The influence of non-habenular afferents of the mesopontine rostromedial tegmental nucleus

The mesopontine rostromedial tegmental nucleus (RMTg) is a newly identified brain structure that exerts previously unrecognized, profound inhibitory control on the dopaminergic ventral tegmental area/substantia nigra compacta (VTA/SNc) projection system, which itself has been for decades the object of intense investigation, due to its prominent role in the control of many critical aspects of behavior. The RMTg mediates strong inhibition of VTA/SNc activity and is strongly modulated by input from the lateral habenula (LHb) and, consequently, most studies have focused primarily on LHb-RMTg-VTA/SNc connectivity. Less clear is to what extent non-habenular afferents of the RMTg, such as from the lateral preoptic area (LPO) and the intermediate and deep layers (i/d) of the superior colliculus (SC), also exert controls on behavior. Experiments described herein confirm some aspects of the neuroanatomical connectivity relating the LPO and i/d SC to the RMTg and reveal new ones, all of which, interpreted in conjunction with the accompanying drug infusion and behavioral analyses, suggest that non-habenular afferents of the RMTg are particularly important in the regulation of locomotor activation and the affective tone that underlies it. We show here that single LPO neurons project to the VTA/SNc and RMTg, which, on the surface, is paradoxical due to the further observation that stimulation of the LPO produces robust locomotion that is blocked by activation of the RMTg. The conundrum is reconciled if LPO projections are inhibitory and selectively target, in addition to the RMTg, local GABA interneurons within the VTA to produce a global disinhibition of dopamine neurons, and thereby the observed locomotor activation. Our finding that the lateral i/d SC preferentially targets the contralateral RMTg and ipsilateral SNc suggests the SC may utilize these projections to effect unilateral dopamine release, consistent with our observation that stimulation of the lateral i/d SC causes contraversive rotations that are blocked by activation of the RMTg. Finally, we also show that activating the RMTg blocks conditioned locomotion, which reflects behavior driven not by an artificial stimulation of neural pathways, but rather by a particular mental state. These studies establish an anatomical and functional framework of RMTg involvement in affective processing.