Monosynaptic ventral tegmental area glutamate projections to the locus coeruleus enhance aversive processing

Distinct excitatory synaptic inputs to the locus coeruleus (LC), the primary source of norepinephrine for the central nervous system, modulate behavioral flexibility. Here we identify a novel monosynaptic glutamatergic input to the LC from the ventral tegmental area (VTA). We show VTA glutamatergic axons project robustly to the dorsal pons and provide direct glutamatergic transmission onto LC neurons. Despite weak summation of this synaptic input, optogenetic activation of these axons in LC enhances tonic firing and facilitates real-time and conditioned aversive behavior. We hypothesized this VTA-LC glutamatergic projection may provide modulatory synaptic integration with other excitatory inputs. To test this notion, we used coincident photostimulation of VTA-LC axons and local electrical stimulation and demonstrate enhanced burst induction in the LC. To determine whether this integration also occurs in vivo , we took an analogous approach using the Punishment Risk Task to measure the reward-seeking behavior during unpredictable probabilistic punishment. Here, optogenetic activation of the VTA-LC glutamatergic projections with a concurrent noxious stimulus did not delay the reward-seeking behavior, but increased the probability of task failure. Together, our findings identify a novel VTA-LC glutamatergic projection that drives concurrent synaptic summation during salient stimuli to promote behavioral avoidance.