PhD Defense | Isabeau De Bie | Targeting noradrenergic pathways to protect the juvenile brain against radiation-induced damage

Targeting noradrenergic pathways to protect the juvenile brain against radiation-induced damage

Abstract: Pediatric brain tumor survivors face a high risk of long-term neurocognitive impairments, with radiotherapy being a major contributing factor. These impairments affect multiple cognitive domains including attention, memory, and executive functions, substantially affecting children’s quality of life. Despite their clinical significance, the mechanisms underlying radiation-induced cognitive decline remain incompletely understood, and no established pharmacological strategies currently exist. The locus coeruleus (LC) is the brain’s primary source of noradrenaline (NA) and projects widely to regions critical for cognition, thereby contributing significantly to learning, memory, and attention. In addition to its classic neurotransmitter function, NA has significant anti-inflammatory and neuroprotective properties. Conversely, damage to the LC can exacerbate neuroinflammation, impair neuronal survival, and promote cognitive decline. Accordingly, this work addressed two complementary questions: how irradiation affects the LC-noradrenergic system, and whether pharmacological targeting of this system, using reboxetine (REB) or atipamezole (ATI), can prevent or mitigate cognitive decline. Using juvenile mouse models, this work shows that treatment with REB or ATI significantly reduces hippocampal damage at a cellular, structural, and functional level. Specifically, REB and ATI significantly reduce hippocampal cell death and microglial activation, preserve hippocampal structure, and mitigate memory decline, highlighting modulation of the noradrenergic system as a promising neuroprotective strategy. In parallel, irradiation disrupts the LC-noradrenergic system itself, altering key enzymes involved in NA metabolism, and reducing LC calcium dynamics in response to stress and environmental novelty. Noradrenergic treatment partially prevents these cellular and functional impairments, highlighting the LC as a previously underrecognized target of radiation-induced neurotoxicity. Taken together, the findings of this doctoral work reveal that radiation-induced neurotoxicity is characterized by damage to the hippocampus and the LC-noradrenergic system and demonstrate that noradrenergic modulation can provide significant neuroprotection. This work not only advances our understanding of the neurobiological mechanisms driving cognitive decline after cranial irradiation but also identifies a promising therapeutic avenue to preserve long-term cognitive function.

Promoters:

Prof. Dr. Robrecht Raedt, Ghent University

SCK CEN mentors:

Dr. Irina Primac