Cranial irradiation at early postnatal age impairs stroke-induced neural stem/progenitor cell response in the adult brain

Abstract

Cranial irradiation (IR) is commonly used to treat primary brain tumors and metastatic diseases. However, cranial IR-treated patients often develop vascular abnormalities later in life that increase their risk for cerebral ischemia. Studies in rodents have demonstrated that IR impairs maintenance of the neural stem/precursor cell (NSPC) pool and depletes neurogenesis. We and others have previously shown that stroke triggers NSPC proliferation in the subventricular zone and migration towards the stroke-injured neocortex. Whether this response is sustained in the irradiated brain remains unknown. Here, we demonstrate that cranial IR in mice at an early postnatal age significantly reduced the number to neuronal progenitors responding to cortical stroke in adults. This was accompanied by a reduced number of microglia/macrophages in the peri-infarct cortex; however, the astrocytic response was not altered. Our findings indicate that IR impairs the endogenous repair capacity in the brain in response to stroke, hence pointing to another side effect of cranial radiotherapy which requires further attention. Cranial irradiation (IR) is a routine clinical treatment for primary brain tumors and metastasis, it however causes long-lasting side effects in cancer survivors such as neurocognitive sequelae 1-4. This has been particularly problematic in pediatric patients, as their brain is still developing 5. Nowadays, irradiation of the brain in pediatric patients is largely abandoned or delayed until the neuronal maturation. Possible mechanisms for cognitive effect have been suggested to be related to depletion of postnatal and juvenile neurogenesis 6 and the development of cerebrovascular complications, and even stroke in later life 7 , which collectively leads to poor quality of life for the cancer survivors 8-10. In the CNS of most mammals, neurogenesis exists throughout life. Neural stem/precursor cells (NSPC) reside in discrete regions e.g. the subventricular zone (SVZ) of the lateral ventricle and other areas along the ventricular system 11,12. In the mouse SVZ, NSPCs give rise to neuroblasts that migrate to the olfactory bulb where they differentiate into neurons that integrate into the pre-existing neuronal networks 13,14. NSPCs are highly proliferative and therefore are susceptible to DNA damage caused by IR leading to cell death 15,16. In experimental animal models, moderate doses of IR lead to a long-lasting decline in NSPC proliferation and neurogenesis in a doseand age-dependent manner 17-20. On the other hand, cerebral ischemia increases NSPC proliferation in the SVZ and reroutes migration of the neuronal progenitors towards the injury site 21-26. Whether this progenitor cell response to stroke is affected by IR remains unknown. In this study, we investigated the NSPC response to cortical stroke in the adult mouse brain after exposure to IR at an early postnatal stage. We assessed NSPCs migration and neuroinflammation in

Fractionated brain irradiation profoundly reduces hippocampal immature neuron numbers without affecting spontaneous behavior and cognition in mice

“…Neurogenesis has repeatedly shown to be decreased after brain irradiation independent of age, sex or species used [23][24][25][26][27][28][29][30][31][32][33] , which is in line with our findings showing a reduction of immature neurons in the dentate gyrus. However, we did not detect changes in spontaneous behavior, suggesting that the irradiated animals do not show abnormalities in activity, mobility and behavioral patterns.…”

Ultra-High Dose Rate Helium Ion Beams: First In Vivo Evidence for Neuroprotective FLASH Effect

“…Even though several studies have reported a reduction in Iba1 expression following radiotherapy [38][39][40], the complex role of microglial activation following irradiation injury remains only partially deciphered [15]. However, transition of microglia to a pro-inflammatory state may lead to neural and endothelial tissue damage [41].…”