Expression of aversive memories is key for survival, but the underlying brain mechanisms are not fully understood. Medial habenular (MHb) axons corelease glutamate and acetylcholine onto target postsynaptic interpeduncular (IPN) neurons, but their role in aversive memories has not been addressed so far. We found that cannabinoid type 1 receptors (CB1R), key regulators of aversive responses, are present at presynaptic terminals of MHb neurons in the IPN. Conditional deletion of CB1R from MHb neurons reduces fear-conditioned freezing and abolishes conditioned odor aversion in mice, without affecting neutral or appetitively motivated memories. Interestingly, local inhibition of nicotinic, but not glutamatergic receptors in the target region IPN before retrieval, rescues these phenotypes. Finally, optogenetic electrophysiological recordings of MHb-to-IPN circuitry revealed that blockade of CB1R specifically enhances cholinergic, but not glutamatergic, neurotransmission. Thus, presynaptic CB1R control expression of aversive memories by selectively modulating cholinergic transmission at MHb synapses in the IPN.
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