li SB. : CSC China Scholarship Council: Dopamine and the hippocampus. 09/2010-08/2013.

We activate the dopaminergic system pharmacologically, electrically, or optogenetically following virus-mediated transfer of channelrhodopsin, to investigate the role of endogenous dopamine in hippocampal synaptic plasticity and network activity in brain slices and in awake mice during learning and memory formation.

Schneider M, Spanagel R, Schneider P. : KFO 256 AP 1: Modulationen der Mutter-Kind Beziehung und soziale Zurückweisung bei juvenilen Ratten als Tiermodell zur Erzeugung einer BP-ähnlichen Symptomatik . 01/2012-12/2014.

BMBF - Bundesministerium für Bildung und Forschung 01ZX1611A: e:Med II - SPs 3: Central Resource II: Transcriptomics platform. 01/2017-12/2018.

SP3 provides human post-mortem brain material from deceased alcoholics, iPSC lines from humanised mouse models and humans, and transcriptomic profiles of these biological materials to the consortium. In the first two years we have (i) enlarged our human brain bank through effective national and international collaborations, (ii) established the routine generation of iPSC lines from mouse and humans (almost 20 m/hiPSC lines have been generated), (iii) analyzed opioid and dopamine system adaptations at both transcriptional and protein levels in post-mortem brains from alcoholics and alcohol addicted rats (SP5) and developed a new molecular model of a hyper-dopaminergic state that drives alcohol craving (Hirth et al., 2015), and finally (iv) established with a collaborator from NIAAA, Bethesda USA, a database of brain miRNA profiles from the prefrontal cortices of abstinent alcohol dependent rats.

BMBF - Bundesministerium für Bildung und Forschung 01ZX1611A: e:Med II - SPs 5: Central Resource IV: Animal model of alcohol addiction. 01/2017-12/2018.

SP5 provides a further key resource to the consortium, namely alcohol addicted animals that derive from a DSM-based rat model. These alcohol addicted rats were used in the first two years of funding for (i) the categorization of drinking patterns with a statistical model of the periodic time series of drinking events and (ii) the study of new putative anti-relapse compounds targeting either calpains or melatonin receptors (Vengeliene et al., 2015a, b). In particular, the re-purposing of agomelatine or the use of melatonin provides new clinical treatment options that can be tested by SP12 on the platform for experimental human studies. It was also planned to use the alcohol addicted animals for the proposed electrophysiological studies in SP7 and SP11. However, during the course of experiments a limitation of the use of these animals became apparent. Similar to the human condition, animals become addicted only after a long period of alcohol drinking, following which rats are too old for reliable in vivo electrophysiological measurements. To circumvent these unexpected problems we are now using for electrophysiologcal experiments another animal model (referred to as the “post-dependent model”), extensively examined in our laboratory for many years and resulting in adaptive changes in brain function characteristic of alcohol addiction4.

BMBF - Bundesministerium für Bildung und Forschung 01ZX1611A: e:Med II SPs 11 - Functional Validation III: Functional local network activity and neurotransmitter release. 01/2017-12/2018.

The research goals of SP11 are to study the electrophysiological properties of m/hiPSCs deriving from SP3, to compare local field potentials (LFPs) and multiple single-units in alcohol addicted rats from SP5 (same limitations as in SP7 therefore animals from the “post-dependent model”7, and to validate the neurochemical prediction from SP8 via in vivo microdialysis. Major progress has been made in in vivo tetrode recordings and we have examined the effect of acute alcohol treatment in the medial prefrontal cortex. Most importantly, we have validated by in vivo microdialysis the in silcio prediction made in SP8 by demonstrating a hyper-dopaminergic state in protracted abstinence (Hirth et al., 2015).

BMBF - Bundesministerium für Bildung und Forschung 01ZX1611A: e:Med II SPs10 - Functional Validation II: Neuroimaging x genetics. 01/2017-12/2018.

In SP10 neuroimaging x genetics predictions are studied (see Fig. 2). During the first two years data collection of neuroimaging, neuropsychology, psychometrics, genetics and epigenetics for the follow-up of the NGFN-plus sample was initiated. Recruitment for the follow-up assessments (alcohol addicted patients from the NGFNplus study, 1st degree relatives and healthy individuals) is in line with the initially proposed time plan. In the meantime we have performed data analysis from existing data (NGFNplus, IMAGEN) and reported on SNPs of genes coding for molecular components of the opioidergic and glutamatergic signaling and their association to neural cue reactivity, craving and relapse (Bach et al., 2015a, b).

DFG - Deutsche Forschungsgemeinschaft KL 2359/1-1: SPP1226 Nikotin: Molekulare und Psychiologische Effekte im Zentralen Nervensystem (ZNS). 10/2011-09/2014.

Background: Consistent evidence for the heritability of smoking behaviours has led to genetic studies designed to elucidate the specific genetic factors involved in nicotine addiction. The most advanced scientific approaches to address this question include genome-wide association studies (GWAS) in smokers and gene expression profiling studies in animal models of nicotine self-administration. Convergent translational genomics approaches allow integrating genetic findings from animal models with a GWAS approach in humans and have proven to be very successful in generating priority candidate gene lists. However, the demonstration of a causal relationship of a candidate gene with a given pathological phenotype remains the biggest challenge in the emerging field of genetic research. Goals: In this proposal we want to integrate our previous genetic findings from massive gene expression profiling in animals that underwent chronic nicotine self-administration with the human genetic data sets deriving from the German Priority Programme on Nicotine Research SPP1226 (Project P2 (Dahmen), P3 (Winterer), P9 (Brenner), P10 (Winterer), and P11 (Steinlein)). By applying a convergent translational genomics approach data integration will be performed and a priority candidate gene list for the entire SPP1226 will be generated. From this priority gene list for nicotine addiction we will functionally validate the top hits in an animal model of nicotine self-administration and relapse by means of recombinant adeno-associated virus (rAAV)-mediated gene transfer into brain sites of the reward system (especially into the nucleus accumbens shell). The advent of AAV vectors carrying cDNA for, or short hairpin RNA against, specific genes allows now for the first time the rapid bidirectional manipulation of gene function in nicotine self-administering animals. Both applicants have proven expertise in animal models of addictive behaviour and rAAV-mediated gene transfer technology, respectively.

DFG - Deutsche Forschungsgemeinschaft SFB 1134: B05: Charakterisierung und Molulation neuronaler Ensembles des Belohnungslernens. 01/2015-12/2018.

DFG - Deutsche Forschungsgemeinschaft SFB 1134: TP B04: Untersuchung von verhaltensrelevanten raum-zeitlichen Aktivitätsmustern neuronaler Netzwerke im Präfrontalcortex der Ratte mit Hilfe der in vivo Weitfeldmikroendoskopie. 01/2015-12/2018.

DFG - Deutsche Forschungsgemeinschaft SFB 1134: TP C03: Calcium induzierte Änderungen der Expression bei ko-aktiven Neuronen des ventalen tegmentalen Areals während erlernter Nikotin-Sensitisierungen . 01/2015-12/2018.

DFG - Deutsche Forschungsgemeinschaft SP 383/12-1: International Scientific Events World Congress on Alcohol and Alcoholism. 09/2016-06/2016.

This will be the first joint World Congress on Alcohol and Alcoholism of the International Society of Biomedical Research on Alcoholism (ISBRA) and the European Society for Biomedical Research on Alcoholism (ESBRA) and will take place in Berlin in September 2nd-5th, 2016. Both societies are promoting excellence either on the European or international level in biomedical research on alcohol and alcoholism. During this World Congress key opinion leaders will share the recent innovations in their respective fields which impact on basic and preclinical knowledge on alcoholism and alcoholrelated biomedical phenomena, as well as on diagnosis, treatment and quality of life of our patients. In high scientific level sessions (plenary lectures, symposia, young investigator symposia, interactive and educational workshops and debates) a wide range of outstanding data in scientific fields from the biomedical basis of alcoholism in animal and human experimental models to alcohol-related treatment issues, all the way to alcohol-related psychosocial aspects and epidemiology and health economics will be offered. The motto of this meeting will be translation and cross-fertilization, so to speak mutual exchange, as between dissimilar findings, concepts and ideas. This will enhance understanding and will produce something beneficial to biomedical research on alcohol and alcoholism.

DFG - Deutsche Forschungsgemeinschaft SP 383/6-1: Tiefe Hirnstiumation im Rattenmodell der Alkholabhändigkeit. 10/2011-09/2014.

Die pathophysiologischen Grundlagen der Alkoholerkrankung sind bislang nicht hinreichend geklärt. Betrachtet man die Alkoholabhängigkeit als eine Dysfunktion spezifischer neuronaler Netzwerke mit einer konsekutiven Dysregulation spezifischer Neurotransmittersysteme, könnte die Darstellung eben dieser an der Manifestation der Alkoholabhängigkeit beteiligten Netzwerke es ermöglichen, therapeutisch gezielt und direkt in diese einzugreifen und damit die pathologisch dysregulierten Neurotransmittersysteme zu readjustieren. Vor diesem Hintergrund kommt der Tiefen Hirnstimulation (THS) eine besondere Bedeutung zu, die ihre klinische Effektivität über Veränderungen der Aktivitätszustände stimulierter und assoziierter Komponenten neuronaler Netzwerke erreicht. Veränderungen der Netzwerkaktivität unter THS erlauben nicht nur eine (kausal)-therapeutische Intervention in der Behandlung einer ansonsten therapierefraktären Patientengruppe, sondern bieten in der experimentellen Nutzung auch einen Erkenntnisgewinn über Erkrankungen zugrundeliegende pathophysiologische Mechanismen sowie über die daran beteiligten neuronalen Netzwerke. In dem vorliegenden tierexperimentellen Antrag soll die THS eingesetzt werden, um selektiv die Aktivität ausgewählter Funktionseinheiten zu beeinflussen und die Auswirkung auf Verhalten und funktionelle/biochemische Aktivierungsparameter von alkoholabhängigen Ratten zu untersuchen.

Durstewitz D, Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01GQ1003B: BCCN TP D1: In-silico neuropharmacology. 05/2010-04/2015.

EU - Europäische Union 668863: SyBil-AA System Biology of Alcohol Addiction. 01/2016-12/2019.

Alcohol addiction ranks among the primary global causes of preventable death and disabilities in human population, but treatment options are very limited. Rational strategies for design and development of novel, evidence based therapies for alcohol addiction are still missing. Alcohol dependence is characterized by cycles of excessive alcohol consumption, interspersed with intervals of abstinence, and frequent relapses. Relapse is a key element of this disease process and blocking relapse is therefore a key objective for the treatment of alcohol dependent patients. In this project we will provide a novel discovery strategy based on the principles of systems medicine that uses mathematical and network theoretical models to identify brain sites and functional networks that can be targeted specifically by therapeutic interventions. To build predictive models of the ‘relapse-prone’ state of brain networks we will use magnetic resonance imaging, electrophysiology and neurochemical data from patients and laboratory animals. The mathematical models will be rigorously tested through experimental procedures aimed to guide the network towards increased resilience against relapse. We expect to identify hubs that promote ‘relapse-proneness’ and to predict how aberrant network states could be normalized. Proof of concept experiments in animals will need to demonstrate this possibility by showing directed remodeling of functional brain networks by targeted interventions suggested by the theoretical models. Thus, our translational goal will be achieved by a theoretical and experimental framework for making predictions based on fMRI and mathematical modeling, which is verified in animals, and which can be transferred to humans. With our highly interdisciplinary EU consortium (PIs from seven European countries and Israel with outstanding expertise) it is expected that after having such a world-wide unique effort in place, new neurobiologically-defined treatment strategies will be delivered to our addicted patients and thus help to address a serious and widespread health problem in our European societies.

Flor H, Spanagel R. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP MGK: Integriertes Graduiertenkolleg Translationale Neurowissenschaften. 01/2015-12/2015.

The overarching aim of the SFB Graduate Program "Translational Neuroscience" is to enable transfer of knowledge between basic and clinical sciences. All of our PhD and MD students shall gain insight into both areas of research by attending an interdisciplinary teaching program including electives in different interacting groups. We also provide a framework for regular advice to the students and individual support wherever techniques or knowledge are lacking. The international and interdisciplinary program accepts students from a wide variety of natural and social sciences as well as medical students. Much of the translational work within SFB 636 is done by junior scientists, mostly MD and/or PhD students. During the current funding period, the graduate program was instrumental in cross-linking different approaches and system levels within the SFB. All students were provided with a common knowledge base allowing them to understand the translational aspects of their own projects and to interact successfully with colleagues from other disciplines. The Graduate Program pursues its goals by offering a compact course (60 hours) in neurosciences which covers a large variety of relevant topics and methods (qualification concept). This core curriculum is taught on a regular basis and covers 4 hours/week (usually on Friday, with social events to follow). This introductory course ends with a written exam, ensuring a common knowledge base for all students. It is important that the program does not distract students from their own research projects. Therefore, the second part of the curriculum is individual, i.e. specifically adapted to the needs of individual students. This is supported by several measures: students have regular meetings with the members of the student advisory board; they can visit German and foreign laboratories, including those in industry, in order to acquire specific techniques; they can invite guest scientists. Most importantly, each student has to choose two special topics (major and minor) for extended studies throughout the PhD or MD course. Students with projects rooted in basic sciences chose a clinical minor and have to visit a clinical unit for an elective. Conversely, students with a clinical focus stay for some time in a laboratory. In-depth education in the major continues with courses of 2 hours/week throughout the entire period of the PhD or MD thesis work. In addition, we offer regular autumn schools focussed on selected topics in translational neuroscience. In order to represent the students' interests and to train their rganizational skills, these courses have been organized by the students themselves (with help of the board members of the Integrated Graduate Program). In addition, students have been offered specific training courses in “soft skills” such as presentation techniques or group work in cooperation with the Graduate Academy of Heidelberg University. The students choose one main laboratory and advisor with whom they are affiliated at the very beginning of the program. In order to foster the idea of translational research we have also encouraged the possibility to split the dissertation work between a basic/preclinical laboratory and a clinical unit. Accepted students thus chose one main laboratory and advisor and two additional advisors who have had regular meetings twice a year with the student and follow the progress of his or her work. We are strongly encouraging first-author publications by the students and allow for a short, cumulative version of the dissertation script after 1 or 2 articles have been accepted (depending on the extent of the work invested) and one additional article has been submitted at the time of the completion of the degree. The Graduate Program is run by a governing board that also involves student representatives. From our experience with the program so far, we found that both the scientists within SFB 636 and the students greatly profit from this structured program in advanced neuroscience teaching. It increases the students´ professional prospects in the growing area of translational neurosciences and it creates a platform for interdisciplinary dialogue within the SFB, thus fostering preclinical-clinical cooperations. In the new funding period we have kept the basic structure of the program but have added additional offers: mentoring can now be done by our international collaborators; there is more career counselling; recruitment efforts for medical students will be intensified; and additional self-organized activities of the students have been included.

Hansson AC. DFG - Deutsche Forschungsgemeinschaft HA 6102/1-1: Interaktionen zwischen Dopamin Rezeptor D1 und Corticotropin Releasing Hormon Rezeptor 1 in der Amygdala bei Alkoholabhängigkeit. 09/2010-08/2013.

Up-regulated corticotropin releasing hormone (CRH) and CRH receptor subtype 1 (CRHR1) signaling within the amygdala is critically involved in alcohol dependence. So far the molecular mechanism underlying this long-term up-regulation is unknown. Here, we propose a role for dopamine (DA) in the progressive recruitment of CRH signaling during the transition into alcohol dependence resulting in a maladaptive functional interaction between the two neurotransmitter systems. Within the amygdala there exist DA D1 and CRHR1 receptor rich neuronal populations - the intercalating cell masses (ICM) - with important gating functions for intra-amygdala signal flow. We hypothesize that within these cells D1/CRHR1 receptor interactions play an important role in controling the CRH drive within the amygdala. We will use an integrative neuroanatomical, behavioral and molecular approach for studying animal models of alcoholism, including advanced conditional knockout mice and viral vector gene transfer. Our experiments are aimed 1) to establish the intracellular co-localization of D1 and CRHR1 receptors in the amygdala of alcohol-naive and dependent animals, 2) to prove the functional importance of D1/CRHR1 interactions for the alcohol dependent phenotype, and 3) to identify candidate genes associated with dependence-induced neuroplasticity in amygdala D1 and CRHR1 neuronal populations. The proposed project seeks to significantly improve our understanding of amygdala function in alcohol dependence, to identify mechanisms that are specific for this region and, in a broader perspective, to contribute to a better understanding of addictive behavior in general as well as other psychopathologies such as anxiety and depression, which may eventually lead to novel pharmacotherapeutical approaches.

Kiefer F, Kirsch P. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP D06: Belohnungslernen und Extinktionstraining bei alkoholabhängigen Patienten: Einfluss der frontostriatalen Konnektivität. 01/2012-12/2015.

Eine gesteigerte Reizreaktivität auf alkoholassoziierte Reize gilt als ein wichtiger pathophysiologischer Mechanismus der Alkoholabhängigkeit. Ergebnisse der letzten Förderperiode zeigen, dass ein Extinktionstraining diese gesteigerte Reizreaktivität von Alkohol-Patienten reduziert. Im nun vorliegenden Projekt soll mit Hilfe funktioneller und struktureller Hirnbildgebung untersucht werden, inwieweit Aktivierung und Konnektivität frontaler und striataler Regionen die Extinktion modulieren. Wir erwarten, dass uns diese Methoden erlauben, Subgruppen von Patienten zu definieren, die unterschiedlich stark von einem Extinktionstraining profitieren.

Kiefer F. BMBF - Bundesministerium für Bildung und Forschung 01EE1406C: Verbund AERIAL im Forschungsnetz für psychische Erkrankungen - Mechanismen von Suchterkrankungen: Sozialer Ausschluss, Vorhersage von Erkrankungsrisiken, Widerstandsfähigkeit und angepasste Theorien, Projekt 6. 02/2015-12/2019.

We will define the impact of social influences on drug consumption patterns across lifespan in the rat. In particular, social exclusion from peers during adolescence is suggested as an early risk factor for psychopathologies and social stressors in adolescent individuals facilitate drug abuse-related behaviors [1]. However, it is unclear how social exclusion during adolescence impacts on drug consumption patterns and the risk to develop SUD across the lifespan. By studying the impact of social exclusion in the adolescent rat we will provide essential epigenetic, transcriptomic, molecular and neurochemical information to Project 1 to better define neurobehavioral predictor profiles for SUD later in life. We will use our novel animal model of social exclusion [2] where inadequate playful interactions in adolescent rats produces life-long adverse consequences such as alterations in social behavior, emotional and pain-reactivity. Rats deriving from this model will be studied for gender-dependent alcohol consumption patterns, nicotine self-administration behavior and vulnerability to develop addictive behavior. Beside this behavioral characterization we will examine neurobiological alterations induced by social exclusion within the dopaminergic and the endocannabinoid systems by longitudinal translational PET studies and adjunct in vivo microdialysis, post mortem biochemical and immunohistochemistry experiments. In parallel, together with partners from Project 7 we will conduct genome-wide methylation and gene expression studies in socially excluded vs. non-excluded rats and will functionally study by virus-mediated gene transfer epigenetically altered genes in their role in later alcohol drinking, nicotine self-administration and addictive behavior. In a convergent approach our validated datasets will be merged with the databank of Project 1. Having defined genetic and neurobehavioral risk profiles we will manipulate in animals the genetic and neurobehavioral mechanisms identified in our corresponding animal and humans experiments. This approach aims to inform the identification of marker sets in humans as well as the development of targeted early interventions.

Kiefer F. BMBF - Bundesministerium für Bildung und Forschung 01GS08152: NGFN Plus GENALC TP13: Endophenotyping with fMRI: genetic modulation and treatment response. 06/2011-05/2013.

Kiefer F. BMBF - Bundesministerium für Bildung und Forschung 01ZX1311A: Alcohol Addiction-A Systems-Oriented Approach (SysMedAlcoholism); Teilprojekt 10: Functional Validation II: Neuroimaging X genetics. 01/2014-12/2018.

Das Teilprojekt 10 ist eine in Berlin und Mannheim durchgeführe Studie (SysMedAlcoholism – eMEDS), die mit Hilfe bildgebender Verfahren (fMRT= Kernspintomographie) bei alkoholabhängigen Patienten (N= 112) und ihren Angehörigen 1. Grades (n= 112), den Zusammenhang von genetischer Veranlagung zur Alkoholabhängigkeit, neuropsychologischen Maßen und strukturellen und funktionellen Veränderungen des Gehirns untersucht. Die Grundidee dabei ist, dass sich auf Gehirnebene schon Effekte genetischer „Risikovarianten“ nachweisen lassen, auch wenn Verhalten oder Klinik völlig unauffällig sind. Für die einzelne Person ist dieses genetische „Risiko“ aber so gering und klinisch unbedeutend, dass man solche Untersuchungen in größeren Gruppen durchführen muss, um klinisch relevante Aussagen zu machen, z.B. ob sich anhand solcher Gehirnveränderungen bzw. aus Kombination von Gehirnveränderung und Genetik (Imaging Genetics) die Wahrscheinlichkiet von Rückfällen oder Alkoholkonsum in einer Gruppe vorhersagen lassen. Deshalb werden neu erhobene Daten (SysMedAlcoholism) mit Daten aus anderen großen Untersuchungen (NGFNplus: Erwachsene, IMAGEN: Jugendliche), die ähnliche Fragestellungen verfolgen, und an denen die Projektleiter beteiligt sind, kombiniert, um eine bessere Aussagekraft zu erlangen und Befunde gegenseitig zu überprüfen (Kreuzvalidierung). The goal of the multicenter subproject 10 of the eMED Alcohol Addiction Consortium - A Systems-Oriented Approach is to study neuroimaging x genetics predictions in an existing sample (NGFNplus) of tightly endophenotyped and genome-wide genotyped alcohol dependent subjects (N=240) and controls (N=240); (ii) to translate the results of neuroimaging and genetic analyses from an adolescent risk sample (IMAGEN) to adult disease (NGFNplus sample) by examing related MRI-paradigms tagging the same functional brain systems in both samples (e.g. reward system, inhibitory control system, emotion processing, working memory); (iii) to conduct a follow-up neuroimaging study on the NGFNplus sample validating the neurobehavioral risk profiles predicitve for juvenile harmful alcohol use in adult patients with alcohol addiction, (iv) to expand the NGFNplus sample by including a new set of healthy subjects with high genetic risk (1st degree relatives of patients with alcohol addiction). We will do so by using elaborate imaging genetic methods that are already available and successfully used in other multicenter studies by our group (e.g. univariate analyses, functional and effective connectivity analyses, polygenetic scores, network topology) as well as by using complex computational algorithms and mathematical models, in particular advanced machine learning methods, developed in TP 6. Our approach aims in the long to to predict and characterize longitudinal outcomes in patients with alcohol addiction (5 years following our index session) and to complement the NGFN-sample with an add-on study with 1st degree relatives that will allow us to test the generalizability of the identified predicitive risk profiles for early risk identification.

Kiefer F. Ministerium für Soziales und Integration Baden-Württemberg Az.: 55-5072.1: Evaluation und Definition des therapeutischen Interventionsbedarfs bei Patienten mit häufigen stationären Wiederaufnahmen bei Alkoholabhängigkeit. 01/2017-06/2018.

Um die Hypothese zu prüfen, ob unter den häufig wiederkehrenden Patienten („Heavy User“) in den Suchtkliniken von PZN und ZI ein erhöhter Anteil von Patienten mit komorbider Emotionaler Instabilität, adultem ADHS und Traumaerfahrung anzutreffen ist, soll den Patienten, die auf Grund des Krankheitsverlaufs als „Heavy User“ (mindestens 5 stationäre Aufnahmen in einem Jahr oder 10 stationäre Aufnahmen in den vergangenen 5 Jahren) identifiziert wurden, auf Basis spezifischer diagnostischer Testungen der drei genannten Krankheitsbilder mit Patienten verglichen werden, die in der Vergangenheit einen eher günstigeren Krankheitsverlauf zeigten (max. zwei Aufnahmen in den vergangenen 5 Jahren). Hierbei sollen diagnostische Instrumente zum Einsatz kommen, die nach Ende der Studie auch in die stationäre Routineversorgung integriert werden können.

Köhr G. BMBF - Bundesministerium für Bildung und Forschung 01DN12062: Noradrenaline and the cortex. 06/2011-12/2013.

Recent evidence has revealed that noradrenaline modulates the state of cortical inhibition in addition to its control of excitatory glutamatergic transmission. Using behaviorally-relevant electrical stimulations in cortical slices, we could induce long-term depression (LTD) of inhibitory postsynaptic currents in layer II/III pyramidal cells. In the presence of beta-adrenergic agonists, however, we were able to induce long-term potentiation (LTP) instead of LTD, and are therefore currently examining the underlying mechanisms.

Köhr G. DFG - Deutsche Forschungsgemeinschaft KO 1064/7: Pathway-dependent plasticity. 01/2010-12/2014.

Hippocampal CA1 pyramidal neurons receive direct sensory information from the entorhinal cortex and indirect information from CA3 pyramidal neurons which project via the Schaffer collateral/commissural fibers to apical and basal CA1 dendrites. We compare the latter two pathways in acute brain slices, because we observe differences when applying spike-timing-dependent plasticity paradigms. Such differences could be relevant to the timing of interactions between these two major pathways during hippocampal network activity.

Köhr G. DFG - Deutsche Forschungsgemeinschaft SFB 636: Addiction and the nucleus accumbens. 06/2012-12/2015.

We are planning to monitor changes in synaptic strength in the nucleus accumbens in vivo via chronically implanted electrodes in rats during long-term cocaine exposure, and examine the mechanism of underlying synaptic changes in brain slices of addicted versus non-addicted rats in distinct disease states.

Mann KF, Ende G, Sommer WH. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP D07: Neuroplastische Veränderungen von Glutamat/ Glutamine im Gehirn und Zusammenhang mit der Therapieresponse bei Alkoholismus. 01/2012-12/2015.

D07 erforscht neurochemische und funktionelle Veränderungen der zerebralen Erregbarkeit in Alkoholentzug und Abstinenz. In einem translationalen und multimodalen Ansatz wird das präfrontale Glutamat/Glutamin Verhältnis in Patienten und „alkoholabhängigen“ Ratten mittels Magnetresonanzspektroskopie (MRS) gemessen. Die Werte könnten relevant für Rückfälle sein und sich als Biomarker eignen. Die humanen MRS Untersuchungen werden mit Blutoxygenierungsiveau abhängigen funktionell-magnetresonanztomographisch gemessener Reagibilität auf alkoholrelevante Reize als Prädiktor für Alkoholverlangen und Rückfall kombiniert. Damit könnten wir einen Ansatz zur „personalisierten Behandlung“ liefern. Parallel werden die Tiere während Alkoholexposition, Entzug und Abstinenz mit MRS untersucht. Die Wirkung antiglutamaterger Substanzen wird in beiden Spezies geprüft.

Schneider M, Friemel CM, Spanagel R. MWK - Ministerium für Wissenschaft Forschung und Kunst Baden-Württemberg : Neurobiologische Untersuchungen zu der altersabhängigen reduzierten Empfindlichkeit gegenüber natürlichen Verstärkern und Drogenverstärkern.

Motivational factors and reward processing have a great impact on key symptoms of frailty. Thus, appetite loss, apathy, and exhaustion are a result, at least in part, of altered reward processing in elderly people. Reward processes involve complex behavioral patterns, including appetitive and hedonic activities which all remain essential as we age. However, the interactions of rewards with an aged brain are only poorly understood. The present project is therefore aiming to investigate age-related changes in the reward system and the behavioral consequences. The main focus will be based on the measurement of the development of sensitivity for food reward during aging and also on the influence of the dopaminergic (DA) and endocannabinoid (ECB) system on this process.

Sommer WH. BMBF - Bundesministerium für Bildung und Forschung 01EW1112: ERA-Net NEURON TRANSALC TP1: Multimodales Neuroimaging in Tiermodellen des Alkoholismus. 03/2011-02/2014.

Sommer WH. BMBF - Bundesministerium für Bildung und Forschung 01EW1112: ERA-Net NEURON TRANSALC: Translationale Hirnbildgebung zur Erkennung alkoholismusbedingter Stö-rungen in neuronalen Netzwerken und zur Beurteilung pharmakologischer Therapieansätze. 03/2011-02/2014.

Schätzungsweise erkranken jährlich mehr als 23 Millionen europäische Bürger an Alkoholismus. Neben dem unsäglichen Leid für die Patienten und deren Familien, verursacht die Erkrankung auch immense Belastungen für das öffentliche Gesundheits- und Gemeinwesen. Seit einiger Zeit gibt es pharmakologische Behandlungsansätze für die Erkrankung, allerdings kann ein Durchbruch bisher nicht verzeichnet werden, was zu einem bedeutenden Teil auch auf mangelnde Effektivität der eingesetzten Arzneimittel zurückzuführen ist. Das Ziel dieses Projektes ist es, die Aussagekraft von tierexperimentellen Studien für die Entwicklung wirksamer Medikamenten zur Rückfallprophylaxe bei Alkoholismus zu erhöhen. Sollte uns dies gelingen, könnte ein im Versuchtier beobachteter pharmakologischer Effekt besser auf seine potentielle Wirksamkeit im Menschen eingeschätzt werden, was zur Effektivitätssteigerung in der pharmakologische Forschung beitragen sollte. Das Vorhaben soll quantitative und longitudinale in vivo Untersuchung am Gehirn von Patienten und Versuchstieren unter Einsatz der neuronalen Bildgebung erreicht werden. Wir erwarten, über den Vergleich von Alkoholeffekten und deren Modifikation durch klinisch geprüfte Anti-Alkoholismusmedikamente (Campral, Revia) in Patienten und entsprechenden Tiermodellen, Aussagen über behandlungsresponsive Regionen innerhalb eines erkrankungsspezifischen neuronalen Netzwerks (translational „disease-network“) machen zu können.

Spanagel R, Schneider M. DFG - Deutsche Forschungsgemeinschaft KFO 256, 2nd funding period: TP 07 Neurobiological Consequences and Mechanisms of Early Social Rejection Experiences. 08/2015-07/2018.

1 Results of the first funding period The major aim of the present proposal is to further elucidate the molecular consequences and mechanisms of social rejection or ostracism in a rodent model with relevance to borderline personality disorder (BPD). The experience of social rejection by others is a major source of distress in humans and has been implicated in the development of various psychiatric disorders including BPD. BPD patients often report experiences of neglect and rejection during childhood and adolescence, and display a heightened sensitivity toward social rejection in adulthood. During the first funding period of our associated project (AP1) we accomplished the establishment of an innovative animal model for the long-term consequences of early adverse social experiences in laboratory rats. By manipulation of social requirements during childhood and/or adolescence we were able to evoke persistent behavioral changes in adult female rats that resemble core aspects BPD, such as disturbed social interaction and recognition memory and decreased pain sensitivity. In addition to these behavioral changes, our initial findings show alterations in the endocannabinoid system (ECS) as a long-term consequence to rejection experiences. In particular, adolescent social rejection was found to enhance levels of the endocannabinod anandamide (AEA) on the long-term. Related to our findings, a recent study reported alterations of peripheral endocannabinoid levels in BPD patients, which is in support of a relevant role of the ECS not only in our animal model but also in BPD patients that may led to an improved understanding and new therapeutic approach to BPD. 2 New questions and work schedule Although it is well established that social rejection plays a major role in BPD, the neurobiological consequences and mechanisms linked to social rejection are largely unknown. We here aim to further examine these neurobiological processes by investigating the consequences of alterations in social requirements in adolescent rats - alone, and in combination with early modulations of mother-infant interaction. Our investigations will be focused on neurochemical systems involved in the modulation of social behavior and pain processing. Aside from our initial findings on alterations in the ECS we here aim to extend our analysis to the central oxytocin and the endogenous opioid system. These three neurochemical systems have been identified by our CRU as the most promising candidate systems for medication development and are also studied in the context context of the other IPs. Here we plan to utilize inter alia imaging techniques such as positron emission tomography (PET) and molecular (Western blot, autoradiography) and neurochemical analysis (e.g. liquid chromatography/ tandem mass spectrometry (LC/MS-MS)). Alterations in thermal pain reactivity will be used as behavioral readout. Based on our previous findings we now also intend to monitor the time course of neurobiological consequences of social rejection experiences throughout adolescence and early adulthood at different time points more closely, in order to shed light on the timing of the mechanistic processes mediating the persistent behavioral and neurobiological changes in adulthood. Furthermore, in order to gain a causal link of a given molecular change and a specific BPD-like behavioral feature we will use a regional viral-mediated gene transfer approach in an additional rescue experiment. A first target will be the normalization of enhanced amygdalar AEA levels and the hereby expected normalization of pain perception. Other identified persistent molecular changes will be also selectively targeted by viral-mediated gene transfer. This approach will not only provide a mechanistical inside for BPD but will also deliver new intervention strategies for our CRU.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01EW1404: NEURON-Verbund COCADDICT: Cocaine addiction: A translational study of identify and characterize dysfunctional neuronal networks. 05/2014-04/2017.

Substance misuse is associated with economic costs equal to cancer, cardiovascular diseases or all other psychiatric disorders combined. The illicit substance with the highest societal costs is cocaine. Although the chronic relapsing nature of addictive behaviours suggests a reorganization of neural circuits processing drugs and drug-related stimuli, an integrated understanding is lacking. Now, the present translational research team offers a rare opportunity to characterize, in a coordinated fashion, the relevant features in both humans and a high face validity animal model. In brief, identical functional and anatomical connectivity neuroimaging strategies will be used in human an rats; studies in the latter will be augumented by in vivo multisite electrophysiological recordings and optogenetic manipulations in behaving animals. Together, we will: 1. Establish a valid translation between rodent and human for addiction-related brain network reorganization, 2. Map transmitter specific neuronal circuits, and 3. Test the contribution of these circuits to the development, expression and inhibition of addiction-like behaviours. Together, this innovative approach increases our ability to identify neurobiological trajectories and novel treatment targets. We are starting with addictions because the societal needs are high, the animal models are best established, and the translational strategies requierd are most clear; once in place, though the same strategies could be applied to research on other disorders.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01GS08152: NGFN Plus GENALC TP1: Koordination. 06/2011-05/2013.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01GS08152: NGFN Plus GENALC TP8: Behavioural annaysis of animal models. 06/2011-05/2013.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01GS08152: NGFN Plus GENALC: Genetik der Alkoholsucht. 06/2008-05/2011.

Alkoholismus ist eine der häufigsten neuropsychiatrischen Erkrankungen, mit enormen gesundheitlichen und sozioökonomischen Auswirkungen auf unsere Bevölkerung. Genetische Ursachen spielen bei der Entwicklung von Alkoholismus eine entscheidende Rolle. In letzter Konsequenz ist jedoch abhängiges Verhalten das Ergebnis der genetischen und der epigenetischen Ausstattung eines Individuums, zusätzlich zu den kumulativen Reaktionen auf Alkoholexposition und zahlreichen Umweltfaktoren im zeitlichen Verlauf. Diese komplexe Interaktion von Alkohol x Gen x Umwelt führt zu einer großen klinischen Heterogenität sowohl in Bezug auf die Symptomatik und die Schwere der Störung als auch auf die Wirksamkeit einer Behandlung. Das Ziel von unserem Forschungsverbund ist die komplexen Gen x Umwelt Interaktionen in einem systembiologischen Ansatz zu untersuchen. In 13 Teilprojekten werden tier- und humanexperimentell Untersuchungen durchgeführt. Mit Hilfe von Genexpressionsanalysen und genomweiten Assoziationsuntersuchungen werden anhand von konvergierenden genomischen Analysen Kandidatengene identifiziert, die anschließend im Tiermodell funktionell untersucht werden. In einem zweiten größeren Forschungsansatz wird die glutamaterge Theorie der Alkoholsuchentwicklung systematisch untersucht und auch in einem translationalen Ansatz direkt am Menschen geprüft. Vergleichend werden auch andere Drogen z.B. Kokain in verschiedenen Tiermodellen untersucht.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01ZX1311A: Alkohlabhängigkeit: Eine system-orientierte Herangehensweise. 01/2014-12/2016.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01ZX1311A: e:Med - Maßnahmen zur Etablierung der Systemmedizin. 01/2014-12/2016.

Mit dem Förderkonzept soll zur Etablierung der Sytemmedizin in Deutschland beigetragen werden. Es bedarf hierzu einer disziplinübergreifenden Vernetzung von klinischen Arbeitsgruppen, von hochdurchsatz-orientierten Arbeitsgruppen der biomedizinischen Grundlagen-forschung sowie von Expertise für Informationstechnologien und Datenmanagement bzw. für mathematische Modellierung. Um weitere Synergieeffekte auszulösen und hierdurch die Forschungsförderung zu optimieren, ist beabsichtigt, die zur Förderung kommenden "Forschungskonsortien zur Systemmedizin" verbundübergreifend zu vernetzen.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01ZX1611A: e:med II - Alcohol Addiction: A Systems-Oriented Approach . 01/2017-12/2018.

Our SP1 on coordination of the consortium was very productive in delivering (i) the consortium contract, (ii) a perspective article on systems medicine in alcoholism research with a description of our consortium in Addiction Biology (Spanagel et al., 2014; this article has already been cited 20 times), (iii) our website (www.sysmedalc.eu), (iv) meetings and reports (kick-off meeting, annual meetings, and method meetings) , (v) two press releases and public relation outreach involving radio and TV, and (vi) organization of the World Congress on Alcohol and Alcoholism in Berlin 2016 (www.isbra-esbra-2016.org) and co-organization of the Gordon Research Conference on Alcohol and the Nervous System (Galveston 2014).

Spanagel R. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP B01: Rekonsolidierung von alkoholassoziierten Gedächtnisinhalten: Untersuchungen von zellulären Mechanismen und glutamatergen Interventionen. 01/2012-12/2015.

Drug-associated conditioned stimuli (CS) can induce craving and precipitate relapse behavior. Therefore, disruption of these learned associations may reduce the subsequent risk of relapse. Within the context of SFB636 we are interested in extinction and reconsolidation processes of these CS-drug memories and have conducted in the 2nd funding period of SFB636 several extinction studies demonstrating the importance of glutamate receptors in extinguishing CS-drug associations and subsequent relapse behavior. However, the clinical efficacy of extinction-based therapies in drug addicts or alcohol-dependent patients might be limited due to the fact that a persistent weakening of a CS-drug association seems hardly to be achieved. Although some patients do benefit, many relapse due to cue-, drug priming-, or stress-induced reinstatement of previous drug-seeking behavior. Alternatively, disruption of reconsolidation processes can be used to interfere with CS-drug associations. In the process of reconsolidation, a retrieved memory transiently returns into a labile state and requires new protein synthesis to persist further. During this labile state, the memory is amenable to enhancement or disruption. We have now shown for the first time that pharmacological disruption of reconsolidation of alcohol-associated memories can be achieved by use of protein synthesis inhibitors and by N-methyl-D-aspartate (NMDA-) antagonists and may thus provide a potential new therapeutic strategy for the prevention of relapse in alcohol addiction. In the new funding period we will systematically examine the neuronal ensembles mediating the reconsolidation of alcohol-associated memories in rats by using a novel method ermed “Daun02 inactivation”. This is, to the best of our knowledge, the only method that allows selective silencing of activated neuronal ensembles mediating a particular learned behavior. In a first set of experiments we will anatomically map the brain sites and neuronal ensembles involved in the reconsolidation of CS-alcohol memories. In a second set of experiments we will probe with the prodrug Daun02 the functional relevance of the morphologically identified neuronal ensembles. In summary, these experiments will provide a better neurobiological understanding of reconsolidation process. Since NMDA receptors are crucial for the reconsolidation process of cue-alcohol associated memories we will further define in a preclinical setting the cue/context and temporal parameters that lead to the most pronounced disruption of the reconsolidation process of alcohol-associated memories by NMDA receptor blockade. Two NMDA receptor antagonists will be studied: memantine and the noble gas xenon - as both substances are already approved in Germany for different indications with a limited side effect profile. In the case that we achieve a successful disruption of alcohol-related memories in alcohol-addicted rats with either one of these compounds we will propose an experimental medicine study in alcohol dependent patients.

Spanagel R. DFG - Deutsche Forschungsgemeinschaft SP 383/11-1: Geschlechtsunterschiede bei der Prozessierung von Belohung und Sucht. 06/2015-05/2016.

Brain correlates of cue and reward processing in adolescent males and females: findings from the IMAGEN study. Women progress through the landmark stages of addiction, from initial use to dependence for cocaine, alcohol, and other addictive substances, at a faster rate than do men (Kosten et al., 1993, Brady and Randall, 1999). Females also have greater motivation to obtain and/or use drugs of abuse (Becker and Hu, 2008) and escalate drug use more rapidly after relapse (Paliwal et al., 2008). We hypothesize that women more rapidly acquire drug-taking because, compared with men, in females there is less of an increase in the neurotransmitter dopamine (DA) in the reward system of the brain (focusing on the nucleus accumbens (NAc)). Thus, more drug is needed to achieve comparable increases in DA. We further hypothesize that the transition to compulsive drug taking in females is facilitated by enhanced DA transmission in dorsolateral striatum and putamen relative to NAc. Such a sex difference is found in rodent studies (Cummings et al., 2014). As a first test of this hypothesis in humans, we propose to examine whether there are sex differences in connectivity among the NAc (ventral striatum), dorsomedial striatum, and putamen as well as in the response to reward anticipation in the IMAGEN data set, and whether the response obtained during baseline or after a cue correlate with later drug or alcohol consumption.

Spanagel R. DFG - Deutsche Forschungsgemeinschaft SP 383/4-1: SPP1226 Nikotin: Molekulare und Psychiologische Effekte im Zentralen Nervensystem (ZNS). 09/2009-09/2012.

Background: Consistent evidence for the heritability of smoking behaviours has led to genetic studies designed to elucidate the specific genetic factors involved in nicotine addiction. The most advanced scientific approaches to address this question include genome-wide association studies (GWAS) in smokers and gene expression profiling studies in animal models of nicotine self-administration. Convergent translational genomics approaches allow integrating genetic findings from animal models with a GWAS approach in humans and have proven to be very successful in generating priority candidate gene lists. However, the demonstration of a causal relationship of a candidate gene with a given pathological phenotype remains the biggest challenge in the emerging field of genetic research. Goals: In this proposal we want to integrate our previous genetic findings from massive gene expression profiling in animals that underwent chronic nicotine self-administration with the human genetic data sets deriving from the German Priority Programme on Nicotine Research SPP1226 (Project P2 (Dahmen), P3 (Winterer), P9 (Brenner), P10 (Winterer), and P11 (Steinlein)). By applying a convergent translational genomics approach data integration will be performed and a priority candidate gene list for the entire SPP1226 will be generated. From this priority gene list for nicotine addiction we will functionally validate the top hits in an animal model of nicotine self-administration and relapse by means of recombinant adeno-associated virus (rAAV)-mediated gene transfer into brain sites of the reward system (especially into the nucleus accumbens shell). The advent of AAV vectors carrying cDNA for, or short hairpin RNA against, specific genes allows now for the first time the rapid bidirectional manipulation of gene function in nicotine self-administering animals. Both applicants have proven expertise in animal models of addictive behaviour and rAAV-mediated gene transfer technology, respectively.

Spanagel R. DFG - Deutsche Forschungsgemeinschaft SP 383/5-1: Reinhart Koselleck-Projekt: Multimodales Neuroimaging x Optogenetics: ein neuer Ansatz zur Untersuchung von Belohnungsprozessen unter pathologischen Bedingungen. 08/2010-07/2015.

Background: Midbrain dopamine neurons play a key role in reward processing and subsequent goal-directed behaviour. Altered dopaminergic activity and dysfunctional reward processing occurs in several psychiatric disorders. Especially in drug addiction goal-directed behaviour is severely impaired, as the behavioural activities of a drug addict become increasingly drug-oriented at the expense of all other daily activities. The underlying neurobiology of altered reward processing during the development, maintenance, and possible remission of an addicted behaviour is poorly understood. Goals: To study the dynamics of midbrain dopamine neurons and their connectivity within the reward system by multimodal 9.4T magnetic resonance imaging (MRI) in rats that show addictive-like behaviour. Following a prolonged period of intravenous cocaine self-administration approx. 15% of rats develop addictive-like behaviour similar to that seen in human cocaine users diagnosed as addicts. Using this animal model, alterations in reward processing and underlying dopaminergic activity and connectivity will be studied longitudinally by means of repeated multimodal MRI in animals that become addicted versus animals that show resilience to addictive behaviour. Outcome: These studies will provide fundamental new insights into reward processing and underlying alterations in dopaminergic function and connectivity in the context of addictive behaviour. Given that outcome measures from experimental animals will be derived from neuroimaging studies the findings will be directly translatable to the human condition and will dramatically impact on our knowledge of drug addiction, pathological gambling, depression, and several other psychiatric disorders.

Spanagel R. EU - Europäische Union 037286: IMAGEN WP3: Reinforcement-related behaviour in normal brain function and psychopathology: Gene identification. 02/2007-07/2012.

Generation and validation of candidate genes in a hypothesis-free approach. Brain tissue from rats showing extremes in impulsive and reward-related behaviour (one deliverable from WP1) will be studied for differential gene expression in relevant brain regions such as the nucleus accumbens, prefrontal cortex and amygdala. For screening purposes, an Affymetrix platform and a Serial Analysis of Gene Expression (SAGE) platform will be used. Our research consortium set up a patented micro-method for transcriptome characterization using the SAGE technique. An in-house generated database consisting of > 1.2 million SAGE tags sampled from the rat brain will be screened to identify genes preferentially expressed in brain regions involved in reward-related behavioural traits. Furthermore, a highly standardized Affymetrix platform will be used for the search of candidate genes. Selected genes will be confirmed with an independent method namely realtime RT-PCR (SYBR green or Taq-Man). Confirmed, selected genes will be further analysed by in situ hybridization and if possible selected genes will be also evaluated on the protein level by Western blotting and immunohistochemistry.

Spanagel R. MWK - Ministerium für Wissenschaft Forschung und Kunst Baden-Württemberg 32-731.0/92: Arbeitsgruppe Translationale Suchtforschung. 09/2011-08/2014.

Die Arbeitsgruppe „Translationale Suchtforschung“ soll als Schnittstelle zwischen präklinischer Forschung und klinischer Entwicklung dienen. Sie beschäftigt sich mit der Übersetzung von Befunden, die z.B. mit Hilfe von Tiermodellen gewonnen wurden, in die Anwendung am Menschen. Das hier vorgestellte Konzept basiert auf drei Säulen: die mit der Suchtklinik gemeinsame Erforschung neurobiologischer Grundprinzipen der Sucht, die Charakterisierung genetischer Risikoprofile und biologischer Konstrukte (Biomarker) von Suchterkrankungen, sowie die Entwicklung von neuen Behandlungsstrategien (pharmakologische Interventionen und Verhaltenstherapien).