Reward system activation improves recovery from acute myocardial infarction

Abstract Introduction Psychological processes play a crucial role in the recovery from acute myocardial infarction (AMI), yet the underlying mechanisms of these effects remain elusive. Here, we focused on the reward system, which mediates positively valenced emotions, motivation, and expectation and is based mainly on dopaminergic neurotransmission from the ventral tegmental area (VTA). Purpose The study examines the impact of activating dopaminergic neurons in the VTA following AMI in mice, aiming to understand the extent and mechanisms through which motivational brain network contribute to cardiac recovery process. Methods We used Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) to target neuronal activity. We performed an AMI model and assessed cardiac function using cardiac magnetic resonance (CMR). We used histology, immunohistochemistry, proteomic analysis, ELISA, reverse transcription-PCR, endothelial tube formation assay, and pseudorabies-virus neuronal tracing to investigate the mechanism. Results Chemogenetic activation of dopaminergic neurons in the VTA significantly modified the remodeling processes by reducing scar tissue (Fig. 1a) and increased vascularization (Fig. 1b) 15 days following AMI, leading to improved left-ventricular performance compared to control (Fig. 1c). These effects were mediated through several physiological mechanisms, including alterations in immune activity, and reduced adrenergic inputs to the liver. We further demonstrate an anatomical connection between the VTA and the liver that follows AMI manifested by altered transcription of complement component 3 (C3). We established the essential role of C3 in endothelial tube formation in vitro and its necessity in the beneficial effects of VTA activation on the recovery from AMI in vivo (Fig.2). Conclusion These findings establish a causal connection between a motivational brain network and recovery from AMI, introducing potential new therapeutic avenues for intervention.Effects of VTA activation on cardiac recMechanism of VTA effects