Age-Related Trajectories of Functional Coupling between the VTA and Nucleus Accumbens Depend on Motivational State

Abstract

Over-engagement of the mesolimbic dopamine system is thought to enhance motivation in adolescents. Whereas human neuroimaging has characterized event-evoked responses of the mesolimbic system in adolescents, research has yet to characterize state-dependent engagement (i.e., seconds to minutes) of this system in goal-relevant contexts. In the current longitudinal study, we characterized age-related changes in state-dependent coupling in male and female human participants ranging in age from adolescence to adulthood. Analyses focused on two key regions of the mesolimbic dopamine system, the ventral tegmental area (VTA) and nucleus accumbens (NAcc). Although there were no differences in VTA-NAcc functional coupling in a resting-state context, VTA-NAcc functional coupling was enhanced in preadolescence/early adolescence and decreased into adulthood in a motivational context, in which individuals had to translate goal-relevant cues into instrumental actions. Furthermore, we found that task-related activation in orbitofrontal cortex, middle temporal gyrus, and visual association cortex partially mediated age-related changes in state-dependent VTA-NAcc functional coupling. These results extend prior models of neurodevelopment by showing a relationship between cortical event-evoked activation and state-dependent increases in subcortical engagement of mesolimbic systems. Adolescence is characterized by increased motivated behavior, which is thought to result from an over-engagement of mesolimbic dopamine systems. Rodent models show increases in state-dependent engagement of mesolimbic systems in adolescence. However, human neuroimaging research has mainly focused on event-evoked responses (i.e., reward cues). We show that in motivational contexts, there is increased state-dependent coupling across mesolimbic systems in preadolescence/early adolescence that decreases into adulthood and is further predicted by event-evoked cortical responses. Critically, these developmental trajectories were specific to motivationally relevant contexts and were not apparent during resting state. These findings extend emerging models of human development and suggest that state-dependent increases in dopamine signaling may underlie heightened motivation.

Dopamine-related striatal neurophysiology is associated with specialization of frontostriatal reward circuitry through adolescence

“…On a portion of trials, after receiving feedback, participants performed "bonus trials" consisting of either a rewarded or unrewarded anti-saccade task (described previously in Geier et al, 2010;Murty et al, 2018;Ordaz et al, 2013). Although these data were modeled in the fMRI analyses described below, data is not presented here.…”

“…The six 5 min runs were concatenated, providing 30 minutes of data to optimally estimate and remove task-evoked BOLD responses. Task-evoked events were modeled with a TENT function to estimate the hemodynamic response for 24 s after each event in 1.5 s increments (using 3dDeconvolve in AFNI; Murty et al, 2018). In comparison to the canonical hemodynamic response function (HRF), the TENT function makes no assumptions about the shape of HRF responses, and should therefore remove more variability due to task-evoked signals from the time series (Chen et al, 2015).…”

“…We tested linear and inverse (age -1 ) functional forms of age and selected the model with the lowest Akaike Information Criterion (AIC), indicating best model fit. In the case that the AIC for each model was equivalent, we characterized developmental changes with an inverse age function, as we hypothesize that development is characterized by an initial period of rapid growth followed by stabilization into adulthood, and previous studies have shown that inverse age provides a better fit for developmental changes through adolescence (Luna et al, 2004;Murty et al, 2018;Ordaz et al, 2013;Simmonds et al, 2017). Sex and visit number were included as covariates, to ensure the robustness of the associations.…”

Amygdala and ventral tegmental area differentially interact with hippocampus and cortical medial temporal lobe during rest in humans

“…One reason these differences may develop is that biases in functional connectivity with the VTA and amygdala may emerge only during affective or motivational states. In line with this interpretation, prior work has shown that VTA interactions with both cortical and subcortical structures are more prominent in the context of motivationally relevant states when compared to resting state or an intrinsic baseline (Ballard et al, 2011; Murty et al, 2018). In the ensuing logic, VTA modulation over the hippocampus may emerge only in affective states that engage VTA, which has been previously been shown in the context of reward motivation (Adcock et al, 2006; Gruber, Watrous, Ekstrom, Ranganath, & Otten, 2013; Murty & Adcock, 2014; Wolosin, Zeithamova, & Preston, 2013), novelty (Wittmann, Daw, Seymour, & Dolan, 2008), and curiosity (Gruber, Gelman, & Ranganath, 2014).…”

Age-related cognitive decline in baboons: modeling the prodromal phase of Alzheimer's disease and related dementias

“…Compelling evidence suggests the dopaminergic system that projects from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) and other structures of the forebrain is a major substrate of reward and reinforcement [66,67]. Interestingly, a recent study demonstrated an age-related decrease in VTA-NAcc coupling in the context of motivation level [68]. However, further studies are required to demonstrate the implication of the dopaminergic system in the declined motivation seen in aged baboons.…”