Dickstein Dara L, Zhang Richard, Ru Ning, Vozenin Marie-Catherine, Perry Bayley C, Wang Juan, Baulch Janet, Acharya Munjal M, Limoli Charles L
Uniformed Services University of Health Sciences.
University of California, Irvine School of Medicine.
Res Sq. 2024 Jul 22:rs.3.rs-4656938. doi: 10.21203/rs.3.rs-4656938/v1.
Evidence shows that ultra-high dose-rate FLASH-radiotherapy (FLASH-RT) protects 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 of granule 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. To explore the sensitivity of different neuronal populations to cranial irradiation and dose-rate modulation, hippocampal CA1 and medial prefrontal cortex (PFC) pyramidal neurons were analyzed by 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 length and head diameter of smaller non-perforated synapses. Similarly, irradiation caused no change in PFC 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 (3×10Gy) 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 more radioresistant irrespective of radiation dose-rate.
证据表明，超高剂量率的FLASH放疗（FLASH-RT）可预防受照射脑部的正常组织并发症和功能减退。过去的研究表明，与传统剂量率（CONV，0.1 Gy/s）放疗相比，FLASH-RT（> MGy/s）后未观察到同等程度的辐射诱导认知障碍、神经炎症和颗粒细胞神经元结构复杂性降低。为了探究不同神经元群体对颅脑照射和剂量率调节的敏感性，通过电子显微镜和共聚焦显微镜对海马CA1和内侧前额叶皮质（PFC）锥体神经元进行了分析。10 Gy的FLASH或CONV-RT照射后，通过电子显微镜进行的神经元超微结构分析表明，照射对CA1区的树突复杂性和突触密度影响较小，但确实增加了较小的无穿孔突触的长度和头部直径。同样，照射对PFC前边缘/下边缘轴棘突触密度没有影响，但无穿孔突触直径减小。虽然与对照组相比，照射导致髓鞘变薄，但这些指标均对剂量率不敏感。与我们过去对颗粒细胞神经元的分析相反，对荧光标记的CA1神经元的分析显示，在整体树突复杂性或棘突密度方面没有辐射诱导或剂量率依赖性变化。临床给药模式（3×10 Gy）后的超分辨率共聚焦显微镜显示，CA1区内兴奋性囊泡谷氨酸转运体1和抑制性囊泡GABA转运体斑点密度显著降低，且在很大程度上与剂量率无关。总的来说，这些数据表明，与颗粒细胞神经元相比，CA1和mPFC神经元无论辐射剂量率如何都更具放射抗性。
