The habenula-interpeduncular nucleus-median raphe pathway regulates the outcome of social dominance conflicts in mice

The habenula (Hb) to interpeduncular nucleus (IPN) projection is highly conserved across vertebrates and, in zebrafish, has been shown to regulate the decision between continuing to fight and surrender during social conflict. We have recently shown that, in loser zebrafish, habenular acetylcholine release acts on postsynaptic α7 nicotinic receptors to induce the expression of Ca²⁺-permeable AMPA receptors on the silent synapses of the IPN neurons that project to the median raphe (MnR). Leveraging this evolutionary conservation, we demonstrate that the disruption of cholinergic transmission from the Hb to the IPN biases mice toward winning social conflicts, whereas optogenetic activation has the opposite effect of biasing toward losing. Further circuit dissection revealed that the losing bias is likely to be mediated via inhibition of serotonin (5-hydroxytryptamine [5-HT]) neurons in the MnR by the IPN.