Decoding the dual regulatory systems: Contemporary insights into the lateral habenula and rostromedial tegmental nucleus physiology

The lateral habenula (LHb) and the rostromedial tegmental nucleus (RMTg) are critical brain structures involved in reward processing, aversive signaling, and mood regulation. Recent research has uncovered significant progress in understanding their physiological functions, neural circuits, and implications in neuropsychiatric disorders. By integrating signals from the limbic system and projecting into the midbrain monoaminergic system, the LHb encodes negative reward prediction error and mediates behaviors associated with depressive as well as stress response. Its overactivation can inhibit dopamine release, resulting in anhedonia. As the main downstream target of LHb, the RMTg exerts inhibitory control over dopaminergic neurons in the ventral tegmental area (VTA) via γ-aminobutyric acid (GABA), and participates in reward inhibition, addiction withdrawal and hyperalgesia regulation. The LHb activates GABAergic neurons within the RMTg through glutaminergic projection, thereby inhibiting dopamine release in the VTA neurons. This neuronal circuitry is critically involved in the pathophysiological mechanisms of depression, addiction and other neuropsychiatric disorders‌. Here, we reviewed the anatomical features and molecular markers of both LHb and RMTg along with their inputs, outputs and physiological functions of LHb and RMTg. This research is of great significance for understanding the neural mechanisms underlying neuropsychiatric diseases.