LDT cholinergic inputs to the nucleus accumbens neurons facilitate cocaine reinforcing properties

The laterodorsal tegmentum (LDT) is a brainstem nucleus that sends direct projections to the nucleus accumbens (NAc), a key brain region involved in reward and motivation. We have previously shown that LDT-NAc inputs are crucial for reward value, triggering preference and shifting value of natural rewards. However, if and how these specific projections mediate the rewarding properties of drugs of abuse remains elusive. Importantly, ex-vivo studies showed that cocaine exposure triggers neuroplasticity changes in the LDT and in the NAc, suggesting that LDT-NAc circuitry may be an important target of cocaine action.We conducted extensive high-density multi-site recordings in the NAc and LDT in animals subjected to repeated cocaine exposure. NAc neurons were clustered based on previously identified electrophysiological properties. Since the electrophysiological signature of LDT neurons in vivo was not available, we performed optotagging to identify cholinergic, GABAergic and glutamatergic cells.Our findings indicate that both LDT and NAc neurons exhibit persistent functional alterations following cocaine pre-exposure. Cocaine-exposed animals presented increased firing rate of putative MSNs in baseline conditions. Conversely, LDT cholinergic neurons present reduced basal firing rate in vivo, in line with the observed decrease in excitability of these cells in slices. We further show that different neuronal subtypes of the LDT and NAc responded very differently to an acute cocaine challenge, especially in animals that had prior exposure to cocaine.Importantly, optogenetic inhibition of LDT-NAc cholinergic projections abolishes cocaine-induced place preference, supporting a prominent role for LDT-NAc cholinergic inputs in mediating the reinforcing properties of cocaine.