22nd Annual NASA Space Radiation Investigators' Workshop (2011)
7082.pdf
CNS NSCOR Overview
G. Nelson1, J. Fike2, C. Limoli3, A. Obenaus1, J. Raber4, I. Spigelman5 and R. Vlkolinsky1
Loma Linda University (1), U. California San Francisco (2), U. California Irvine (3),
Oregon Health and Sciences University (4), U. California Los Angeles (5)
The CNS NSCOR focuses on the functional consequences of exposure of the central nervous system to
charged particles. This work builds on previous results that demonstrated altered synaptic function, neurogenesis,
microvasculature organization and structural modification of the hippocampus. The approaches used will explicitly
examine the roles of reactive oxygen species and neurogenesis in mediating the effects of radiation exposure. They will
also examine the functional properties of neurons and local circuits and will link these properties to the fidelity of
behavioral output. Finally, aspects of radiation quality and dose rate will be assessed for the endpoints above.
Radiation exposure protocols include single, acute whole body exposures to protons, silicon and iron ions.
Complex exposure regimens include: 1) adaptation to priming doses of protons followed by challenge doses of iron ions
and 2) dose rate will be assessed using fractionated iron ions. The animal models are 10 week old C57BL/6 males and
transgenic MCAT males which over-express human catalase in mitochondria. To date we have irradiated mice with
protons and silicon ions and these are evaluated at 90 days post irradiation. In vitro models are cultured murine and
human neural stem cells irradiated with several ions that are evaluated at times from days to months.
Highlights from our ongoing studies are as follows (in-depth presentations by NSCOR team members will be
presented separately in oral talks and posters):
Human and rodent neural stem cells were irradiated with several ions at energies from 300-1000 MeV/n in the
dose range 0.75 to 30 cGy. Data suggest that significant changes in oxidative stress occur that alter radiosensitivity,
proliferation and differentiation. Overall trends indicate that acute increases in ROS/RNS correlate with particle
energies while longer-lived changes in oxidative stress (observed weeks to months post-irradiation) correlate with
particle LET.
The hippocampus-dependent contextual fear conditioning paradigm is used to assess cognition. Results to date
from silicon ion and proton irradiations suggest U-shaped dose response curves for contextual fear conditioning in
which 0.1 to 0.25 Gy exposures produce enhanced levels of the fear response than controls or higher doses. To link
cognitive performance with other endpoints, brains from a subset of behaviorally tested animals are used for
assessments of neurogenesis and Arc, and a second subset of mice is used for electrophysiology.
Tissues obtained from irradiated animals were processed for quantitative analyses of Arc protein expression
and markers of neurogenesis and neuroinflammation. Data show that Arc protein expression correlates with cognitive
performance. While the relationship between Arc expression and cognition is complex, our data suggest that radiation
effects on hippocampus-dependent cognition might depend upon the prominence (salience) of environmental stimuli
and blade-specific Arc expression.
Electrophysiology on hippocampal slices is used to assess local circuit activity and changes in individual
neurons. A multi-electrode system records field potentials from groups of neurons at several locations in the
hippocampus and assesses neural transmission within the tissue while patch clamp recordings of identified cells in
regions CA1 and DG assess neuron function. For individual DG neurons, there was a proton dose dependent decrease
in GABA mediated inhibitory currents (mIPCSs) but no other kinetic parameters were significantly affected. For
excitatory activity in CA1 pyramidal neurons, proton irradiation produced decreases in amplitudes of excitatory
postsynaptic currents (EPSCs) without affecting EPSC frequency and also significantly reduced transmembrane
currents at certain membrane voltages. Other electrophysiological parameters were not significantly affected.
Observations with extracellular electrode arrays found that in proton irradiated CA1 (but not CA3) synaptic
potentials displayed decreased excitability at 0.5 and 1.0 Gy. On the other hand, in the neurogenic DG region,
irradiation with proton appeared to increased synaptic excitability. Reduced paired-pulse facilitation (PPF, a measure of
short-term synaptic plasticity) was observed in proton-irradiated mice only at 1 Gy while long-term potentiation (a
measure of long-term plasticity and memory formation) was consistently inhibited at 0.5 and 1.0 Gy in CA1 but tended
to increase with dose in DG. The increase in PPF in CA1 was confirmed using conventional extracellular recordings in
the same animals. Unlike protons, silicon irradiated mice showed no changes in synaptic excitability but increases in
PPF were observed (in CA1 and CA3 fields but not DG) suggestive of decrements in presynaptic glutamate release.
Together these observations highlight regional and cell type differences in radiation responses that also vary in
a complex way with radiation quality and dose. Both acute and long term changes are found in both in vivo and in vitro
test systems and are trying to establish the correlations and potential causal relationships between the different
endpoints. We are now conducting parallel tests on transgenic mice with altered reactive oxygen metabolism to
determine the role of ROS in mediating the radiation effects. Experiments with other ions are scheduled for the fall and
spring NSRL runs.