Molecular Mechanisms of Behavioral Adaptation

The major focus of our research activity is the identification of the physiological and pathophysiological roles of the endocannabinoids system (ECS) in the brain. Our research is aimed at two main goals. First, better define by which psychological mechanisms the endocannabinoid system interferes with acquired fear responses and motivation towards positive reinforcers, such as food or drugs of abuse. Second, identify the cell type, the brain circuits and the specific endocannabinoid(s) trough which the ECS exerts these functions. In order to reach these goals we will use the cell type- specific conditional mouse mutants for the CB1 receptor generated during the past years. In addition, we will develop new genetically modified mouse lines that will allow identifying also the brain circuits and the specific endocannabinoid(s) involved in particular functions of the ECS. These mutant mouse lines will be studied using innovative behavioural models, which will allow underpinning the processes mediating specific functions of the ECS. In particular, these models will allow us to understand: 1. the respective roles of the ECS in the modulation of habituation, cognitive and interval timing processes during extinction of fear memories; 2. the motivational component (drive or incentive) by which the ECS modulates food intake; 3. the involvement of the ECS in the shift from drug use to addiction.

1. Monory K, Massa F, Egertová M, Eder M, Blaudzun H, Westenbroek R, Kelsch W, Jacob W, Marsch R, Ekker M, Long J, Rubenstein J, Goebbels S, Nave KA, During M, Klugmann M, Wölfel B, Dodt H.-U., Zieglgänsberger W, Wotjak CT, Mackie K, Elphick MR, Lutz B* and Marsicano G.* (2006). The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron - in press. *, share senior authorship

2. Cannich A, Wotjak C, Kamprath C, Hermann H, Lutz B and Marsicano G. (2004). CB1cannabinoid receptors modulate kinase and phosphatase activity during extinction of conditioned fear in mice. Learning & Memory 11(5):625-32.

3. Marsicano G.*, Goodenough S*, Monory K*, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Ortega Gutiérrez S, van der Stelt M, López-Rodríguez ML, Casanova E, Schütz G, Zieglgänsberger W, Di Marzo V, Behl C and Lutz B (2003). CB1 Cannabinoid Receptors and On-demand Defense Against Excitotoxicity. Science 302:84-88.

4. Marsicano G.*, Cota D*, Tschöp M, Grübler Y, Schubert M, Auer D, Thöne-Reinecke C, Ortmann S, Flachskamm C, Cervino C, Linthorst A, Pasquali R, Lutz B, Stalla GK and Pagotto U (2003) The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J. Clin. Invest. 112(3):423-31.

5. Marsicano G.*, Wotjak C*, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang, J, Hofmann C, Zieglgänsberger W, Di Marzo V and Lutz B (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530-34.