A NOVEL BRAINSTEM REWARD CENTER INHIBITS THE LATERAL HABENULA

The lateral habenula (LHb) regulates behavioral flexibility that is essential for effective decision-making. LHb activity can facilitate aversion or reward-seeking behavior as a function of its excitatory/inhibitory inputs. However, despite LHb's abundant connections with hindbrain areas, the role of brainstem inputs remains unclear. Using viral tract tracing, in vivo electrophysiology, single-cell sequencing, fiber photometry, and optogenetic behavioral experiments in transgenic mice, we identified a previously unrecognized gamma-aminobutyric acid (GABA)-ergic neuronal population in the pontine central grey, named the subventricular tegmental nucleus (SVTg). SVTg neurons send direct inhibitory input to the lateral habenula (LHb) and were activated by rewarding and reward-predicting events, leading to inhibition of LHb activity. In addition, inhibition of SVTg impaired reward location memory formation. Moreover, SVTg neurons were also activated by aversive stimuli, suggesting their role in balancing negative experiences. Electrophysiological recordings revealed that SVTg neurons characteristically exhibit bursting firing patterns and are strongly excited by serotonin. Single-cell transcriptomic profiling identified the genetic signature of SVTg neurons, including the markers Satb1, Pax6, and Reln, enabling their identification in the brainstem of both primates and humans. Together, these findings reveal a conserved GABAergic pontine nucleus, the SVTg that modulates LHb activity, plays a key role in reward encoding, and may contribute to the regulation of mood-related behaviors.