A cholinergic medial septum input to medial habenula mediates generalization formation and extinction of visual aversion

Generalization of visual aversion is a critical function of the brain that supports survival, but the underlying neurobiological mechanisms are unclear. We establish a rapid generalization procedure for inducing visual aversion by dynamic stripe images. By using fiber photometry, apoptosis, chemogenetic and optogenetic techniques, and behavioral tests, we find that decreased cholinergic neurons??? activity in the medial septum (MS) leads to generalization loss of visual aversion. Strikingly, we identify a projection from MS cholinergic neurons to the medial habenula (MHb) and find that inhibition of the MS->MHb cholinergic circuit disrupts aversion-generalization formation while its continuous activation disrupts subsequent extinction. Further studies show that MS->MHb cholinergic projections modulate the generalization of visual aversion possibly via M1 muscarinic acetylcholine receptors (mAChRs) of downstream neurons coreleasing glutamate and acetylcholine. These findings reveal that the MS->MHb cholinergic circuit is a critical node in aversion generalization formation and extinction and potentially provides insight into the pathogenesis of affective disorders.

Automated summary

Generalization of visual aversion is a critical brain function for survival, but the mechanisms underlying this process are unclear. This study establishes a rapid generalization procedure for inducing visual aversion and investigates the role of cholinergic neurons in the medial septum (MS) in visual aversion generalization. The researchers discover a cholinergic circuit between MS and the medial habenula (MHb) that plays a crucial role in aversion generalization formation and extinction. The findings suggest that modulation of aversion generalization via cholinergic projections may involve M1 muscarinic acetylcholine receptors. These findings provide insight into the pathogenesis of affective disorders.