Abstract
BackgroundCosmic 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.MethodsAdult mice were administered a dietary inhibitor (PLX5622) of colony stimulating factor-1 receptor (CSF1R) to deplete microglia 2 weeks after whole body helium irradiation (4He, 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.ResultsPLX5622 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 pre-frontal 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.ConclusionsOur 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.
Highlights
As National Aeronautics and Space Administration (NASA) continues to plan for deep space missions, the potential harmful effects of the space radiation environment on the central nervous system (CNS) functionality have received increased scrutiny
We found a significant interaction for the radiation effect for the immunoreactivity of Postsynaptic density protein 95 (PSD-95)+ puncta (F(1, 16) = 10.51, P = 0.005, two-way Analysis of variance (ANOVA))
Given the extensive evidence indicating that such exposures may prove problematic at a number of levels relevant to mission critical performance and/or longer-term neurocognitive health, studies are increasingly focused on various strategies to prevent and/or mitigate the adverse effects of whole-body cosmic radiation exposure on the CNS as well as the rest of the body
Summary
As NASA continues to plan for deep space missions, the potential harmful effects of the space radiation environment on the central nervous system (CNS) functionality have received increased scrutiny. Elimination of “old” microglia through CSF1R blockade and subsequent repopulation rejuvenated the microglial phenotype and promoted reversal of age-related changes in cognition, dendritic spine densities, neurogenesis, synaptogenesis, and long-term potentiation [30]. This and other works have clearly pointed to the potential benefits of promoting microglial turnover in the aged or injured brain, and point to the importance of reducing the yield of chronically activated microglia that appear to perpetuate chronic inflammatory signatures in the irradiated brain. We investigated the potential neurocognitive benefits of microglia depletion following low dose whole body exposure to helium ions
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