Biology subjects

Treadway, M. T.

Publications and source records attributed to Treadway, M. T..

3 recordsLinked to original sources

bioRxiv2025

Nociceptin Orphanin F/Q Pathways are Dysregulated by Stress and Modulate Reward Learning and Motivation Across Species

Nociceptin orphanin F/Q has been implicated in stress-related depressive phenotypes. Specifically, exposure to chronic stressors upregulates nociceptin receptors (NOPR), whereas NOPR antagonism has anti-depressant/anti-anhedonic effects. The mechanisms underlying these effects remain, however, unclear. Here, we investigated the role of NOPR in depressive phenotypes alongside potentially prohedonic effects of NOPR antagonism across species. In Study 1, we evaluated whether exposure to early-life adversity (ELA) upregulated ventral tegmental area (VTA) and striatal prepronociceptin (Pnoc) gene expression in adult mice. In Study 2, we tested whether chronic social defeat altered Pnoc gene expression in reward-related regions. To establish whether direct NOPR modulation is implicated in reward-related behaviors, in Study 3, we assessed whether NOPR antagonism alters reward learning in rats. Finally, in Study 4, we tested whether NOPR antagonism boosts motivation among depressed humans. ELA induced anhedonic behavior and increased Pnoc expression in the VTA; in females (but not males), ELA increased Pnoc expression in the dorsal striatum (Study 1). Furthermore, chronic stress reduced Pnoc-expressing cells in the VTA, dorsal striatum and prefrontal cortex and susceptible rats showed reduced VTA NOPR gene (Oprl1)-expressing cells (Study 2). In a behavioral assay, a single 30-mg dose of a NOPR antagonist (BTRX-246040) boosted reward learning in rats (Study 3). Finally, in depressed humans, relative to placebo, 8-week treatment with BTRX-246040 increased incentive motivation (Study 4). Collectively, our findings indicate that chronic stressors alter Pnoc and mRNA levels of Pnoc-expressing cells in a sex-selective and region-specific manner impacting reward structures, and that NOPR antagonism shows anti-anhedonic properties.

neuroscience↗

bioRxiv2022

A mesocorticolimbic signature of pleasure in the human brain

Pleasure is a fundamental driver of human behavior, yet its neural basis remains largely unknown. Rodent studies highlight opioidergic neural circuits connecting the nucleus accumbens, ventral pallidum, insula, and orbitofrontal cortex as critical for the initiation and regulation of pleasure, and human neuroimaging studies exhibit some translational parity. However, whether activation observed across these regions reflects a common, generalizable code for pleasure driven by opioidergic mechanisms remains unclear. Here we use pattern recognition techniques to develop a human functional magnetic resonance imaging signature of mesocorticolimbic activity unique to states of pleasure. In independent validation tests, we find this signature has high sensitivity to pleasant tastes and positive affect evoked by humor. The signature is spatially coextensive with mu-opioid receptor gene expression, and its response is attenuated by the opioid antagonist naloxone. These findings provide evidence of a basis for pleasure derived from primary and secondary rewards in humans that is distributed across brain systems, and suggest that similar mechanisms underlie hedonic impact across mammalian species.

neuroscience↗

bioRxiv2020

Distinct striatal subregions and corticostriatal connectivity for effort, action and reward

The ventral striatum is believed to encode the subjective value of cost/benefit options; however, this effect has strikingly been absent during choices that involve physical effort. Prior work in freely-moving animals has revealed opposing striatal signals, with greater response to increasing effort demands and reduced responses to rewards requiring effort. Yet, the relationship between these conflicting signals remains unknown. Using fMRI with a naturalistic, effort-based navigation paradigm, we identified functionally-segregated regions within ventral striatum that separately encoded action, effort, and discounting of rewards by effort. Strikingly, these sub-regions mirrored results from a large-sample connectivity-based parcellation of the striatum. Moreover, individual differences in striatal effort activation and effort discounting signals predicted striatal responses to effort-related choices during an independent fMRI task. Taken together, our results suggest that a dorsomedial region primarily associated with action may instead represent the effort cost of actions, and raises fundamental questions regarding the interpretation of striatal "reward" signals in the context of effort demands.

neuroscience↗