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

Abstract

The brain renin angiotensin II system plays a pivotal role in cognition and neuropathology via the central angiotensin II type 1 receptor (AT1R), yet the lack of a biologically informed framework currently impedes translational and therapeutic progress. We combined imaging transcriptomic and meta-analyses with pharmaco-resting state fMRI employing a selective AT1R antagonist in a discovery-replication design (n=132 individuals). The AT1R was densely expressed in subcortical systems engaged in reward, motivation, stress, and memory. Pharmacological target engagement suppressed spontaneous neural activity in subcortical systems with high AT1R expression and enhanced functional network integration in cortico-basal ganglia-thalamo-cortical circuits. AT1R-regulation on functional network integration was further mediated by dopaminergic, opioid and corticotrophin-releasing hormone pathways. Overall, this work provides the first comprehensive characterization of the architecture and function of the brain renin angiotensin II system indicating that the central AT1R mediates human cognition and behavior via regulating specific circuits and interacting with classical transmitter systems.