Conditional deletion of TMEM16A in cholinergic neurons of the medial habenula induces anhedonic-like behavior in mice

The medial habenula (mHb), a subregion of the habenula, is involved in diverse brain functions, such as nicotine addiction, anxiety, and anhedonia. We recently reported that TMEM16A deficiency, a calcium-activated chloride channel, decreased the activity of mHb cholinergic neurons. Since downregulated activity in cholinergic neurons of the mHb is involved in anhedonia-like behavior, we here investigated whether conditional deletion of TMEM16A in mHb cholinergic neurons also displays anhedonia-like behavior. The conditional deletion of TMEM16A in the mHb cholinergic neurons of mice (TMEM16A cKO mice) was generated by crossing ChaT-Cre (+) with floxed TMEM16A f/f mice. TMEM16A cKO mice displayed significantly reduced social interaction, sucrose preference, female urine sniffing, and increased marble burying. These behavioral data suggest the potential role of TMEM16A in anhedonic-like behavior in mice. Taken together, the presented data suggest that TMEM16A-mediated mHb activity might be a therapeutic target for anhedonia-related symptoms.