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