UNVEILING AN ENDOGENOUS SOURCE OF CHOLINERGIC TRANSMISSION IN THE LATERAL HABENULA

The neural circuits of the epithalamic lateral habenula (LHb) are associated with coding information originating from external cues with predominantly negative valence. The LHb is a key relay node linking forebrain structures with midbrain monoaminergic nuclei and thus contributes to the regulation of hedonic balance via serotonergic and dopaminergic neuromodulation. Consequently, dysregulation of LHb signaling can lead to pathological conditions such as depression. Signaling within the LHb is predominantly glutamatergic and GABAergic. However, growing evidence supports the presence of cholinergic signaling within the LHb. Yet, in contrast to the well-characterized properties of glutamatergic and GABAergic afferent inputs, the sources and functions of endogenous cholinergic afferent inputs remain largely unexplored. Here, we have uncovered a cholinergic plexus within the LHb originating from the basal forebrain. Using viral tracing, optogenetics, and ex vivo electrophysiology, our results show that basal forebrain axons co-transmit acetylcholine and glutamate onto neurons located in the ventro-lateral portion of the LHb, eliciting fast inward excitatory post-synaptic currents mediated by glutamatergic AMPA receptors and slow outward currents mediated by muscarinic receptor activation. Building on these findings, we are currently investigating LHb cholinergic dynamics in vivo using GRABACh and GCaMP-based imaging during stress-related behavioral paradigms. These ongoing experiments will aim at revealing how cholinergic signaling contributes to LHb activity patterns in affective states. Our work will hopefully open new perspectives on the exploration of LHb function in affective behaviors.