Unit of Neuromodulation and Synaptic Integration

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

This report focuses on progress made in the last year and future directions to elucidate how three neuropeptide systems regulate prefrontal cortical (PFC) circuits, motivation, and affect. We demonstrated that the Dynorphin/kappa-opioid receptor (KOR) signaling in the ventromedial PFC (vmPFC) toggles afferent control of vmPFC neurons through KOR-mediated presynaptic inhibition of excitatory afferents and suppression of local inhibitory microcircuits, from mice to non-human primates (NHP) to humans (Yarur et al. 2023 Molecular Psychiatry; Yarur, Shirley et al. unpublished). We demonstrated that vmPFC Dynorphin signaling constrains passive defensive behavior that limits reward-seeking in the face of threats, by permitting vmPFC network transitions from a basal to an emergent fear state (Wang et al. 2024 Neuron; Bravo-Rivera, Limoges et al. in revision Nature Communications; Yarur et al. unpublished observations) . We report that SST transmission during associative learning facilitates binding aversive outcomes to coincident behaviors and cues to form configural dmPFC neuronal representations, an emergent property of cortical networks, to influence discrimination (Arenivar et al. Nature Neuroscience in revision). Our laboratory elucidated how enkephalin acting via opioid receptors regulates interneuron activity across species to gate consummatory behavior (Yarur et al. in preparation) . We found that ventral striatal dopamine signaling through co-expressed D3 and D1 GPCRs controls motivation and reinforcement, respectively, via dissociable physiological processes (Enriquez-Traba et al. 2024, Nature Neuroscience). We are at the forefront of characterizing and implementing novel, cutting-edge tools and approaches to dissect and monitor neuromodulator function, including genetically-encoded fluorescent sensors (Dong. et al. 2024 Nature Neuroscience), two-photon miniaturized microendoscopic imaging in freely-moving mice, cell-type specific pharmacological approaches (DART), CRISPR for cell-specific gene deletion, and enhancer and promoter-based viruses and intersectional mouse lines to gain genetic access to distinct cell types. We leveraged unique translational NIH resources to expand work across species, will expand technological approaches in this domain, and collaborate in a clinical trial testing an opioid receptor antagonist. Our mission addresses unexplored elementary principles of cellular communication by neuromodulatory signals and the emergent properties they modulate underlying affect and motivation. This has the potential to elucidate novel insight to brain disorders.