Neuropeptide Y and representation of salience in human nucleus accumbens

Abstract

Neuropeptide Y (NPY) produces anxiolytic effects in rodent models, and naturally occurring low NPY expression in humans has been associated with negative emotional phenotypes. Studies in rodent models have also demonstrated that NPY elicits reward behaviors through its action in the nucleus accumbens (NAc), but the impact of NPY on the human NAc is largely unexplored. We recruited 222 healthy young adults of either sex and genetically selected 53 of these subjects at the extremes of NPY expression (Low-NPY and High-NPY) to participate in functional magnetic resonance imaging. Responses of the NAc and surrounding ventral striatum were quantified during a monetary incentive delay task in which stimuli varied by salience (high versus low) and valence (win versus loss). We found that bilateral NAc responses to high-salience versus low-salience stimuli were greater for Low-NPY subjects relative to High-NPY subjects, regardless of stimulus valence. To our knowledge, these results provide the first evidence in humans linking NPY with salience sensitivity of the NAc, raising the possibility that individual differences in NPY expression moderate the risk for disorders of mesoaccumbal function such as addictions and mood disorders. Additionally, we found that head motion was greater among High-NPY subjects, consistent with previous reports linking NPY with hyperactivity. Future studies in animal models are warranted to elucidate the neural mechanisms through which NPY influences NAc function and related behaviors.

Sex differences in the human reward system: convergent behavioral, autonomic and neural evidence

“…In a previous publication ( Warthen et al., 2018 ), we described the effect of neuropeptide Y (NPY) genotype group on fMRI responses for the subset of 53 imaged subjects. Participants selected for imaging fell into one of two NPY genotype groups.…”

“…This task is well suited to our aims as it allows for independent variation of both valence and salience of stimuli. Details are described in the Supplement and in a previous report ( Warthen et al., 2018 ) and briefly summarized here. The five trial types were: high-salience and positive-valence (uncertain win); high-salience and negative-valence (uncertain loss); low-salience and positive-valence (certain win); low-salience and negative-valence (certain loss) and neutral.…”

“…The five conditions were presented in pseudo-random order with 20 repetitions per condition. After the MID task, subjects rated each cue stimulus on arousal and affect ( Warthen et al., 2018 ). For affect, participants rated ‘how positive or negative you feel,’ from 1 (negative) to 5 (positive).…”

“…Task-evoked blood oxygenation-level-dependent (BOLD) T2 * -weighted data were acquired on a 3-Tesla scanner and images were processed using SPM and custom software, as previously described ( Warthen et al., 2018 ). See supplement for imaging details.…”

“…We used a version of the monetary incentive delay (MID) task that quantified anticipatory responses and allowed us to distinguish sensitivity to salience (behavioral relevance) vs sensitivity to valence (win vs loss). This task strongly engages the mesoaccumbal pathway (NAc and midbrain) as well as the broader salience network, which is centered on the dorsal anterior cingulate cortex (dACC) and anterior insula (AI), so those structures were examined as regions of interest ( Menon, 2015 ; Warthen et al., 2018 ). We also measured sex differences in psychological traits related to reward and punishment sensitivity ( Carver and White, 1994 ; Torrubia et al., 2001 ; Jackson and Smillie, 2004 ) to complement these reward task-related metrics, and to evaluate how commonly measured traits map onto behavior.…”