Functional Principles of Posterior Septal Inputs to the Medial Habenula

The medial habenula (MHb) is an epithalamic hub contributing to expression and extinction of aversive states by bridging forebrain areas and midbrain monoaminergic centers. Although contradictory information exists regarding their synaptic properties, the physiology of the excitatory inputs to the MHb from the posterior septum remains elusive. Here, combining optogenetics-based mapping with ex vivo and in vivo physiology, we examine the synaptic properties of posterior septal afferents to the MHb and how they influence behavior. We demonstrate that MHb cells receive sparse inputs producing purely glutamatergic responses via calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), heterotrimeric GluN2A-GluN2B-GluN1 N-methyl-D-aspartate (NMDA) receptors, and inhibitory group II metabotropic glutamate receptors. We describe the complex integration dynamics of these components by MHb cells. Finally, we combine ex vivo data with realistic afferent firing patterns recorded in vivo to demonstrate that efficient optogenetic septal stimulation in the MHb induces anxiolysis and promotes locomotion, contributing long-awaited evidence in favor of the importance of this septo-habenular pathway.