Ventral tegmental area acetylcholine generates appetitive and aversive incentive motivation

Ventral tegmental area neurons participate in reward learning, motivation, and movement but also have an emerging role in the regulation of aversive behaviors. While these diverse contributions have been attributed to distinct projections of ventral tegmental area neurons, it remains unresolved how these neurons inherit their array of behavioral functions. The ventral tegmental area is rich with acetylcholine receptors and receives dense cholinergic input from the mesopontine tegmentum. While it is known that acetylcholine release in the ventral tegmental area can increase dopamine output we lack an understanding of the scenarios which necessitate ventral tegmental area acetylcholine release. We sought to provide a comprehensive overview of the participation of ventral tegmental area acetylcholine signaling across valence to motivated behavior. Rats were trained on a diverse array of tasks that allowed for the isolation of the contribution of acetylcholine release in the ventral tegmental area to cue- and context-driven behavior. We used intracranial pharmacology to determine the receptor mechanisms that contribute to acetylcholine’s effects. Ultimately, we found that acetylcholine release in the ventral tegmental area is necessary for appetitive and aversive states to become motivationally relevant and spur reward-seeking and threat-avoidance. We propose that this state-dependent contribution allows ventral tegmental area acetylcholine to act as a motivational gate for behavior across valence. This work expands our view of the interaction between neuromodulatory systems in the brain and opens new directions to the understanding of ventral tegmental area neurons in health and disease.