Brain function... Something to think about while Elon Musk travels to Mars with a CMNS Energy tech electric space drive powered Starship... The Atomic Starship.
Cite this article
Allen, B.D., Syage, A.R., Maroso, M. et al. Mitigation of helium irradiation-induced brain injury by microglia depletion. J Neuroinflammation 17, 159 (2020). https://doi.org/10.1186/s12974-020-01790-9
Published 19 May 2020
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"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 (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.
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 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.
Introduction
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. A wealth of data from a number of labs have now documented an impressive array of adverse neurocognitive outcomes following exposure to a variety of radiation types and exposure paradigms [1,2,3,4,5,6,7,8,9]. Findings from many different rodent models subjected to space relevant, low dose, whole body radiation exposures find long-lasting cognitive impairments [3]. The persistence of these detrimental effects coincides with alterations in biochemical [10,11,12,13,14], molecular [15, 16], cellular [2, 17, 18], structural [1,2,3, 19], and electrophysiological processes [3, 20,21,22] that point to the pleiotropic effects of charged particle exposures on the brain. Of particular note, is the persistent inflammatory footprint caused by radiation exposure involving a persistent elevation of “primed” or “activated” microglia.
As the principal immune cells of the CNS microglia represent ~ 12% of all CNS cell types and respond to injury, infection or disease to eliminate accumulated debris thereby serving a neuroprotective role [23, 24]. Recent data have shown microglia to be dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival [25]. CSF1R signaling is critical for early brain development [26], and in healthy adult brains, microglia are the principle cell type expressing CSF1R. Pharmacological CSF1R inhibition elicits a rapid and extensive depletion of microglia in the adult brain [25, 27,28,29], that can be reverted by removal of CSF1R inhibition. Previous studies also showed that microglia depletion does not induce cognitive impairments [25, 27] and a recent report has demonstrated the potential therapeutic benefits of microglial replacement in the aged brain [30]. 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.
An adaptation of the foregoing approach has demonstrated that transient microglia depletion could forestall cognitive impairments resulting from space-relevant, helium ion (4He) exposure [18]. A strength of this approach was the temporary CSF1R blockade using a high-affinity inhibitor, PLX5622, formulated in mouse chow (afforded by an equivalent PLX5622 diet). However, mice were scrutinized using only two behavior tasks, which presents certain limitations. Our past data have shown the lasting effects of charged partial irradiation on cognitive function using six independent behavior tasks [1,2,3] where improvements on either neurocognitive or neuroinflammation endpoints from 6 weeks to 52 weeks post-exposure were not observed. To more thoroughly evaluate the beneficial neurocognitive and anti-inflammatory effects of PLX5622 against low dose (30 cGy) 4He ion irradiation, mice underwent a longer-term PLX5622 administration regimen and were subjected to an extensive battery of seven behavioral tasks 4 to 6 weeks post-irradiation. This testing platform provided a rigorous assessment of cognitive function that was not overly reliant on a single task, cognitive domain, or specific brain region. Our data corroborate much of the past work performed using multiple injury models [27, 31], including cosmic radiation exposure [18], and show marked neurocognitive benefits of CSF1R blockade in the irradiated brain. Although microglial elimination improved cognition when evaluated 4 to 6 weeks following 4He exposure, other morphologic, synaptic, and electrophysiological properties of neurons showed relatively subtle or no rescue (i.e., mitigation) effects, suggesting other undefined, possibly more prominent neural targets or effects of CSF1R blockade.
