Orexin-Driven Inhibitory Microcircuits in the Lateral Habenula Promote Aggression
Flanigan ME, Aleyasin H, Li L, Burnett CJ, Chan KL, LeClair KB, Lucas EK, Matikainen-Ankney B, Durand-de Cuttoli R, Takahashi A, Menard C, Pfau ML, Golden SA, Bouchard S, Calipari ES, Nestler EJ, DiLeone RJ, Yamanaka A, Huntley GW, Clem RL, Russo SJ. Orexin signaling in GABAergic lateral habenula neurons modulates aggressive behavior in male mice. Nat Neurosci 2020;23(5):638-650. doi: 10.1038/s41593-020-0617-7.
Background: Aggression is a feature of several neuropsychiatric disorders and may arise from dysregulation in brain reward systems. In mice, some individuals find aggression rewarding and seek opportunities to fight. The lateral habenula (LHb), which processes aversive and rewarding stimuli, has been linked to aggression, but its local circuitry remains unclear. Evidence of a small GABAergic population expressing glutamic acid decarboxylase 2 (GAD2) suggests possible inhibitory control within the LHb.
Hypothesis: This study tested the hypothesis that orexinergic projections from the lateral hypothalamus activate GAD2-expressing neurons in the LHb through orexin receptor 2 (OxR2) signaling, thereby modulating aggressive behavior and the rewarding properties of aggression in male mice.
Methods: The authors used a combination of fiber photometry (FP3001), optogenetics, chemogenetics, electrophysiology and molecular analyses in male mice. They monitored LHb activity during aggression tests, manipulated specific neuronal populations and examined how orexin signaling influenced LHb GAD2 neuron activity and aggression-related behaviors, including conditioned place preference for aggression-paired contexts.
Results: Aggressive encounters were associated with decreased overall LHb activity but increased activity in GAD2 LHb neurons. Optogenetic activation of GAD2 neurons or orexin terminals in the LHb enhanced aggression and aggression reward, while their inhibition or OxR2 knockdown reduced both. GAD2 neurons provided local inhibition within the LHb, and orexin directly excited these cells via OxR2.
Conclusions: These findings reveal a novel orexin-sensitive inhibitory microcircuit within the LHb that promotes aggression by suppressing overall LHb activity. The study identifies orexin signaling in LHb GAD2 neurons as a key mechanism linking hypothalamic arousal systems to the motivational control of aggressive behavior.
