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Projects: Psychopharmacology

Meinhardt M. MWK - Ministerium für Wissenschaft Forschung und Kunst Baden-Württemberg : Einrichtung eines 3R-Zentrums im Rhein-Neckar Raum . 12/2020-11/2025.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01KC2004A: AhEAD Preclinical Phase II Assessment of Exosomes in Alcohol Addiction. 11/2020-10/2023.

Worldwide two billion people drink alcohol regularly. A major health consequence is alcohol addiction that is characterized by chronic relapses. Preventing relapse is the main treatment goal. Current pharmacological treatments have limited efficacy, thus better treatments and prediction approaches that can be easily translated into the clinical situation are warranted. One major hypothesis in alcohol research is that chronic alcohol intake leads to neuroinflammation that in turn triggers addictive behaviour. It has been shown that intranasal delivery of mesenchymal stem cell-derived exosomes reduces relapse behaviour in rats. Here we propose a multi-center placebo-controlled trial in rats as a preclinical confirmatory proof. We aim to confirm the hypothesis that treatment with exosomes will have long-lasting positive effects on relapse behaviour in animal models of alcohol addiction. The preclinical trial design will follow the guidelines on the development of medicinal products for the treatment of alcohol addiction provided by the European Medicines Agency (EMA), will adhere to the standards proposed for confirmatory biomedical research (Dirnagl, 2016) for nonclinical laboratory studies, and publication of the results will follow the ARRIVE guidelines. An independent third-party company focusing on the evaluation of data quality and practice in biomedical research will ensure adequate quality management and monitoring of our preclinical trial at the best possible level.

Meinhardt M. DFG - Deutsche Forschungsgemeinschaft ME 5279/3-1: Scrutinizing an epigenetic driven dysregulation of prefrontal mGluR2 function in alcohol dependence . 10/2020-09/2023.

DFG - Deutsche Forschungsgemeinschaft : SFB 1158, B04 Translational studies in pain chronicity: role of corticothalamostriatal pathway in stress-sensitisation and comorbidity development. 07/2019-06/2023.

Psychiatric comorbidities, such as depression, anxiety and alcohol abuse are a major medical challenge in chronic pain, especially in female pain patients with adverse childhood experiences. However, it is unknown whether these comorbidities are caused by specific brain circuit alterations. A brain area that is strongly activated by pain and mediates motivational and affective behaviors is the paraventricular thalamic nucleus (PVT). PVT neurons project to nucleus accumbens (NAc) and anterior cingulate cortex (ACC) – both key nodes of motivational and affective processing. Current knowledge highlights that plasticity alterations in NAc and ACC may cause comorbidities related to chronic pain. Our translational project in humans and mice aims to understand whether plasticity in PVT-to-NAc/-ACC projections causally mediates pain comorbidities and whether adverse childhood experiences and gender have significant influence on these circuit alterations. In adult mice, we will mechanistically disentangle the role of plasticity in PVT-to-NAc/ACC projections for development of comorbidities during chronic stages of neuropathic pain using patch-clamp electrophysiology and fiber photometry in combination with neurobehavioral testing and opto-/chemogenetics. In patients suffering from chronic musculoskeletal pain, we will cross-sectionally investigate structural and functional alterations of PVT-to-NAc/ACC projections using high-resolution neuroimaging, diffusion tensor imaging, fMRI and fiber tracking analysis and determine their correlations to motivational/ affective alterations in daily life and to biomarkers for allosteric load. Both in humans and in rodents, we will investigate whether early childhood adversity especially in female subjects significantly sensitizes these circuit alterations. For the future, we aim to modulate PVT activity by targeted neurofeedback- or TMS/tDCS and hence test, whether PVT circuitry can be a novel target region for therapy of chronic pain-related motivational deficits and anxiety. Our translational study will unravel novels mechanistic insights in higher-order processing of chronic pain and may open up the door for specific therapy of one of the major challenges in chronic pain.

Hansson AC, Sommer WH. DFG - Deutsche Forschungsgemeinschaft : CRC TRR 265: Project B02: Habit formation and its relevance in alcohol addiction. 07/2023-06/2023.

Both habit formation and skill learning involve two principal steps, initial acquisition and subsequent consolidation, which are differentially controlled by ventral and dorsal striatal neurons, respectively, and their dopamine D1 and D2 receptors. These mechanisms are likely shared among different striatal learning paradigms and impacted by alcohol dependence. We will use advanced genetically modified rodent models that allow for spatial, temporal and circuit-specific control of neuronal activity to identify pathophysiological mechanisms underlying habit formation and to find ways to improve control over the behavior.

Kirsch P, Koppe G, Sommer WH. DFG - Deutsche Forschungsgemeinschaft : CRC TRR 265: Project B08: Aversion discounting in behavioral control in animal models and human addiction. 07/2019-06/2023.

To date, reward discounting but not aversion discounting was examined in SUD. Our working hypothesis of increased temporal aversion discounting in AUD patients will be tested by novel tasks for reliable and quantitative assessment of aversion discounting in humans and animal models. We will study the underlying neurobiology of aversion discounting by fMRI in humans and calcium imaging microendoscopy in rats. Computational analyses will be used to model the decision-making processes and deliver a detailed and formal parametrization of aversion discounting on multiple levels of analysis. In the future, such information can be used for the development of therapeutic approaches that strengthen self-regulation and cognitive control

Spanagel R. DFG - Deutsche Forschungsgemeinschaft : CRC TRR 265: Project A05: Intensive behavioral monitoring and dynamical state transitions in animal models of addiction. 07/2019-06/2023.

Using novel approaches established in statistical physics and dynamical systems, we will investigate whether early warning signs that are indicative of critical state transitions into addictive behavior can be detected by intensive longitudinal data (ILD) derived from a rat model for alcohol addiction and from a long-term nicotine self-administration model.

Spanagel R. DFG - Deutsche Forschungsgemeinschaft SFB/Transregio 265 : Teilprojekt A05: Intensive behavioral monitoring and dynamical state transitions in animal models of addiction. 07/2019-06/2023.

Spanagel R. DFG - Deutsche Forschungsgemeinschaft SFB/Transregio 265: Teilprojekt B08: Aversion discounting in animal models and human addiction. 07/2019-06/2023.

DFG - Deutsche Forschungsgemeinschaft : Deciphering alcohol addiction-associated gene regulation changes on a single cell level. 01/2020-12/2022.

Changes in brain structure and function that results from chronic exposure to alcohol suggest that neuroadaptive alterations in gene regulation substantially contribute to addictive behavior. Transcriptional and epigenetic profiling of brain tissue from animal models and post-mortem human samples has identified multiple candidate genes to be dysregulated upon chronic alcohol exposure. However, a detailed assignment of those changes to specific cell types has not been performed due to technical limitations and lack of appropriate tissue. In this planned consortium, we will apply paralleled single cell sequencing to decipher transcriptional and epigenetic changes underlying alcohol addiction. We will perform single nuclei RNAsequencing (snRNA-seq) and snATAC-seq epigenetic profiling using postmortem tissue from a well-defined, high-quality brain bank of deceased alcohol addicts. We have previously established a novel snRNA-seq platform that allows isolating and sequencing of individual nuclei from snap-frozen brain samples obtained from patients with other neuropsychiatric diseases. In parallel we will use standardized human iPSC-derived forebrain organoids from controls and alcohol addicts to monitor alcohol-induced changes in gene regulation and gene expression in an isogenic (non-exposed vs. exposed; acute, chronic intermitting, acute withdrawal) forward approach. We expect that the proposed project will deliver the largest available database on alcohol addiction-associated gene regulation changes on a single cell level and help define critical contributors in the pathogenesis of alcohol addiction eventually eading to new therapeutic paradigms.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01ZX1909A: SysMedSUDs - A systems-medicine approach towards distinct and shared resilience and pathological mecha-nisms of substance use disorders. 11/2019-10/2022.

According to the WHO, 2 billion people drink alcohol, 1.3 billion smoke, 182 million consume cannabis, and almost 250 million use illicit drugs. Many of those alcohol, tobacco and drug users become addicted. Substance use disorders (SUDs) generate the largest disease burden and are categorized by DSM-5 and ICD11. SUDs are defined by compulsive drug use, craving, and re-lapses that can occur even after years of abstinence. SUDs encompass several drug classes including alcohol, nicotine, cannabis, opioids, and stimulants. One fundamental question in psy-chiatric research is: “How distinct are the different SUDs and what are the shared pathological phenomena?” Here we aim to determine the extent to which alcohol, nicotine, heroin, cannabis, and cocaine use disorders share genetic, epigenetic, transcriptomic and neurochemical mecha-nisms. In a convergent approach, multiple system levels in SUDs will be studied concurrently in humans and rats. Large samples from SUDs patients from several consortia (e.g. PGC and UK biobank) together with post-mortem brain tissue of deceased patients will give us comparative insights into distinct and overlapping genetic, epigenetic, and transcriptomic signatures of SUDs. Comparative analysis of brain organoids derived from SUD patients will reveal drug-induced tran-scriptional changes on a single cell level. A novel in silico approach and spectroscopy in patients will reveal alterations in neurochemical connectomes in SUDs. Rat models for addiction provide great face, construct and predictive validity and will be used to examine the functional relevance of our multi-level analyses of human biomaterial and in silico driven predictions. In sum, our in-terdisciplinary consortium will lead to an understanding of distinct and shared resilience and pathomechanisms of SUDs. This will have implications for diagnosis, precision medicine, comor-bidities, addiction theories, and socio-political decisions such as legalization and taxation.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 031L0190A : Target-OXY - Towards Targeted Oxytocin Treatment in Alcohol Addiction. 06/2019-05/2022.

Worldwide two billion people drink regularly alcohol. A major health consequence is alcohol addiction that is characterized by chronic relapses. Preventing relapse is the main Treatment goal. Current pharmacological treatments have limited effectiveness and there is a large heterogeneity in the treatment response. Better treatments and prediction approaches that can be easily translated into the clinical situation are warranted. In our e:Med funded SysMedAlcoholism consortium we have identified early warning signs and drinking profiles that predict future relapse behavior and treatment response of clinically used anti-relapse medications. We have also identified in a multi-omics approach alterations in the oxytocin (OXY) system in alcoholic patients suggesting OXY as a candidate medication to reduce relapse. Here our Goals are (i) to demonstrate the clinical applicability of OXY and (ii) to computationally predict elapse and identify treatment responsive individuals. For the demonstration of the clinical applicability of OXY, we propose a new module in the drug development process, namely a preclinical multicenter placebo controlled trial in rats with a step-wise translation into a naturalistic pilot trial with ambulatory assessment in alcoholic patients. As a comparator, we will use datasets from previous trials where we tested placebo vs acamprosate – which is a clinically effective medication. These data will be contrasted with a 3-arm design in male and female alcohol addicted rats where two doses of intranasally applied OXY will be tested against placebo in a well-validated rat model for alcohol addiction. From this preclinical trial we will obtain intensive longitudinal data (ILD) sets on drinking and activity. Using new in silico approaches we will then be able to identify early warnings signs and drinking clusters for relapse and OXY treatment responsive individuals. This preclinical work will guide our naturalistic Trial with ambulatory assessment in alcoholic patients.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01EW1908: PsiAlc - Preclinical Phase II Testing of Psilocybin in Alcohol Addiction and Epigenetic and Neuroimaging Studies on the Mode of Action. 05/2019-04/2022.

Alcohol use disorders create the largest health burden globally. Alcohol addiction in particular is a chronic disease characterized by dysfunctional behavior and impairment in quality of life, and thus represents a tremendous burden for the patient, health care services, and the general society. Current pharmacological treatment approaches have limited effectiveness. Due to the need for more efficacious treatments and encouraging safety and feasibility data, scientific interest in the potential clinical benefits of serotonergic hallucinogens such as psilocybin has recently returned, and here we wish to study the effects of psilocybin on alcohol relapse behavior and its underlying neurobiological mechanisms. Prior to time-intensive discussions with regulatory bodies, dose determination and finally cost-intensive phase II clinical testing for psilocybin in alcoholics, we propose for the first time with respect to mental disorders a preclinical multi-center placebo controlled trial in rats with a step-wise translation into alcoholic patients. Our preliminary experiment indicates that psilocybin reduces relapse behavior in rats and we hypothesize that a single administration of psilocybin will have long-lasting effects on relapse behavior. We will use a 4-arm design: placebo vs. acamprosate - a clinically effective medication used as a reference compound - vs. two doses of psilocybin will be tested in our DSM5-based rat model for alcohol addiction. The entire preclinical trial design will follow the guidelines on the development of medicinal products for the treatment of alcohol addiction provided by the European Medicines Agency (EMA) and will adhere to Good Laboratory Practice (GLP) for nonclinical laboratory studies. As preclinical and clinical evidence suggests that sex and gender influence disease trajectories and interventions in alcoholics, male and female rats will be studied in direct comparison in our 4-arm design. Therefore, the first aim of our proposal is to test the long-lasting efficacy of psilocybin in male and female subjects on relapse behavior. Many studies on psilocybin in humans describe very long-lasting positive effects on disease trajectories and quality of life. How can such long-lasting effects be explained and what is the mode of action of psilocybin? Epigenetic effects occur as one possible candidate mechanism, and at a higher systems level, restoration of normal network function in the diseased brain is another candidate. Here we propose to study genome-wide alterations in methylation and transcription in a longitudinal fashion in alcohol addicted rats and humans following a single application of psilocybin. We will also examine resting state activity longitudinally (using rs-fMRI) and subsequent alterations in reward processing in alcohol addicted rats and humans following a single application of psilocybin. Therefore, the second aim of our proposal is to provide translational information on the epigenetic, transcriptional, functional brain network, and behavioral levels to understand the neurobiological underpinnings and mode of action of psilocybin in the alcohol addicted brain.

Hansson AC. Hetzler Stiftung : Cross-talk of neuronal ensembles in reward-seeking processes. 04/2021-03/2022.

Our daily life activities are driven by rewards which can be conditioned to specific stimuli and environmental contexts. Reward-seeking processes depend on the formation of reward learning, conditioned associations that persist over time, and lead to changes of distinct subsets of neurons –so called neuronal ensembles – within the extended reward system. Here we want to characterize functional ensembles in natural reward (saccharin)-seeking and alcohol-seeking processes. Our behavioral paradigm involves a sequence of specific operant components: presentation of an occasion setter (tone) → presentation of a cue light → lever presentation → lever response. We assume that each operant component is encoded by a specific neuronal ensemble and therefore a sequence of activated neuronal ensembles (meta-ensemble) encodes for the entire behavioral sequence of this rewardseeking task. We aim to study the cross-talk of these neuronal ensembles at an anatomical and functional level within the prefrontal cortex and adjunct brain sites. We will use CaMPARI as a novel in vivo neuroanatomical approach which generates calcium-dependent neuroanatomical “activity snapshots” of activated neuronal ensembles. The results will be validated by a new optogenetic tool, which allows selectively modifying neuronal ensembles with improved temporal control and specificity. In summary, our approach will give insight into the function of a meta-ensembl, namely the interaction of distinct neuronal ensembles of a reward-seeking task – an important mechanism of information processing during a complex behavioral task.

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.

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. 01/2017-12/2019.

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.

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 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).

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.

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, 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 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.

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.

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.

Flor H, Spanagel R. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP MGK: Integrated research training group "Translational Neuroscience". 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.

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: Neuroplasticity of brain glutamate and glutamine and treatment. 01/2012-12/2015.

The glutamate hypothesis of alcoholism posits that chronic alcohol intake leads to an enhanced activity of the glutamate system. As soon as alcohol is discontinued, withdrawal develops with marked brain hyperexcitability. Under abstinent conditions this hyperglutamatergic state could be reinstated by stress or alcohol cues and precipitate relapse. Anti-glutamatergic compounds are effective in preventing relapse and potentially also in alleviation of withdrawal. Effect sizes of this pharmacotherapy are moderate, a fact which may be accounted for by individual differences in the extent of neuroplastic changes of the glutamate system. Thus, we predict that antiglutamatergic medications work primarily in individuals who develop a pronounced hyperglutamatergic state, a condition that can be identified and monitored by magnetic resonance spectroscopy (MRS). We previously found that alcohol withdrawal is reflected by increased central glutamate levels. A new measure to be studied in the coming funding period is the glutamate/glutamine ratio which we now can also measure reliably in humans. This ratio will be tested as a potential biomarker for monitoring alcoholism, which may lay the grounds for a personalized treatment approach of this condition. We believe that a translational approach involving human patients and “alcohol dependent rats” serves the purpose of our research best. In both species prefrontal cortex changes in metabolite concentrations during acute withdrawal and into several weeks of abstinence are measured with and without pharmacological interference targeting the glutamatergic system. In the last funding period we developed methods for absolute quantification of metabolites in the human and rat brain. Under control conditions glutamate concentrations in the human anterior cingulate cortex (ACC) and the rat medial prefrontal cortex (mPFC) were highly similar. Thus, for the first time direct evidence for increased central glutamate levels during acute alcohol withdrawal in both species was provided. In the animal experiments, we will induce alcohol dependence through chronic, intermittent, ethanol-vapor exposure. Rats will be assessed repeatedly, over the course of acute alcohol withdrawal into abstinence, for neurometabolic changes in the medial-prefrontal cortex, using MRS at 9.4T. In the new funding period we shall concentrate on the effects of experimental pharmacotherapies for alcohol detoxification (glutamate modulators, such as acamprosate, memantine and lamotrigine) on neurometabolic profiles and on alcohol-related behaviors, comparing these therapies to standard treatments (GABAergic: diazepam). We will also compare neurometabolic profiles to in vivo, microdialysis measurements of extracellular glutamate release from parallel groups of rats. In the human study, we will continue to assess the effects of alcohol withdrawal. As a new element, alcohol cues and pharmacological intervention on levels of glutamate, glutamine and GABA in the prefrontal cortices of treatment-seeking alcoholics will be studied. Alcohol dependent inpatients (n=60) will undergo three combined measurements of MRS and fMRI cue reactivity. The first MR session will take place during acute withdrawal (without medication). The second group of measurements will be taken after five days of abstinence, in order to monitor the glutamate/glutamine ratio over time, and to what extent this ratio is affected by the diazepam that will at this point have been administered for withdrawal-symptom relief. The third MR session will take place on day 14 to monitor the effects of abstinence, both for patients under treatment with acamprosate (which will have been initiated as an open-label treatment following the second MR session) and for patients not being treated with medication. Relapse behavior will be monitored in follow-up assessments, and correlated to MRS metabolites. A control group of n=20 healthy subjects will undergo combined MRS and fMRI twice, two weeks apart.

Schneider M, Friemel CM, Spanagel R. MWK - Ministerium für Wissenschaft Forschung und Kunst Baden-Württemberg : The neurobiology of reward processing for natural and drug reward during aging. 01/2014-12/2015.

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.

Spanagel R. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP B01: Reconsolidation of alcohol-associated memories: From underlying cellular mechanisms to glutamatergic interventions. 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 383/5-1: Reinhart Koselleck-Projekt: Multimodal Neuroimaging x Optogenetics: A Novel Approach to Study Reward Processing Under Pathological Conditions. 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.

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

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.

Schneider M, Spanagel R, Schneider P. : KFO 256 AP 1: Modulations of Maternal Care and Adolescent Social Exclusion in Rats as an Animal Model for Aspects of BPD. 01/2012-12/2014.

The major aim of this research project is to establish an animal model with high face and contruct validity towards aspects of the etiology and symptomatology of borderline personality disorder (BPD). This will be accomplished by early modulations of social relationships and social interaction in juvenile and adolescent rats. It is not intended to mimic the complex disorder completely in rodents, we are rather aiming to induce core symptoms of BPD such as emotional regulation, pain sensitivity and impulse control. Experiences of early social neglect and rejection have been indicated as major factors contributing to the emergence of BPD and we are therefore planning to model maternal neglect in juvenile rats, as well as social exclusion in adolescent animals. Additionally, we are going to examine if a combination of both social manipulations might lead to additive effects. The possible lasting consequences of these manipulations on social, emotional and motivational behavior will then be assessed at different time points of life.

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 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.

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).

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: 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.

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.

Hansson AC. DFG - Deutsche Forschungsgemeinschaft HA 6102/1-1: Amygdala dopamine D1 and corticotropin releasing hormone receptor 1 interactions in alcohol dependence. 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.

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.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01GS08152: NGFN Plus GENALC TP1: Coordination of the Consortium. 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. DFG - Deutsche Forschungsgemeinschaft SP 383/4-1: SPP1226 Nikotin: Nicotine: Molecular and Physiological Effects in the. 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. 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. 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).

Zentralinstitut für Seelische Gesundheit (ZI) - https://www.zi-mannheim.de