Lateral habenula induces cognitive and affective dysfunctions in mice with neuropathic pain via an indirect pathway to the ventral tegmental area

Neuropathic pain, which has become a major public health concern, is frequently accompanied by the deterioration of affective behavior and cognitive function. However, the brain circuitry underlying these changes is poorly understood. Therefore, we aimed to identify in a mouse model the converging circuit that influences the sensory, affective, and cognitive consequences of neuropathic pain. The lateral habenula (LHb) and ventral tegmental area (VTA) have been confirmed to play critical roles in the regulation of pain, cognition, and depression. Given the essential role of the LHb in depression and cognition, we attempted to clarify how neural circuitry involving the LHb integrates pain-related information. Our data confirmed that the VTA receives projections from the LHb, but our results suggest that inhibition of this direct pathway has no effect on the behavior of mice with chronic neuropathic pain. The rostromedial tegmental nucleus (RMTg), a GABAergic structure believed to underlie the transient inhibition of DAergic neurons in the VTA, received glutamatergic inputs from the LHb and projected strongly to the VTA. Furthermore, our data suggest that a projection from LHb glutamatergic neurons to RMTg GABAergic neurons in the VTA, constituting an indirect LHb^Glu → RMTg^GABA → VTA^DA pathway, participates in peripheral nerve injury-induced nociceptive hypersensitivity, depressive-like behavior, and cognitive dysfunction. Ex vivo extracellular recordings of LHb neurons showed that the proportion of burst-firing cells in the LHb was significantly increased in indirect projections rather than in direct projections. This may explain the functional discrepancies between direct and indirect projections of the LHb to the VTA. Collectively, our study identifies a pivotal role of the LHb^Glu → RMTg^GABA → VTA^DA pathway in processing pain. This pathway may offer new therapeutic targets to treat neuropathic pain and its associated depressive-like and cognitive impairments.