Habenular CB₁ Receptors Control the Expression of Aversive Memories

Highlights

• CB₁R are presynaptically expressed on MHb neurons projecting to the IPN

• MHb-CB₁R deletion inhibits the expression of aversive memories

• MHb-CB₁R control aversive memories via cholinergic transmission in the IPN

• MHb-CB₁ controls optogenetically evoked cholinergic transmissions in the IPN

Summary

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.