Internal states in the space of neuromodulation

An animal's survival hinges on its capacity for flexible cognition, relying on a continuous dialogue between external information and internal state. Neuromodulators like acetylcholine (ACh), noradrenaline (NA), and serotonin (5-HT) are key candidates to orchestrate internal state. However, past studies investigated these neuromodulators in isolation, creating a fragmented picture with seemingly redundant roles and often conflicting findings, likely due to unappreciated synergistic effects between neuromodulators. Moreover, neuromodulators’ role in shaping internal state is complicated by its elusive nature, which encompasses spontaneous behaviour, brain activity and cognition. Thus, the fundamental question of how different neuromodulators jointly shape internal state remains unanswered. To bridge this critical knowledge gap, I propose an unprecedented set of experiments, combining simultaneous measurements of three neuromodulators with cutting-edge brainwide functional ultrasound imaging in mice engaged in spontaneous behaviours and a cognitive task, complemented by causal manipulations. I will test the hypothesis that ACh, NA and 5-HT jointly define a space of neuromodulation that determines the different facets of internal state: behavioural states (Aim 1), brain states (Aim 2) and cognitive states (Aim 3). The results will uncover the unique and synergistic roles of three major neuromodulators in shaping internal state, revealing the essential mechanisms for cognitive flexibility.