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<p>Evidence shows that ultra-high dose-rate FLASH-radiotherapy (FLASH-RT) provides relative protection against normal tissue complications and functional decrements in the irradiated brain. Past work has shown that radiation-induced cognitive impairment, neuroinflammation and reduced structural complexity ofgranule cell neurons were not observed to the same extent after FLASH-RT (&gt; MGy/s) compared to conventional dose-rate (CONV, 0.1&#xa0;Gy/s) delivery. In this study, we explored the sensitivity of hippocampal CA1 and medial prefrontal cortex (mPFC) pyramidal neurons to cranial irradiation and dose-rate modulation using electron and confocal microscopy. Neuron ultrastructural analyses by electron microscopy after 10&#xa0;Gy FLASH- or CONV-RT exposures indicated that irradiation had little impact on dendritic complexity and synapse density in the CA1, but did increase the length and head diameter of smaller non-perforated synapses. Similarly, irradiation caused no change in mPFC prelimbic/infralimbic axospinous synapse density, but reductions in non-perforated synapse diameters. While irradiation resulted in thinner myelin sheaths compared to controls, none of these metrics were dose-rate sensitive. Analysis of fluorescently labeled CA1 neurons revealed no radiation-induced or dose-rate-dependent changes in overall dendritic complexity or spine density, in contrast to our past analysis of granule cell neurons. Super-resolution confocal microscopy following a clinical dosing paradigm (3 × 10&#xa0;Gy) showed significant reductions in excitatory vesicular glutamate transporter 1 and inhibitory vesicular GABA transporter puncta density within the CA1 that were largely dose-rate independent. Collectively, these data reveal that, compared to granule cell neurons, CA1 and mPFC neurons are relatively more radioresistant irrespective of radiation dose-rate.</p>

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Structural plasticity of pyramidal cell neurons measured after FLASH and conventional dose-rate irradiation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月1日

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  • Dara L. Dickstein,
  • Richard Zhang,
  • Ning Ru,
  • Marie-Catherine Vozenin,
  • Bayley C. Perry,
  • Juan Wang,
  • Janet E. Baulch,
  • Munjal M. Acharya,
  • Charles L. Limoli

摘要

Evidence shows that ultra-high dose-rate FLASH-radiotherapy (FLASH-RT) provides relative protection against normal tissue complications and functional decrements in the irradiated brain. Past work has shown that radiation-induced cognitive impairment, neuroinflammation and reduced structural complexity ofgranule cell neurons were not observed to the same extent after FLASH-RT (> MGy/s) compared to conventional dose-rate (CONV, 0.1 Gy/s) delivery. In this study, we explored the sensitivity of hippocampal CA1 and medial prefrontal cortex (mPFC) pyramidal neurons to cranial irradiation and dose-rate modulation using electron and confocal microscopy. Neuron ultrastructural analyses by electron microscopy after 10 Gy FLASH- or CONV-RT exposures indicated that irradiation had little impact on dendritic complexity and synapse density in the CA1, but did increase the length and head diameter of smaller non-perforated synapses. Similarly, irradiation caused no change in mPFC prelimbic/infralimbic axospinous synapse density, but reductions in non-perforated synapse diameters. While irradiation resulted in thinner myelin sheaths compared to controls, none of these metrics were dose-rate sensitive. Analysis of fluorescently labeled CA1 neurons revealed no radiation-induced or dose-rate-dependent changes in overall dendritic complexity or spine density, in contrast to our past analysis of granule cell neurons. Super-resolution confocal microscopy following a clinical dosing paradigm (3 × 10 Gy) showed significant reductions in excitatory vesicular glutamate transporter 1 and inhibitory vesicular GABA transporter puncta density within the CA1 that were largely dose-rate independent. Collectively, these data reveal that, compared to granule cell neurons, CA1 and mPFC neurons are relatively more radioresistant irrespective of radiation dose-rate.