Juvenile brain irradiation impairs locus coeruleus activity

Cranial radiotherapy is essential in treating pediatric brain tumor patients but also a major contributor to neurocognitive impairments. While hippocampal damage has been extensively studied in this context, radiosensitivity of other cognition-related regions remains largely unexplored. The locus coeruleus (LC), a small brain stem nucleus and the sole source of noradrenaline (NA) to the hippocampus, plays a critical role in modulating synaptic plasticity and memory consolidation. We therefore evaluated the impact of juvenile brain irradiation on the LC-NA system and whether pharmacological modulation of NA could mitigate potential dysfunction.
METHODS
Juvenile mice received a single 10 Gy cranial irradiation at P22. NA agonists, reboxetine or atipamezole, were administered daily for seven days post-irradiation. Sham-treated controls received sterile saline. One month post-radiation, LC damage was investigated by immunohistochemistry (TH, DBH, MAO-A, and NET). Fiber photometry (GCaMP6s in LC, GRABNE2m in hippocampus) during tail suspension stress evaluated functional responses. Finally, novelty-induced cFOS expression was analyzed 90 min. after Y-maze exposure.
RESULTS
At one month post-irradiation, we observed a significant reduction in DBH+ cells and increased MAO-A intensity, which was mitigated by atipamezole treatment. In contrast, NET and TH expression, LC volume, and total DAPI+ cell count remained unchanged. Functionally, fiber photometry showed reduced LC activity during tail suspension stress in irradiated animals, while hippocampal NA release remained unaffected. Reduced novelty-induced cFOS expression further supported LC dysfunction, which was partially restored by atipamezole.
CONCLUSION
This study provides the first evidence of LC damage following irradiation, marked by disrupted NA metabolism and degradation without structural loss. LC vulnerability following irradiation was further supported by fiber photometry recordings, revealing functional deficits in LC activity during tail suspension stress. Altogether, these results underscore the importance of investigating other cognition-related regions beside the hippocampus to better understand and prevent radiation-induced cognitive decline in young cancer survivors.