ABSTRACT
The rostromedial tegmental nucleus (RMTg), a recently discovered mesopontine structure, represents a
key node within valence encoding neural circuitry. The RMTg has been shown to play a role in reward-aversion
signaling, aversive learning involving multimodal sensory inputs, locomotion, and sleep regulation. In rodents
and non-human primates, RMTg GABAergic projections powerfully inhibit ventral tegmental area and substantia
nigra dopaminergic neurons, thus exerting a gating mechanism regulating dopaminergic tone. RMTg function is
robustly regulated by µ -opioid receptors (MOR), which are highly enriched in RMTg neurons. MOR agonism
inhibits the RMTg, in turn releasing mesocorticolimbic and nigrostriatal dopaminergic neurons from the RMTg
brake. Notably, nociceptin receptors (NOPR), also enriched in the rodent RMTg, play a similar role, inhibiting
RMTg neurons and thus increasing the activity of dopaminergic neurons.
The cellular, molecular, and functional properties of the human RMTg have not been investigated to date,
hampering our understanding of the potential role of this nucleus in psychiatric disorders. To address this critical
knowledge gap, we propose studying, for the first time, the human RMTg using a combination of postmortem
techniques and in vivo neuroimaging performed at 7 Tesla. Our overarching hypothesis is that the human RMTg
encodes valence properties of stimuli (i.e., rewarding vs. aversive) of varying modalities. We also hypothesize
that the expression of opioid system markers (i.e., MOR, NOPR, and NOP) in the human RMTg underlies the
cellular and molecular uniqueness in this nucleus. A characterization of MOR, NOPR, and NOP expression in
healthy human donors, together with region-specific molecular marker discovery afforded by spatial
transcriptomics, will accurately delineate the human RMTg with respect to surrounding brain regions and place
it within anatomical landmarks detectable by imaging studies. The objectives of this work are to (i) define
anatomical landmarks of the human RMTg, (ii.) assess novel RMTg markers and MOR, NOPR, and NOP
expression in RMTgs’ neuronal populations, and (iii.) inform on RMTg valence encoding functions in humans.
Importantly, the proposed study will provide a testable and significant instance for the involvement of the RMTg
in human CNS disorders. Our long-term goal is to provide compelling support for the role of the RMTg in the
pathophysiology of psychiatric disorders, opening the doors to a new domain of clinical investigations integrating
this nucleus in circuitry implicated in the disruption of reward-aversion and emotional processing. The specific
aims of the proposed study are: Aim 1: To investigate the chemocytoarchitectonic characteristics and
transcriptional profile of the human RMTg. Aim 2: Characterize functionality and valence encoding properties of
the human RMTg. To study the human RMTg, we will leverage our expertise in neuroanatomical analysis of
human tissue, genetics, the opioid system, and in vivo neuroimaging of psychiatric and neurological illnesses.