The Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610054, People's Republic of China.
Ministry of Education Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology, Chengdu 610054, People's Republic of China.
Proc Natl Acad Sci U S A. 2024 Feb 20;121(8):e2306936121. doi: 10.1073/pnas.2306936121. Epub 2024 Feb 13.
Accumulating evidence suggests that the brain renin angiotensin system (RAS) plays a pivotal role in the regulation of cognition and behavior as well as in the neuropathology of neurological and mental disorders. The angiotensin II type 1 receptor (AT1R) mediates most functional and neuropathology-relevant actions associated with the central RAS. However, an overarching comprehension to guide translation and utilize the therapeutic potential of the central RAS in humans is currently lacking. We conducted a comprehensive characterization of the RAS using an innovative combination of transcriptomic gene expression mapping, image-based behavioral decoding, and pre-registered randomized controlled discovery-replication pharmacological resting-state functional magnetic resonance imaging (fMRI) trials (N = 132) with a selective AT1R antagonist. The AT1R exhibited a particular dense expression in a subcortical network encompassing the thalamus, striatum, and amygdalo-hippocampal formation. Behavioral decoding of the AT1R gene expression brain map showed an association with memory, stress, reward, and motivational processes. Transient pharmacological blockade of the AT1R further decreased neural activity in subcortical systems characterized by a high AT1R expression, while increasing functional connectivity in the cortico-basal ganglia-thalamo-cortical circuitry. Effects of AT1R blockade on the network level were specifically associated with the transcriptomic signatures of the dopaminergic, opioid, acetylcholine, and corticotropin-releasing hormone signaling systems. The robustness of the results was supported in an independent pharmacological fMRI trial. These findings present a biologically informed comprehensive characterization of the central AT1R pathways and their functional relevance on the neural and behavioral level in humans.
越来越多的证据表明，大脑肾素血管紧张素系统（RAS）在调节认知和行为以及神经和精神障碍的神经病理学方面发挥着关键作用。血管紧张素 II 型 1 型受体（AT1R）介导与中枢 RAS 相关的大多数功能和神经病理学相关作用。然而，目前缺乏全面的理解来指导翻译并利用中枢 RAS 在人类中的治疗潜力。我们使用创新的转录组基因表达图谱、基于图像的行为解码以及经过预先注册的随机对照发现-复制药理学静息状态功能磁共振成像（fMRI）试验（N=132），结合选择性 AT1R 拮抗剂，对 RAS 进行了全面表征。AT1R 在包括丘脑、纹状体和杏仁核-海马结构在内的皮质下网络中表现出特别密集的表达。AT1R 基因表达脑图谱的行为解码显示与记忆、压力、奖励和动机过程有关。AT1R 的短暂药理学阻断进一步降低了高 AT1R 表达的皮质下系统中的神经活动，同时增加了皮质基底节-丘脑-皮质回路中的功能连接。AT1R 阻断对网络水平的影响与多巴胺能、阿片样、乙酰胆碱和促肾上腺皮质激素释放激素信号系统的转录组特征特别相关。在独立的药理学 fMRI 试验中支持了结果的稳健性。这些发现提供了对人类中枢 AT1R 途径及其在神经和行为水平上的功能相关性的生物学知情的全面描述。
