Grant: Discovery Grants Program - Individual

Every day, individuals are exposed to situations where they face new and unexpected conditions in the environment and need to decide the best action to take. Even to make simple decisions, individuals need to make cost/benefit analysis which involve integrating information related to risk and reward as well as engagement of several brain circuits involved with high-level cognition including learning, memory and motivation. For instance, to decide on what food to eat, memories of different types of food previously eaten help on the decision process, as well as the satiety and emotional state of the animal. Furthermore, the information about the outcome of a decision is used to update existing memories to ensure appropriate choices in subsequent situations. In general, during the early phases of a trial-and-error learning, choosing the best action depends on a flexible and goal-directed learning system based on association between action and outcome. Upon excessive training, responses become habitual, and depend on associations between preceding stimulus (stimulus-action), without any link to the outcome connected to the response. One of the brain regions important for the integration of learning with basic motivational and emotional processes is the striatum. Importantly, striatal cholinergic interneurons (CINs), have been suggested to participate on the modulation of striatum-dependent behaviours including striatal learning and motivation. However, the exact roles of CINs in these processes are still poorly understood. In this proposal our objective is to study basic questions about how CINs modulate circuits important for decision making. Our hypothesis is that that Glu and ACh released from CINs regulate distinct behaviors independently; with Glu acting preferentially on habit formation, and ACh on decision making, goal-direct behavior and motivation, likely by modulating the activity of MSNs and dopamine secretion. To test these hypothesis, we have generated genetically modified mice with altered release from striatal CINs of ACh, Glu or both neurotransmitters. We will submit these unique mice to a battery of behaviors using state-of-the-art touchscreen systems to define the role of ACh and Glu released from CINs on different components of decision making. These experiments will dissect how individual and combined contributions of ACh and Glu released by CINs influence different components of decision-making, an executive function essential for adaptation to new challenges and survival. Additionally, results from this proposal will shed light on the role of co-transmission, this novel and previously unappreciated mode of neuronal communication. Development of this program will also allow for training of HQP in mouse genetics, behavioral testing and molecular biology.