Cortical Glutamate/GABA Imbalance after Combined Radiation Exposure: Relevance to Human Deep-Space Missions.

Ionizing radiation (IR) is one of the major biological limiting factors of human deep-space missions. Despite the dominant paradigm about the negative effects of IR on the CNS, the anxiolytic, antidepressant, anti-aggressive, and pro-cognitive effects have recently been discovered. The mechanisms of these phenomena remain undisclosed. Here, we study the effects of combined IR exposure (γ-rays and 12C nuclei) on the psycho-emotional state, cognitive abilities, and the metabolism of glutamate and GABA in Wistar rats, with an emphasis on the age factor. Irradiation resulted in the anxiogenic effect, reversing during maturation, and the sustained increase in spatial learning performance. A persistent decrease in the content of GABA was observed, which confirmed the hypothesis of disinhibition of the CNS under irradiation with moderate doses, proposed earlier. Glutamate/GABA imbalance was accompanied by an increase in the metabolism of these neurotransmitters: an increase in expression level of GLT-1, GAD65, GABAT and GAT1. Besides, a decrease in the expression level of NR1 subunit of the NMDA receptor was noted. Notably, the maturation of rats led not only to the rebalancing of the glutamate/GABA ratio by reducing the glutamate content, but also to leveling the differences in the expression levels of the analyzing biomolecules. Thus, the combined action of IR at moderate doses resulted in long-term changes in psycho-emotional status and, surprisingly, an increase in the efficiency of spatial learning performance. We suggest that IR (within the range of composition and doses used) can be relatively safe for the functions of the CNS.

Neurochemical insights into the radiation protection of astronauts: Distinction between low- and moderate-LET radiation components.

Radiation protection of astronauts remains an ongoing challenge in preparation of deep space exploratory missions. Exposure to space radiation consisting of multiple radiation components is associated with a significant risk of experiencing central nervous system (CNS) detriments, potentially influencing the crew operational decisions. Developing of countermeasures protecting CNS from the deleterious exposure requires understanding the mechanistic nature of cognitive impairments induced by different components of space radiation. The current study was designed to identify differences in neurochemical modifications caused by exposure to low- and moderate-LET radiations and to elucidate a distinction between the observed outcomes. We exposed rats to accelerated protons (170 MeV; 0.5 keV/µm) or to carbon ions (12C; 500 MeV/u; 10.5 keV/µm) delivered at the same dose of 1 Gy. Neurochemical alterations were evaluated 1, 30, and 90 days after exposure via indices of the monoamine metabolism measured in five brain structures, including prefrontal cortex, hypothalamus, nucleus accumbens, hippocampus and striatum. We obtained the detailed patterns of neurochemical modifications after exposure to the mentioned radiation modalities. Our data show that the enhancement in the radiation LET from relatively low to moderate values leads to different neurochemical outcomes and that a particular effect depends on the irradiated brain structure. We also hypothesized that exposure to the moderate-LET radiations can induce a hyperactivation of feedback neurochemical mechanisms, which blur metabolic deviations and lead to the delayed impairments in brain functions. Based on our findings we discuss possible contribution of the observed changes to behavioural impairments.

Radiation damage to neuronal cells: Simulating the energy deposition and water radiolysis in a small neural network.

Radiation damage to the central nervous system (CNS) has been an on-going challenge for the last decades primarily due to the issues of brain radiotherapy and radiation protection for astronauts during space travel. Although recent findings revealed a number of molecular mechanisms associated with radiation-induced impairments in behaviour and cognition, some uncertainties exist in the initial neuronal cell injury leading to the further development of CNS malfunction. The present study is focused on the investigation of early biological damage induced by ionizing radiations in a sample neural network by means of modelling physico-chemical processes occurring in the medium after exposure. For this purpose, the stochastic simulation of incident particle tracks and water radiation chemistry was performed in realistic neuron phantoms constructed using experimental data on cell morphology. The applied simulation technique is based on using Monte-Carlo processes of the Geant4-DNA toolkit. The calculations were made for proton, 12C, and 56Fe particles of different energy within a relatively wide range of linear energy transfer values from a few to hundreds of keV/µm. The results indicate that the neuron morphology is an important factor determining the accumulation of microscopic radiation dose and water radiolysis products in neurons. The estimation of the radiolytic yields in neuronal cells suggests that the observed enhancement in the levels of reactive oxygen species may potentially lead to oxidative damage to neuronal components disrupting the normal communication between cells of the neural network.

Exposure to (12)C particles alters the normal dynamics of brain monoamine metabolism and behaviour in rats.

Planning of the deep-space exploration missions raises a number of questions on the radiation protection of astronauts. One of the medical concerns is associated with exposure of a crew to highly energetic particles of galactic cosmic rays. Among many other health disorders, irradiation with these particles has a substantial impact on the central nervous system (CNS). Although radiation damage to CNS has been addressed extensively during the last years, the mechanisms underlying observed impairments remain mostly unknown. The present study reveals neurochemical and behavioural alterations induced in rats by 1Gy of 500MeV/u (12)C particles with a relatively moderate linear energy transfer (10.6keV/µm). It is found that exposure to carbon ions leads to significant modification of the normal monoamine metabolism dynamics as well as the locomotor, exploratory, and anxiety-like behaviours during a two-month period. The obtained results indicate an abnormal redistribution of monoamines and their metabolites in different brain regions after exposure. The most pronounced impairments are detected in the prefrontal cortex, nucleus accumbens, and hypothalamus that illustrate the sensitivity of these brain regions to densely ionizing radiations. It is also shown that exposure to (12)C particles enhances the anxiety in animals and accelerates the age-related reduction in their exploratory capability. The observed monoamine metabolism pattern may indicate the presence of certain compensatory mechanisms being induced in response to irradiation and capable of partial restoration of monoaminergic systems' functions. Overall, these findings support a possibility of CNS damage by space-born particles of a relatively moderate linear energy transfer.

Simulation of the charge migration in DNA under irradiation with heavy ions.

A computer model to simulate the processes of charge injection and migration through DNA after irradiation by a heavy charged particle was developed. The most probable sites of charge injection were obtained by merging spatial models of short DNA sequence and a single 1 GeV/u iron particle track simulated by the code RITRACKS (Relativistic Ion Tracks). Charge migration was simulated by using a quantum-classical nonlinear model of the DNA-charge system. It was found that charge migration depends on the environmental conditions. The oxidative damage in DNA occurring during hole migration was simulated concurrently, which allowed the determination of probable locations of radiation-induced DNA lesions.

A quantitative model of the major pathways for radiation-induced DNA double-strand break repair.

We have developed a model approach to simulate the major pathways of DNA double-strand break (DSB) repair in mammalian and human cells. The proposed model shows a possible mechanistic explanation of the basic regularities of DSB processing through the non-homologous end-joining (NHEJ), homologous recombination (HR), single-strand annealing (SSA) and two alternative end-joining pathways. It reconstructs the time-courses of radiation-induced foci specific to particular repair processes including the major intermediate stages. The model is validated for ionizing radiations of a wide range of linear energy transfer (0.2-236 keV/µm) including a relatively broad spectrum of heavy ions. The appropriate set of reaction rate constants was suggested to satisfy the kinetics of DSB rejoining for the considered types of exposure. The simultaneous assessment of several repair pathways allows to describe their possible biological relations in response to irradiation. With the help of the proposed approach, we reproduce several experimental data sets on γ-H2AX foci remaining in different types of cells including those defective in NHEJ, HR, or SSA functions. The results produced confirm the hypothesis suggesting existence of at least two alternative Ku-independent end-joining pathways.

The role of the bacterial mismatch repair system in SOS-induced mutagenesis: a theoretical background.

A theoretical study is performed of the possible role of the methyl-directed mismatch repair system in the ultraviolet-induced mutagenesis of Escherichia coli bacterial cells. For this purpose, mathematical models of the SOS network, translesion synthesis and mismatch repair are developed. Within the proposed models, the key pathways of these repair systems were simulated on the basis of modern experimental data related to their mechanisms. Our model approach shows a possible mechanistic explanation of the hypothesis that the bacterial mismatch repair system is responsible for attenuation of mutation frequency during ultraviolet-induced SOS response via removal of the nucleotides misincorporated by DNA polymerase V (the UmuD'2C complex).

Model of SOS-induced mutagenesis in bacteria Escherichia coli under ultraviolet irradiation.

A mathematical model of the mutation process in bacteria Escherichia coli induced by ultraviolet radiation is developed. Our model is based on the experimental data characterizing the main processes of the bacterial SOS response. Here we have modeled a whole sequence of the events leading to the fixation of the primary DNA lesion as a point mutation. A quantitative analysis of the key ways of the SOS mutagenesis was performed in terms of modern system biology. The dynamic changes of the basic SOS protein concentrations and the process of the translesion synthesis by the modified replication complex are described quantitatively. We have also demonstrated the applicability of the developed model to the description of the mutagenesis in individual genes. As an example, an estimation of the mutation frequency in E. coli's lacI gene is performed.