Indirect, but not direct, lateral habenula projections to ventral tegmental area regulate the long-term consequences of neuropathic pain

Chronic pain, in which pain persists or recurs for more than 3 months, is a major cause of suffering and disability worldwide.Chronic pain caused by an insult to the somatosensory nervous system is known as neuropathic pain.Individuals affected by prolonged neuropathic pain often experience cognitive and emotional disturbances such as pain catastrophizing, anxiety, depressive symptoms, and fear or avoidance of movement and injury [1].Researchers have found that pain-induced cognitive and affective changes correspond to functional changes in brain regions involved in pain processing, attention to pain, emotion, motor activity, and top-down pain inhibition [1].Among these regions, the lateral habenula (LHb) has recently been of interest for its roles at the intersection of pain processing and pain-related cognitive and affective functions.LHb is a crucial processor of motivational and cognitive information, and one of its major targets is the ventral tegmental area (VTA).VTA is involved in learning, motivation, and importantly, the development of depressive symptons and cognitive dysfunction.LHb controls dopamine release from VTA via direct and indirect pathways.In the direct pathway, glutamatergic LHb neurons form monosynaptic connections with dopaminergic, GABAergic, and other VTA cell-types [2].Activation of this pathway is aversive and dependent on dopamine receptors in the prefrontal cortex [3].In the indirect pathway, LHb Glu neurons synapse onto rostromedial tegmental nucleus (RMTg) neurons which in turn provide feedforward GABA release onto VTA DA neurons (Fig. 1).While activation of this pathway is also aversive [4], the direct and indirect pathways exert differential control on the dopaminergic system.In the present study, Liu et al. find that the indirect LHb Glu RMTg GABA VTA DA pathway is a converging circuit for chronic pain processing, depressive symptoms, and cognitive impairments in neuropathic pain.Furthermore, the authors identify anatomical and electrophysiological differences between the indirect and direct pathways which may underlie their different functions [2].Liu et al. used a model of neuropathic pain resulting in distinct short-term and long-term symptoms.Mice received spared nerve injury surgery in which the sciatic nerve was partially lesioned and were evaluated at two-and six-weeks post-surgery for mechanical and thermal pain sensitivity, depressive-like symptoms in the