Dopaminergic Modulation of Hippocampal CA1: Uncovering the Activity Dynamics of VTA and LC Inputs during Behavior and Learning

Dopaminergic activity in the hippocampus modulates synaptic plasticity, alters place cell activity, and affects hippocampal dependent learning and memory processes. Traditionally these effects were attributed to the release of dopamine from sparse projections originating in the ventral tegmental area (VTA) and extending to the hippocampus. However, the role of VTA inputs in dopaminergic modulation of the hippocampus has recently been brought into question, as denser inputs from the locus coeruleus (LC) have been shown to release dopamine in the dorsal hippocampus, and impact hippocampal dependent learning and memory. To dissect the impacts of both VTA and LC dopaminergic circuits on hippocampal activity and memory, we functionally imaged the activity of VTA and LC axons in dorsal CA1 (dCA1). During spatial navigation, VTA inputs exhibited a ramping to reward signal that depended on the animals' reward expectation. Inhibiting VTA dopaminergic neurons largely replicated the effects of reward expectation extinction: reducing overrepresentation of rewarded locations, inducing place field remapping, and decreasing place field trial-to-trial reliability. We conclude that reward expectation restructures CA1 place cells and determines map reliability through the modulation of dopaminergic VTA-CA1 reward proximity signals. In contrast, LC inputs were devoid of the reward-proximity signal observed in VTA axons and instead exhibited velocity correlated activity and increases in activity prior to motion onset. Interestingly, a marked divergence emerged in novel VR environments. LC axon activity sharply and persistently increased for over a minute, while the previously observed VTA axon reward-proximity signal disappeared. We conclude that LC inputs to dCA1 encode the animals' brain state, as changes in behavior and environmental novelty are associated with heightened arousal. This observation further strengthens the roles of LC neurons in influencing brain states and in novelty encoding in the hippocampus. Together, these findings demonstrate VTA and LC inputs encode unique information, likely contributing todifferential modulation of hippocampal activity during behavior and learning.