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