Chronic stress and chronic pain are two major predisposing factors to trigger depression. Enhanced excitatory input to the lateral habenula (LHb) has been implicated in pathophysiology of depression. However, the contribution of inhibitory transmission remains elusive. Here, we dissect an inhibitory projection from sensory thalamic reticular nucleus (sTRN) to LHb, which is activated by acute aversive stimuli. Repeated activation of the LHb-projecting sTRN neurons prevents CRS-induced depression onset and hyperexcitability of LHb neurons. Moreover, acute inhibition of sTRN-LHb circuit induces depressive-like behaviors in healthy mice, while enhancing this circuit relieves depression induced by both chronic stress and chronic pain. Intriguingly, both neuropathic pain and comorbid pain in chronic stress are unaffected by this pathway. Finally, we dissected sTRN upstream brain regions associated with stress. Together, our study demonstrates an inhibitory sTRN-LHb circuit in establishing and modulating depression, thus shedding light on potential therapeutic targets for preventing or managing depression.

Chronic pain causes both physical suffering and comorbid mental disorders such as depression. However, the neural circuits and molecular mechanisms underlying these maladaptive behaviors remain elusive. Here, we report a pathway from vesicular glutamate transporter3 neurons in the dorsal raphe nucleus to dopamine neurons in the ventral tegmental area (VGluT3DRN→DAVTA), of which population activity in response to innocuous mechanical stimuli and sucrose consumption, is respectively inhibited and attenuated by chronic neuropathic pain. Mechanistically, neuropathic pain dampens VGluT3DRN→DAVTA glutamatergic transmission and DAVTA neural excitability. VGluT3DRN→DAVTA activation alleviates neuropathic pain and comorbid depression-like behavior (CDB) by releasing glutamate, which subsequently promotes DA release in the nucleus accumbens medial shell (NAcMed) and produces analgesia and antidepressant effects via D2 and D1 receptors, respectively. In addition, VGluT3DRN→DAVTA inhibition produces pain-like hypersensitivity and depression-like behavior in healthy mice. These findings reveal a novel VGluT3DRN→DAVTA→D2/D1NAcMed pathway in establishing and modulating chronic pain and comorbid depressive-like behavior.