Mitigation of helium irradiation-induced brain injury by microglia depletion

Abstract

Background: Cosmic radiation exposures have been found to elicit cognitive impairments involving a wide-range of underlying neuropathology including elevated oxidative stress, neural stem cell loss, and compromised neuronal architecture. Cognitive impairments have also been associated with sustained microglia activation following low dose exposure to helium ions. Space-relevant charged particles elicit neuroinflammation that persists long-term post-irradiation. Here, we investigated the potential neurocognitive benefits of microglia depletion following low dose whole body exposure to helium ions. Methods: Adult mice were administered a dietary inhibitor (PLX5622) of colony stimulating factor-1 receptor (CSF1R) to deplete microglia 2 weeks after whole body helium irradiation (4 He, 30 cGy, 400 MeV/n). Cohorts of mice maintained on a normal and PLX5622 diet were tested for cognitive function using seven independent behavioral tasks, microglial activation, hippocampal neuronal morphology, spine density, and electrophysiology properties 4-6 weeks later. Results: PLX5622 treatment caused a rapid and near complete elimination of microglia in the brain within 3 days of treatment. Irradiated animals on normal diet exhibited a range of behavioral deficits involving the medial prefrontal cortex and hippocampus and increased microglial activation. Animals on PLX5622 diet exhibited no radiation-induced cognitive deficits, and expression of resting and activated microglia were almost completely abolished, without any effects on the oligodendrocyte progenitors, throughout the brain. While PLX5622 treatment was found to attenuate radiation-induced increases in post-synaptic density protein 95 (PSD-95) puncta and to preserve mushroom type spine densities, other morphologic features of neurons and electrophysiologic measures of intrinsic excitability were relatively unaffected. Conclusions: Our data suggest that microglia play a critical role in cosmic radiation-induced cognitive deficits in mice and, that approaches targeting microglial function are poised to provide considerable benefit to the brain exposed to charged particles.

Sex-Specific Cognitive Deficits Following Space Radiation Exposure

“…Increased yields of activated M1 microglia may enhance the release of pro-inflammatory factors that exacerbate neuroinflammatory responses. These data are consistent with previous findings where lower phagocytic activity of microglia coincided with improvements in cognition after cosmic radiation exposure (Krukowski et al, 2018a;Allen et al, 2020).…”

“…In support of this, two recent studies have determined that elimination of microgliafacilitates the functional recovery of the irradiated brain. Following higher-dose x-irradiation (Acharya et al, 2016) or lower-dose 4 He irradiation (Acharya et al, 2016;Krukowski et al, 2018a;Allen et al, 2020), data showed an improved cognitive function, reduced inflammation, and a preservation of certain morphologic parameters in microglia-depleted brains. Once activated, microglia initiate and participate in pro-inflammatory signaling pathways in the brain (Fellner et al, 2013;Fiebich et al, 2018;York et al, 2018).…”

Radioprotective Effect of Flavonoids on Ionizing Radiation-Induced Brain Damage

“…Radiation exposure causes a wide range of neuronal damage, including increased oxidative stress, loss of neural stem cells and damage to neuronal structures [35]. It can also cause changes in calcium signaling cascades, significant activation of free radical processes, overproduction of reactive oxygen species in living cells, changes in neural and cognitive functions and destruction of the BBB [36].…”

Modeling Space Radiation Induced Cognitive Dysfunction Using Targeted And Non-Targeted Effects

“…The types of radiation damage that trigger NTE signal production can include unrepaired/misrepaired DNA double strand breaks, protein and lipid oxidation by radiation-induced reactive oxygen and nitrogen species, and mitochondrial damage. These events may lead to chronic in ammation, oxidative stress, and microglia activation 7 .…”

“…Radiation-induced central nervous system (CNS) damage and consequent cognitive dysfunction are increasingly recognized as important risks for astronauts on long-distance space missions such as exploration of Mars [1][2][3][4][5][6][7] . Mechanistically-motivated mathematical modeling of this phenomenon can provide much needed insight into interpreting the growing amount of relevant experimental data in laboratory animals, generating and testing mechanistic hypotheses, and producing quantitative predictions for radiation quality effects and risk magnitudes for space mission scenarios 4,6 .…”