Cognitive and behavioral effects of whole brain conventional or high dose rate (FLASH) proton irradiation in a neonatal Sprague Dawley rat model

Abstract

Recent studies suggest that ultra-high dose rates of proton radiation (>40 Gy/s; FLASH) confer less toxicity to exposed healthy tissue and reduce cognitive decline compared with conventional radiation dose rates (~1 Gy/s), but further preclinical data are required to demonstrate this sparing effect. In this study, postnatal day 11 (P11) rats were treated with whole brain irradiation with protons at a total dose of 0, 5, or 8 Gy, comparing a conventional dose rate of 1 Gy/s vs. a FLASH dose rate of 100 Gy/s. Beginning on P64, rats were tested for locomotor activity, acoustic and tactile startle responses (ASR, TSR) with or without prepulses, novel object recognition (NOR; 4-object version), striatal dependent egocentric learning ([configuration A] Cincinnati water maze (CWM-A)), prefrontal dependent working memory (radial water maze (RWM)), hippocampal dependent spatial learning (Morris water maze (MWM)), amygdala dependent conditioned freezing, and the mirror image CWM [configuration B (CWM-B)]. All groups had deficits in the CWM-A procedure. Weight reductions, decreased center ambulation in the open-field, increased latency on day-1 of RWM, and deficits in CWM-B were observed in all irradiated groups, except the 5 Gy FLASH group. ASR and TSR were reduced in the 8 Gy FLASH group and day-2 latencies in the RWM were increased in the FLASH groups compared with controls. There were no effects on prepulse trials of ASR or TSR, NOR, MWM, or conditioned freezing. The results suggest striatal and prefrontal cortex are sensitive regions at P11 to proton irradiation, with reduced toxicity from FLASH at 5 Gy.

The Flash Mode of Proton Irradiation in the Bragg Peak Partly Spares the Embryogenesis of the Quail

“…Since the temperature in the room is lower than in the brooder, it is clear that chicks can gather in groups to get warm, which may indirectly indicate the disturbance of energy metabolism, mitochondrial dysfunction [35], and cognitive dysfunction, which show up in a lower inclination for search behavior. Previously, a greater preservation of nervous tissue during irradiation in the FLASH modes has been shown in irradiated mice and rats [4, 9, 10]. The differences identified in this study indicate that the CONV mode has a stronger damaging effect, which probably affects both energy metabolism and cognitive functions.…”

“…Recent investigations confirmed broad potentialities of the FLASH technique, which uses electrons, photons, and protons to diminish the toxicity in healthy tissues in the brain, lungs, intestines, blood, bones, muscles, and skin of animals without reducing the tumoricidal activity of ionizing radiation [3]. In particular, some experiments demonstrated a better preservation of peripheral healthy tissues, the digestive, hematopoietic, pulmonary, cognitive and behavioral functions of the organism, as well as of the regenerative potential of tissues [1,[2][3][4][5][6][7][8][9][10][11]. However, there are several problems that must be solved before this treatment modality can be translated safely in clinical settings [2].…”

Tests for learning and memory in rodent regulatory studies

“…However, we have found effects in 210 cm MWMs. Examples include after exposure to kaolin that induces hydrocephalus ( Williams et al, 2014 ), developmental exposure to some antidepressants, particularly citalopram ( Sprowles et al, 2016 , Sprowles et al, 2017 ), developmental exposure to manganese ( Amos-Kroohs et al, 2017 ), developmental exposure to the pesticide deltamethrin ( Pitzer et al, 2019 ), developmental exposure to the novel street drug 5-methoxy-N,N-diisopropyltrypamine (“Foxy”) and methylenedioxymethamphetamine (MDMA) ( Skelton et al, 2009 , Vorhees et al, 2009 ), developmental exposure to d-fenfluramine ( Morford et al, 2002 ) and ionizing protons ( Williams et al, 2020 , Williams et al, 2022 ). The 244 cm maze size is not size prohibitive since it can be moved into a laboratory in sections and chemically welded by a fabricator.…”

Preclinical Ultra-High Dose Rate (FLASH) Proton Radiation Therapy System for Small Animal Studies

“… 2 The FLASH effect has been reported in several in vivo models spanning multiple body sites and normal tissues including the brain, lungs, and intestinal tract. 3 , 4 , 5 , 6 , 7 , 8 , 9 …”