neuronal circuits; in vivo imaging; addiction; amygdala; goal-directed behavior
Krabbe Sabine, Paradiso Enrica, d’Aquin Simon, Bitterman Yael, Courtin Julien, Xu Chun, Yonehara Keisuke, Markovic Milica, Müller Christian, Eichlisberger Tobias, Gründemann Jan, Ferraguti Francesco, Lüthi Andreas (2019), Adaptive disinhibitory gating by VIP interneurons permits associative learning, in Nature Neuroscience
, 22(11), 1834-1843.
Background: To survive, an organism has to act selectively and flexibly to earn desired goals and avoid non-desired ones. The capacity to choose and perform goal-directed actions depends on the aptitude to learn the relationship between an action and its consequences, namely the goal, and importantly determine the rewarding value of that goal. Indeed, changes in the value of the goal can largely affect action choice and performance. In maladaptive conditions, the inability to form action-reward associations, to estimate goal value, or to prevent intrusive actions, could lead to inappropriate or pathological choices, such as in addiction disorders. In laboratory research, a multitude of behavioral paradigms involve goal-directed behavior, in particular, instrumental conditioning is one of the most studied model systems. Experiments targeting the amygdala have revealed its key role in goal-directed instrumental behavior. However, how defined amygdala circuits support these behaviors remains unknown. This project aims at addressing the circuit mechanisms underlying goal-directed behavior and to translate these findings to animal models of addiction. Funding under the Ambizione scheme would allow me to develop my own line of research, to investigate brain mechanisms of goal-directed behavior and to address maladaptive dysfunction in behavioral models of addiction disorders.Aims: Here I highlight a strategy to reveal how amygdala circuits control goal-directed behavior in mice. The project will involve a multidisciplinary approach combining behavioral paradigms with state-of-the-art in vivo electrophysiological, calcium imaging and optogenetic techniques. To reach this goal, I propose the following specific aims:1) To map neuronal activity in the amygdala related to goal-directed behavior, using calcium-imaging allowing for monitoring neuronal activity of large populations of genetically defined neurons at cellular resolution in behaving mice across multiple days. 2) To perturb implicated circuit elements at well-defined time points based on endogenous activity patterns. To this end, I will apply optogenetics combined with electrophysiological recordings and calcium imaging to address whether and when specific activity patterns are required for goal-directed behavior. 3) To develop a goal-directed behavioral paradigm using addictive substances and to determine how defined amygdala circuit mechanisms evolve during different phases of the establishment of addictive behavior. Relevance: Accumulating evidence suggests that the amygdala is at the core of addiction disorders. Therefore, understanding the neural mechanisms controlling amygdala activity is of direct clinical relevance. Moreover, elucidating how defined amygdala circuits represent goal value across distinct behavioral conditions will be important for our understanding of learning mechanisms and goal-directed behavior in general, both in terms physiological and pathological conditions.