Angiotensin blockade enhances motivational reward learning via enhancing striatal prediction error signaling and frontostriatal communication

Abstract

Adaptive human learning utilizes reward prediction errors (RPEs) that scale the differences between expected and actual outcomes to optimize future choices. Depression has been linked with biased RPE signaling and an exaggerated impact of negative outcomes on learning which may promote amotivation and anhedonia. The present proof-of-concept study combined computational modelling and multivariate decoding with neuroimaging to determine the in uence of the selective competitive angiotensin II type 1 receptor antagonist losartan on learning from positive or negative outcomes and the underlying neural mechanisms in healthy humans. In a double-blind, between-subjects, placebo-controlled pharmaco-fMRI experiment, 61 healthy male participants (losartan, n = 30; placebo, n = 31) underwent a probabilistic selection reinforcement learning task incorporating a learning and transfer phase. Losartan improved choice accuracy for the hardest stimulus pair via increasing expected value sensitivity towards the rewarding stimulus relative to the placebo group during learning. Computational modelling revealed that losartan reduced the learning rate for negative outcomes and increased exploitatory choice behaviors while preserving learning for positive outcomes. These behavioral patterns were paralleled on the neural level by increased RPE signaling in orbitofrontal-striatal regions and enhanced positive outcome representations in the ventral striatum (VS) following losartan. In the transfer phase, losartan accelerated response times and enhanced VS functional connectivity with left dorsolateral prefrontal cortex when approaching maximum rewards. These ndings elucidate the potential of losartan to reduce the impact of negative outcomes during learning and subsequently facilitate motivational approach towards maximum rewards in the transfer of learning. This may indicate a promising therapeutic mechanism to normalize distorted reward learning and fronto-striatal functioning in depression.

Cortical gradient perturbation in attention deficit hyperactivity disorder correlates with neurotransmitter-, cell type-specific and chromosome- transcriptomic signatures

“…This was also paralleled by the finding that such gene expressions were closely related to cognitive functions, such as inhibitory control and reward, at the core of symptomatic dysfunctions in ADHD. Intact inhibitory control and adaptive reward processing are intimately linked to (sub)cortical-cortical communication 73,74 and circuit level dysregulations in the underlying dysfunctionsDLPFC and basal ganglia pathways and their genetic modification have been reported in ADHD 75,76 . In addition, we also revealed metabolic dysfunctions of ADHD in oxygen (CMRO2) and glucose (CMRGlu).…”

The central renin angiotensin II system – a genetic pathway, functional decoding and selective target engagement characterization in humans

“…78,79 Initial pharmaco-fMRI studies in humans furthermore indicate that an AT1R-blockade induced modulation of these circuits may mediate the regulatory role of the AT1R on reward, motivation and decision making in humans. 7,8 Network regulation of the AT1R and its association with dopaminergic, opioid and CRH systems Given that several of the complex effects of the AT1R may be mediated by interactions with other transmitter systems we modelled the spatiotemporal overlap of neurofunctional AT1R effects and receptor maps of selected candidate signaling systems. Our findings indicated that specifically the DRD5, OPRK1 and CRHR2 gene expression showed a distinct association with AT1R effects on brain regional FC such that DRD5 and OPRK1 interacted positively with AT1R blockade induced network level changes, while the CRHR2 exhibited a negative association with the pharmacological blockade effects.…”

“…1,3 Human pharmacological fMRI studies support the functional relevance of these circuits such that the blood-brain barrier permeable selective AT1R antagonist losartan: 1) attenuated amygdala threat reactivity, 21 2) facilitated regulation of threat via amygdala-hippocampal and amygdala-medial prefrontal pathways, 6,22,23 and 3) enhanced ventral striatal prediction errors and coupling in the mesocorticolimbic circuits during motivational paradigms. 7,8 Large population studies further indicate that (chronic) treatment with pharmacological AT1R blockers can reduce the incidence of PTSD symptoms. 10,24 While these results underscore a highly promising therapeutic potential of the AT1R, a recent multi-center randomized controlled clinical trial failed to determine treatment effects of an AT1R antagonist on PTSD symptomatology.…”

“…1 The discovery of a local brain RAS -that is independent of the peripheral system -in the 1970ties kindled research on the role of the RAS in directly regulating brain processes. 3,4 Over the subsequent years, accumulating evidence suggested an involvement of the RAS in affective and cognitive domains including stress, fear, motivation and memory, [5][6][7][8] as well as in the pathology of stress-related and neurodegenerative disorders including Post-Traumatic Stress Disorders (PTSD), depression and dementia. [9][10][11] The hormone angiotensin II (Ang II) and its actions at the angiotensin type 1 and type 2 receptor (AT1R, AT2R) critically mediate most functional effects, with the AT1R mediating both the peripheral and central actions of Ang II.…”

“…Animal models have discovered that the central AT1R regulates highly specific functions such as stress reactivity, motivation and threat avoidance. [18][19][20] Based on these animal models subsequent human pharmacological studies have demonstrated a role of the AT1R in reward and motivational processing, 7,8 emotional memory encoding and fear extinction learning. 6 The effects of the AT1R in these domains are likely mediated by its dense expression in regions involved in motivation, emotion and memory such as the thalamus, striatum, amygdala, hippocampus, and prefrontal cortex.…”