Hypothalamus Participates in Peripheral Sympathetic Hyperactivity After Acute Brain Injury by Regulating Trhr M⁶A...

Sympathetic hyperactivity following acute brain injury (ABI) impedes recovery, yet effective treatments are lacking. Recently, N⁶-methyladenosine (m⁶A) modified by fat mass and obesity-associated gene (FTO) has been demonstrated to play critical roles in multiple neurological diseases. Here, we found that sympathetic hyperactivity occurred in traumatic brain injury and intracerebral hemorrhage patients and mouse models in vivo. In mouse ABI models, the RNA demethylase FTO was upregulated in hypothalamic neurons. Through m⁶A methylation sequencing, we found that FTO mediated m⁶A demethylation of Trhr mRNA, enhancing its stability by inhibiting YTHDF2-dependent decay. This increased neuronal TRHR expression and sensitivity to TRH, culminating in sympathetic hyperactivity. Conversely, restoring hypothalamic FTO or TRHR levels alleviated this condition. We further mapped and functionally validated a monosynaptic projection from lateral hypothalamic TRHR neurons to the rostral ventrolateral medulla (RVLM), demonstrating that modulating these neurons controls sympathetic tone. Collectively, our findings elucidate a novel FTO-Trhr axis in post-ABI autonomic dysfunction and highlight a promising therapeutic target.