Irradiation of Neurons with High-Energy Charged Particles: An In Silico Modeling Approach

In this work, a stochastic computational model of microscopic energy deposition events is used to study for the first time damage to irradiated neuronal cells of the mouse hippocampus. An extensive library of radiation tracks for different particle types is created to score energy deposition in small voxels and volume segments describing a neuron’s morphology that later are sampled for given particle fluence or dose. Methods included the construction of in silico mouse hippocampal granule cells from neuromorpho.org with spine and filopodia segments stochastically distributed along the dendritic branches. The model is tested with high-energy 56Fe, 12C, and 1H particles and electrons. Results indicate that the tree-like structure of the neuronal morphology and the microscopic dose deposition of distinct particles may lead to different outcomes when cellular injury is assessed, leading to differences in structural damage for the same absorbed dose. The significance of the microscopic dose in neuron components is to introduce specific local and global modes of cellular injury that likely contribute to spine, filopodia, and dendrite pruning, impacting cognition and possibly the collapse of the neuron. Results show that the heterogeneity of heavy particle tracks at low doses, compared to the more uniform dose distribution of electrons, juxtaposed with neuron morphology make it necessary to model the spatial dose painting for specific neuronal components. Going forward, this work can directly support the development of biophysical models of the modifications of spine and dendritic morphology observed after low dose charged particle irradiation by providing accurate descriptions of the underlying physical insults to complex neuron structures at the nano-meter scale.

[1]  T. Shirao,et al.  Role of actin cytoskeleton in dendritic spine morphogenesis , 2007, Neurochemistry International.

[2]  Ali Ertürk,et al.  Local Pruning of Dendrites and Spines by Caspase-3-Dependent and Proteasome-Limited Mechanisms , 2014, The Journal of Neuroscience.

[3]  D. Amaral,et al.  The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies). , 2007, Progress in brain research.

[4]  D. Janzing,et al.  A single-shot measurement of the energy of product states in a translation invariant spin chain can replace any quantum computation , 2007, 0710.1615.

[5]  D. Muller,et al.  Dendritic spine formation and stabilization , 2009, Current Opinion in Neurobiology.

[6]  Patricia Bassereau,et al.  Filopodial retraction force is generated by cortical actin dynamics and controlled by reversible tethering at the tip , 2013, Proceedings of the National Academy of Sciences.

[7]  M. Takeichi,et al.  Cadherins in brain morphogenesis and wiring. , 2012, Physiological reviews.

[8]  R. Pötter,et al.  Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience. , 2015, The Lancet. Oncology.

[9]  T. Lømo,et al.  Updating the Lamellar Hypothesis of Hippocampal Organization , 2012, Front. Neural Circuits.

[10]  B. Firestein,et al.  The dendritic tree and brain disorders , 2012, Molecular and Cellular Neuroscience.

[11]  H. Thoenen The changing scene of neurotrophic factors , 1991, Trends in Neurosciences.

[12]  G. Ascoli,et al.  NeuroMorpho.Org: A Central Resource for Neuronal Morphologies , 2007, The Journal of Neuroscience.

[13]  A. Kellerer Chord-Length Distributions and Related Quantities for Spheroids , 1984 .

[14]  Ianik Plante,et al.  Monte-Carlo Simulation of Ionizing Radiation Tracks , 2011 .

[15]  Richard A Britten,et al.  Low (20 cGy) Doses of 1 GeV/u 56Fe-Particle Radiation Lead to a Persistent Reduction in the Spatial Learning Ability of Rats , 2012, Radiation research.

[16]  Francis A. Cucinotta,et al.  Space radiation risks to the central nervous system , 2014 .

[17]  G. Ascoli Mobilizing the base of neuroscience data: the case of neuronal morphologies , 2006, Nature Reviews Neuroscience.

[18]  Roland Krueppel,et al.  Dendritic Integration in Hippocampal Dentate Granule Cells , 2011, Neuron.

[19]  I. J. van der Klei,et al.  The Impact of Peroxisomes on Cellular Aging and Death , 2012, Front. Oncol..

[20]  Vipan K. Parihar,et al.  Persistent changes in neuronal structure and synaptic plasticity caused by proton irradiation , 2015, Brain Structure and Function.

[21]  Ann M. Peiffer,et al.  Radiation-induced brain injury: A review , 2012, Front. Oncol..

[22]  M. Ueffing,et al.  The cognitive defects of neonatally irradiated mice are accompanied by changed synaptic plasticity, adult neurogenesis and neuroinflammation , 2014, Molecular Neurodegeneration.

[23]  M. Sheng,et al.  Role of Septin Cytoskeleton in Spine Morphogenesis and Dendrite Development in Neurons , 2007, Current Biology.

[24]  Stefan J. Kempf,et al.  Ionising Radiation Immediately Impairs Synaptic Plasticity-Associated Cytoskeletal Signalling Pathways in HT22 Cells and in Mouse Brain: An In Vitro/In Vivo Comparison Study , 2014, PloS one.

[25]  Charles J. Mode,et al.  Applications of Monte Carlo Methods in Biology, Medicine and Other Fields of Science , 2011 .

[26]  H. Eichenbaum Hippocampus Cognitive Processes and Neural Representations that Underlie Declarative Memory , 2004, Neuron.

[27]  J. Baulch,et al.  What happens to your brain on the way to Mars , 2015, Science Advances.

[28]  Ianik Plante,et al.  Ionization and excitation cross sections for the interaction of HZE particles in liquid water and application to Monte Carlo simulation of radiation tracks , 2008 .

[29]  F. Gage,et al.  Adult-Born Hippocampal Dentate Granule Cells Undergoing Maturation Modulate Learning and Memory in the Brain , 2009, The Journal of Neuroscience.

[30]  Patrick R Hof,et al.  Changes in the structural complexity of the aged brain , 2007, Aging cell.

[31]  T. Shirao,et al.  X Irradiation Changes Dendritic Spine Morphology and Density through Reduction of Cytoskeletal Proteins in Mature Neurons , 2013, Radiation research.

[32]  T. Mito,et al.  Dendritic and histochemical development and ageing in patients with Down's syndrome. , 2008, Journal of intellectual disability research : JIDR.

[33]  Inbal Israely,et al.  Long Lasting Protein Synthesis- and Activity-Dependent Spine Shrinkage and Elimination after Synaptic Depression , 2013, PloS one.

[34]  A. Koleske Molecular mechanisms of dendrite stability , 2013, Nature Reviews Neuroscience.

[35]  J. Fike,et al.  Cranial Irradiation Alters Dendritic Spine Density and Morphology in the Hippocampus , 2012, PloS one.

[36]  G. Lynch,et al.  BDNF Signaling during Learning Is Regionally Differentiated within Hippocampus , 2010, The Journal of Neuroscience.

[37]  D. Hoffman,et al.  Dendritic ion channel trafficking and plasticity , 2010, Trends in Neurosciences.

[38]  P. Hof,et al.  Changes in dendritic complexity and spine morphology in transgenic mice expressing human wild-type tau , 2010, Brain Structure and Function.

[39]  Remy Kusters,et al.  Barriers in the brain: resolving dendritic spine morphology and compartmentalization , 2014, Front. Neuroanat..

[40]  K. Camphausen,et al.  Bringing the heavy: carbon ion therapy in the radiobiological and clinical context , 2014, Radiation oncology.

[41]  William R Mundy,et al.  Assessment of PC12 cell differentiation and neurite growth: a comparison of morphological and neurochemical measures. , 2004, Neurotoxicology and teratology.

[42]  Richard A Britten,et al.  Low (60 cGy) Doses of 56Fe HZE-Particle Radiation Lead to a Persistent Reduction in the Glutamatergic Readily Releasable Pool in Rat Hippocampal Synaptosomes , 2010, Radiation research.

[43]  D. Chklovskii,et al.  Wiring optimization can relate neuronal structure and function. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[44]  N. Turk-Browne,et al.  Mechanisms for widespread hippocampal involvement in cognition. , 2013, Journal of experimental psychology. General.

[45]  I. Spigelman,et al.  Radiation-Induced Alterations in Synaptic Neurotransmission of Dentate Granule Cells Depend on the Dose and Species of Charged Particles , 2014, Radiation research.

[46]  J. Mellor,et al.  Dentate gyrus granule cell firing patterns can induce mossy fiber long‐term potentiation in vitro , 2011, Hippocampus.

[47]  Yasunori Hayashi,et al.  Structural plasticity of dendritic spines , 2012, Current Opinion in Neurobiology.

[48]  D. Jaffray,et al.  Depletion of New Neurons by Image Guided Irradiation , 2011, Frontiers in Neuroscience.

[49]  Christina M. Weaver,et al.  Dendritic spine changes associated with normal aging , 2013, Neuroscience.

[50]  H. Ewers,et al.  A Septin-Dependent Diffusion Barrier at Dendritic Spine Necks , 2014, PloS one.

[51]  C. Limoli,et al.  Cranial irradiation compromises neuronal architecture in the hippocampus , 2013, Proceedings of the National Academy of Sciences.

[52]  M. Jermann Particle Therapy Statistics in 2013 , 2014 .

[53]  Carlo Sala,et al.  Dendritic spines: the locus of structural and functional plasticity. , 2014, Physiological reviews.

[54]  Bin Liu,et al.  Galactic Cosmic Radiation Leads to Cognitive Impairment and Increased Aβ Plaque Accumulation in a Mouse Model of Alzheimer’s Disease , 2012, PloS one.