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Behavioral performance and microglial status in mice after moderate dose of proton irradiation

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Cognitive impairment is a remote effect of gamma radiation treatment of malignancies. The major part of the studies on the effect of proton irradiation (a promising alternative in the treatment of radio-resistant tumors and tumors located close to critical organs) on the cognitive abilities of laboratory animals and their relation to morphological changes in the brain is rather contradictory. The aim of this study was to investigate cognitive functions and the dynamics of changes in morphological parameters of hippocampal microglial cells after 7.5 Gy of proton irradiation. Two months after the cranial irradiation, 8- to 9-week-old male SHK mice were tested for total activity, spatial learning, as well as long- and short-term hippocampus-dependent memory. To estimate the morphological parameters of microglia, brain slices of control and irradiated animals each with different time after proton irradiation (24 h, 7 days, 1 month) were stained for microglial marker Iba-1. No changes in behavior or deficits in short-term and long-term hippocampus-dependent memory were found, but an impairment of episodic memory was observed. A change in the morphology of hippocampal microglial cells, which is characteristic of the transition of cells to an activated state, was detected. One day after proton exposure in the brain tissue, a slight decrease in cell density was observed, which was restored to the control level by the 30th day after treatment. The results obtained may be promising with regard to the future use of using high doses of protons per fraction in the irradiation of tumors.

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This study was funded under the Russian Government contract of the Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences no. 075-01027-22-00, and was partially conducted in the framework of the Agreement no. 25/22 of Lebedev Physical Institute, Russian Academy of Sciences.

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SS Sorokina and AE Malkov designed and coordinated the work, wrote the main manuscript text and prepared figures and tables. OM Rozanova prepared and drafted the english version of text. Authors contributed in particularly to the following parts: AE Malkov and SS Sorokina - estimate the cognitive functions and morphological parameters of microglia; EN Smirnova and AE Shemyakov - organization and conduction of proton mice irradiation experiment at the Prometheus proton therapy complex. All authors contributed to the text as a whole and critically revised and approved the work.

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Correspondence to S. S. Sorokina.

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The work was conducted in compliance with the ethical principles stipulated in the Declaration of the Federation of European Laboratory Animal Science Association (FELASA). The International, National, and Institutional standards of the care and use of the laboratory animals in research were thoroughly respected.

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Sorokina, S.S., Malkov, A.E., Rozanova, O.M. et al. Behavioral performance and microglial status in mice after moderate dose of proton irradiation. Radiat Environ Biophys 62, 497–509 (2023).

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