Opioid withdrawal engages a habenular subpopulation responsive to aversive states

Opioid withdrawal produces a protracted aversive state that is a driving factor towards relapse for patients with opioid use disorder. The habenula is known to mediate symptoms of withdrawal across several substance use disorders, including alcohol, nicotine, and opioid use disorder. However, it is unclear which habenular populations contribute to withdrawal symptoms. Here, we identify a cell type marker for habenular neurons active during opioid withdrawal. Using immediate early gene analysis, we find that glutamic acid decarboxylase 2-expressing (GAD2 ⁺ ) cells in the lateral habenula (LHb ^GAD2 ) increase activity in response to both spontaneous and naloxone-precipitated opioid withdrawal in mice. Recording neural activity in vivo revealed transient activity at the presentation of aversive stimuli, and a sustained increase in activity during aversive states such as opioid withdrawal and inescapable shock. These results highlight the cell type heterogeneity of the habenula, and the role of specific cell types in opioid withdrawal.