Voluntary Exercise Improves Radiation-induced Brain Injury in Mice

Radiation-induced brain injury (RBI) adversely affects the quality of life and prognosis of patients with brain tumors who undergo radiation therapy. Although rehabilitation strategies are recommended for mitigating RBI, the underlying mechanisms remain poorly understood. Here, we focused on RBI after fractionated whole-brain irradiation (WBI) in adult mice and examined the effects of voluntary exercise (VE) on cognitive function, growth factors, neurogenesis, and synaptic plasticity. Male C57BL/6J mice, aged 10-12 weeks, were divided into four groups: cham control (Ctl), WBI, Ctl + VE, and WBI + VE. The WBI total dose was 8 Gy (4 Gy × 2 fractions). Voluntary exercise was provided for three weeks using a voluntary running wheel that was accessible 24 h a day. The effects of RBI and VE were analyzed using behavioral, biochemical, immunohistological, and electrophysiological evaluations. WBI significantly impaired cognitive functions including spatial working memory, reference memory, and cognitive flexibility. Additionally, WBI led to reduced plasma mature brain-derived neurotrophic factor (mBDNF) levels, neurogenic differentiation 1 (NeuroD1)-positive cell density in the dentate gyrus, and long-term potentiation in the hippocampal cornu ammonis 1 region. Conversely, VE intervention ameliorated these cognitive deficits and increased mBDNF levels, enhanced NeuroD1-positive cell density, and strengthened long-term potentiation. Our findings suggest that VE intervention mitigates the effects of RBI in adult mice by promoting neurogenesis and enhancing synaptic plasticity via growth factor upregulation. These results underscore the importance of physical activity in rehabilitation and suggest that VE is a noninvasive strategy for improving cognitive function in patients affected by RBI.