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proteins (e.g. ATM, FOXO3a, and P-p53Ser15) in bystander NSCs is different when the NSCs are cocultured
with glioma cells alone or glioma cells together with microglia and astrocytes. Further, experiments using
flow cytometry showed that the level of apoptosis in bystander NSCs was greatly increased (p<0.001)
when the cells were incubated with medium harvested from astrocytes and microglia that were irradiated
72 h earlier (greater increases were detected when the medium was harvested at 96h). Strikingly, the
presence of glioma in the irradiated coculture reduced bystander apoptosis (sub-G1 fraction) in NSCs
(p<0.001), but altered the chromosomal content of NSCs (p<0.001). Markedly, growth medium harvested
from sham-treated glioma/astrocyte/microglia coculture also induced apoptosis in NSCs. Together, our
results highlight the sensitivity of bystander NSCs to signals propagated from irradiated cancer cells and
show that the tumor microenvironment plays a significant role in the induced bystander effects.
Supported by grant CA049062 from the NIH.
(PS4-74) Cognitive impairment following low dose heavy-ion radiation is associated with synaptic
dysfunction and reduced dendritic complexity in the dentate gyrus. VIPAN K. PARIHAR; Barrett D. Allen;
Katherine Tran; Trisha G. Macaraeg; Nicole N. Chmielewski; Brianna M. Craver; and Charles L. Limoli,
Deptartment of Radiation Oncology, IRVINE, CA
High (H) atomic number (Z) and energy (E) (HZE) ions are energetic charged particles found in the
galactic cosmic rays and can elicit significant damage to biological structures owing to their high LET and
energy deposition. Exposure of the brain to these energetic, fully ionized particles may elicit earlier onset
and/or more severe types of dementia involving a range of degenerative effects. We hypothesized that
heavy ion irradiation could lead to cognitive decrements by causing ultrastructural changes in dendritic
architecture, spine density and synaptic integrity. We analyzed the effects of oxygen and titanium (5 and
30 cGy) ion (600 MeV) exposure on cognitive performance and a range of micromorphometric parameters
to hippocampal neurons in 6 months old Thy1-EGFP transgenic mice at 6 weeks following irradiation.
Exposure to oxygen or titanium ions impaired object recognition where the tendency to explore novelty
was reduced significantly (P<0.05) in irradiated versus non-irradiated mice. Furthermore, oxygen and
titanium ions were found to impaire object-in-place associative recognition memory, which depends on
interactions between the hippocampus, perirhinal and medial prefrontal cortices. Mice exposed to oxygen
or titanium showed impaired temporal order memory that is crucial for discrimination between familiar
objects and dependent upon neural circuits involving the perirhinal cortex and medial pre-frontal cortex.
Further, dose-dependent reductions (10 to 30 %) in dendritic complexity were found, when dendritic
length, and branching were analyzed 6 weeks after exposure. At equivalent doses and times significant
reductions in the number (20 to 15 %) and density (30-40 %) of dendritic spines were observed in GCL
hippocampal neurons. Moreover, immunohistochemical analysis of GCL neurons exposed to oxygen or
titanium showed elevated levels of postsynaptic density protein (PSD-95) compared to non-irradiated
controls. Our findings confirm that reduced dendritic complexity, arborization, spine and synaptic density
following heavy ion irradiation is associated with cognitive decrements 6 weeks after exposure. This work
was supported by NASA Grants NNX13AD59G and NNX10AD59G (CLL).
276 | P a g e
with glioma cells alone or glioma cells together with microglia and astrocytes. Further, experiments using
flow cytometry showed that the level of apoptosis in bystander NSCs was greatly increased (p<0.001)
when the cells were incubated with medium harvested from astrocytes and microglia that were irradiated
72 h earlier (greater increases were detected when the medium was harvested at 96h). Strikingly, the
presence of glioma in the irradiated coculture reduced bystander apoptosis (sub-G1 fraction) in NSCs
(p<0.001), but altered the chromosomal content of NSCs (p<0.001). Markedly, growth medium harvested
from sham-treated glioma/astrocyte/microglia coculture also induced apoptosis in NSCs. Together, our
results highlight the sensitivity of bystander NSCs to signals propagated from irradiated cancer cells and
show that the tumor microenvironment plays a significant role in the induced bystander effects.
Supported by grant CA049062 from the NIH.
(PS4-74) Cognitive impairment following low dose heavy-ion radiation is associated with synaptic
dysfunction and reduced dendritic complexity in the dentate gyrus. VIPAN K. PARIHAR; Barrett D. Allen;
Katherine Tran; Trisha G. Macaraeg; Nicole N. Chmielewski; Brianna M. Craver; and Charles L. Limoli,
Deptartment of Radiation Oncology, IRVINE, CA
High (H) atomic number (Z) and energy (E) (HZE) ions are energetic charged particles found in the
galactic cosmic rays and can elicit significant damage to biological structures owing to their high LET and
energy deposition. Exposure of the brain to these energetic, fully ionized particles may elicit earlier onset
and/or more severe types of dementia involving a range of degenerative effects. We hypothesized that
heavy ion irradiation could lead to cognitive decrements by causing ultrastructural changes in dendritic
architecture, spine density and synaptic integrity. We analyzed the effects of oxygen and titanium (5 and
30 cGy) ion (600 MeV) exposure on cognitive performance and a range of micromorphometric parameters
to hippocampal neurons in 6 months old Thy1-EGFP transgenic mice at 6 weeks following irradiation.
Exposure to oxygen or titanium ions impaired object recognition where the tendency to explore novelty
was reduced significantly (P<0.05) in irradiated versus non-irradiated mice. Furthermore, oxygen and
titanium ions were found to impaire object-in-place associative recognition memory, which depends on
interactions between the hippocampus, perirhinal and medial prefrontal cortices. Mice exposed to oxygen
or titanium showed impaired temporal order memory that is crucial for discrimination between familiar
objects and dependent upon neural circuits involving the perirhinal cortex and medial pre-frontal cortex.
Further, dose-dependent reductions (10 to 30 %) in dendritic complexity were found, when dendritic
length, and branching were analyzed 6 weeks after exposure. At equivalent doses and times significant
reductions in the number (20 to 15 %) and density (30-40 %) of dendritic spines were observed in GCL
hippocampal neurons. Moreover, immunohistochemical analysis of GCL neurons exposed to oxygen or
titanium showed elevated levels of postsynaptic density protein (PSD-95) compared to non-irradiated
controls. Our findings confirm that reduced dendritic complexity, arborization, spine and synaptic density
following heavy ion irradiation is associated with cognitive decrements 6 weeks after exposure. This work
was supported by NASA Grants NNX13AD59G and NNX10AD59G (CLL).
276 | P a g e
