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

• Published in: Cell reports (Cambridge) 2022-05, Vol.39 (9), p.110882-110882, Article 110882
• Main Authors: Mu, Ronghao, Tang, Susu, Han, Xiaomeng, Wang, Hao, Yuan, Danhua, Zhao, Jiajia, Long, Yan, Hong, Hao
• Format: Article
• Language: English
• Subjects: cholinergic circuits; generalization; medial habenula; medial septum; visual aversion
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110882

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. [Display omitted] •MS cholinergic neurons participate in generalization of visual aversion•MS→MHb cholinergic circuits control generalization of visual aversion•MHb M1 mAChRs in the circuit mediate aversion generalization•MHb glutamatergic/cholinergic neurons in the circuit regulate aversion generalization Mu at al. identify the critical roles of the MS cholinergic neuron and MS→MHb circuit that regulate generalization of visual aversion, revealing that the pathway modulation for controlling aversion generalization and extinction might be via M1 mAChRs of MHb glutamatergic/cholinergic neurons.