A functional variant in the neuropeptide S receptor 1 gene moderates the influence of urban upbringing on stress processing in the amygdala

Abstract

We have previously shown that urban upbringing and city living were associated with stress-induced activity in the amygdala and the perigenual anterior cingulate cortex (pACC). This finding might link the epidemiological risk factor "urbanicity" to neurobiological mechanisms of psychiatric disorders. However, given the heritability of stress-related phenotypes, it appears likely that genetic factors can modulate the effect of urbanicity on social stress processing. In the present exploratory study, we investigated if a functional sequence variation in the neuropeptide S receptor gene (NPSR1 rs324981) is associated with brain activation patterns under acute psychosocial stress and if it modulates the link between urbanicity and central stress processing. In animals, neuropeptide S has strong anxiolytic effects and it induces hypothalamus-pituitary-adrenal (HPA) axis activation. In humans, rs324981 was found to be associated with anxiety and stress-related phenotypes. Forty-two subjects were exposed to a psychosocial stress task for scanner environments (ScanSTRESS). While no main effect of rs324981 on amygdala and pACC activity was detected, we found a distinct interaction between rs324981 and urban upbringing modulating right amygdala responses. Moreover, right amygdala responses were significantly higher in subjects who also showed a salivary cortisol response to the stress exposure. The present finding of a gene × environment interaction further supports the view that the brain NPS system is involved in central stress regulation. This study provides first evidence for the assumption that a NPSR1 variant modulates brain activation under stress, interacting with the environmental risk factor urban upbringing.

Neural responses to social evaluative threat in the absence of negative investigator feedback and provoked performance failures

“…During SET anticipation and performance (contrast: SET > control), we found significantly increased activation in brain regions previously reported to be involved in SET processing (Akdeniz et al, ; Dedovic et al, ; Streit et al, ). Specifically, we detected significant ROI activation increases in the amygdala and pACC, for the performance phase (pACC: [3 53 14], t = 7.03, p FWE < .001, amygdala: [21 −7 −13], t = 8.82, p FWE < .001) and for the anticipation phase (pACC: [−9 38 5], t = 4.57, p FWE = .004, amygdala: [21 −4 −13], t = 4.69, p FWE = .003; Figure ).…”

“…We expected to detect higher online arousal levels during the SET condition compared to the control condition and higher offline arousal levels after IMPRESS task runs compared to measurements before the task, respectively. On the level of brain function, we expected to see significant activation increases in the SET condition compared to the control condition in brain regions previously associated with neural social stress processing, in particular in the amygdala and pACC (Akdeniz et al, ; Dedovic et al, ; Streit et al, ). We further aimed to probe the value of our paradigm by relating variation in established measures of arousal (i.e., heart rate and pupil diameter) and social environmental risk for psychiatric disorders (i.e., ACE and urban living) with variation in SET‐associated brain activity.…”

“…Adaptations of the TSST for fMRI typically emphasize perceptions of uncontrollability and social evaluative threat (SET; Dickerson & Kemeny, ) by combining increased cognitive task demands, time pressure, and social evaluation with negative performance feedback by the investigators, often with additional provocation of performance failures. For example, several studies have applied arithmetic problems with individually adjusted difficulty at performance limit with an intense negative performance feedback to convince the participants that they perform very poorly (Akdeniz et al, ; Dedovic et al, ; Dedovic, D'Aguiar, & Pruessner, ; Lederbogen et al, ; Streit et al, ). While these paradigms achieve their goal of strongly activating social stress‐related circuits, the fMRI experiments also bear several inherent limitations (Dedovic et al, ).…”

Genetic Moderation of Stress Effects on Corticolimbic Circuitry

“…While such studies are rare in a neuroscience context, some studies have used stress manipulations while measuring neural phenotypes and assaying genetic variation (Bogdan et al, 2011;Cousijn et al, 2010;Streit et al, 2014;Xu et al, 2013). These within-participant studies are especially powerful because they afford researchers a unique opportunity to experimentally manipulate stress and ensure that each participant is exposed to the same stressor, providing greater reliability and validity of what stress is across participants that is free from reporting biases.…”

Nutritional psychiatry research: an emerging discipline and its intersection with global urbanization, environmental challenges and the evolutionary mismatch

“…Living in an urban environment [15-17], as well as global shifts associated with urbanicity [18-21], the food supply and food industry [22], climate change [23], food insecurity [24,25], overnutrition and underactivity [26] and an overall transition from traditional lifestyles [27-29] have each been linked to increases in depression and other mental disorders. It is understood that depression and other mental disorders are not exclusive to urban areas; however, higher rates in urban areas have been reported with a degree of consistency [30,31]. Moreover, looking specifically at neighborhood disadvantage, the adjusted odds of experiencing an emotional disorder are 59% higher in urban youth vs those in rural areas [32].…”