Page 76 - 2014 Printable Abstract Book
P. 76
induced a significant decrease in the percentage of resident microglia, while inducing an increase in the
infiltration of peripherally derived CCR2+ macrophages. Although reduced in percentage, there was a
significant increase in F4/80+ activated macrophages in irradiated animals compared to sham. Moreover,
we found that there were altered levels of pro-inflammatory cytokines, chemokines, adhesion molecules,
and growth factors in the hippocampi of wild type irradiated mice as compared to sham. All of these
molecules are implicated in the recruitment, adhesion, and migration of peripheral monocytes to injured
tissue. Importantly, there were no measureable changes in the expression of multiple markers associated
with blood-brain barrier integrity; implicating the infiltration of peripheral CCR2+ macrophages may be
due to inflammatory induced chemotactic signaling. Cumulatively, these data provide evidence that
therapeutic levels of cranial radiation are sufficient to alter the brain’s homeostatic balance and permit
the influx of peripherally-derived CCR2+ macrophages as well as the regional susceptibility of the
hippocampal formation to ionizing radiation. Targeting the CCR2 signaling could provide an effective
approach to reduce or prevent the incidence and severity of the side effects of ionizing irradiation.
(S1903) The relation between cognitive injury, epigenetic change, and altered networks in the brain
1
1
2
following exposure to radiation. Jacob Raber ; Susanna Rosi, PhD ; Damian Zuloaga, PhD ; Timothy
1
2
1
1
Jopson, PhD ; Mitch Turker, PhD ; and Soren Impey, PhD, OHSU, Portland, OR and UCSF, San Francisco,
CA
2
Changes in hippocampal network stability and DNA methylation might contribute to the development of
cognitive dysfunction after space irradiation. Radiation exposure of the central nervous system (CNS) can
affect the hippocampus, a structure critical for cognition. During spatial exploration, when an animal
enters a specific location, a distinct cell responds (cell's place field). As a result of place fields, hippocampal
pyramidal neurons display robust high frequency activity. Place fields create an environment-specific
"map", thought to be critical in establishing the context of a memory. Following visits to an environment
for a second time, the same cells form stable neural networks and respond as a result of cellular activity
induced by a learning experience. Place fields are highly reproducible and stable across multiple visits to
the same environment. This stability is not seen in different environments. Analysis of the temporal
kinetics of the plasticity-related immediate early gene activity-regulated cytoskeletal associated protein
(Arc), allows studying network stability. We hypothesize that the detrimental effects of charged particles
on hippocampus-dependent cognition are associated with Arc-related changes in the hippocampal
networks involved in synaptic plasticity and memory. Space irradiation induces stable changes in
methylation of cytosine (5mC). In the hippocampus and several other brain regions an oxidized variant, 5-
hydroxy-methyl cytosine (5hmC), is abundant. The TET (ten eleven translocation) enzymes convert 5mC
to 5hmC and are highly enriched in brain. While 5mC is associated with the promoters of repressed genes,
5hmC and Tet enzymes accumulate at the promoters of active genes, suggesting a role in transcriptional
activation. Changes in 5mC or 5hmC may represent a major mechanism by which radiation could promote
persistent changes in gene expression. Changes in 5mC, induced by environmental exposures including
radiation and behavioral modification, also play arole in cancer and neurological diseases. Arc-related
changes might involve perturbation of 5mC and/or 5hmC in the hippocampus that affect Arc expression
and expression of other learning and memory genes in the same signaling pathways and networks. The
data generated for this project will be discussed.
74 | P a g e
infiltration of peripherally derived CCR2+ macrophages. Although reduced in percentage, there was a
significant increase in F4/80+ activated macrophages in irradiated animals compared to sham. Moreover,
we found that there were altered levels of pro-inflammatory cytokines, chemokines, adhesion molecules,
and growth factors in the hippocampi of wild type irradiated mice as compared to sham. All of these
molecules are implicated in the recruitment, adhesion, and migration of peripheral monocytes to injured
tissue. Importantly, there were no measureable changes in the expression of multiple markers associated
with blood-brain barrier integrity; implicating the infiltration of peripheral CCR2+ macrophages may be
due to inflammatory induced chemotactic signaling. Cumulatively, these data provide evidence that
therapeutic levels of cranial radiation are sufficient to alter the brain’s homeostatic balance and permit
the influx of peripherally-derived CCR2+ macrophages as well as the regional susceptibility of the
hippocampal formation to ionizing radiation. Targeting the CCR2 signaling could provide an effective
approach to reduce or prevent the incidence and severity of the side effects of ionizing irradiation.
(S1903) The relation between cognitive injury, epigenetic change, and altered networks in the brain
1
1
2
following exposure to radiation. Jacob Raber ; Susanna Rosi, PhD ; Damian Zuloaga, PhD ; Timothy
1
2
1
1
Jopson, PhD ; Mitch Turker, PhD ; and Soren Impey, PhD, OHSU, Portland, OR and UCSF, San Francisco,
CA
2
Changes in hippocampal network stability and DNA methylation might contribute to the development of
cognitive dysfunction after space irradiation. Radiation exposure of the central nervous system (CNS) can
affect the hippocampus, a structure critical for cognition. During spatial exploration, when an animal
enters a specific location, a distinct cell responds (cell's place field). As a result of place fields, hippocampal
pyramidal neurons display robust high frequency activity. Place fields create an environment-specific
"map", thought to be critical in establishing the context of a memory. Following visits to an environment
for a second time, the same cells form stable neural networks and respond as a result of cellular activity
induced by a learning experience. Place fields are highly reproducible and stable across multiple visits to
the same environment. This stability is not seen in different environments. Analysis of the temporal
kinetics of the plasticity-related immediate early gene activity-regulated cytoskeletal associated protein
(Arc), allows studying network stability. We hypothesize that the detrimental effects of charged particles
on hippocampus-dependent cognition are associated with Arc-related changes in the hippocampal
networks involved in synaptic plasticity and memory. Space irradiation induces stable changes in
methylation of cytosine (5mC). In the hippocampus and several other brain regions an oxidized variant, 5-
hydroxy-methyl cytosine (5hmC), is abundant. The TET (ten eleven translocation) enzymes convert 5mC
to 5hmC and are highly enriched in brain. While 5mC is associated with the promoters of repressed genes,
5hmC and Tet enzymes accumulate at the promoters of active genes, suggesting a role in transcriptional
activation. Changes in 5mC or 5hmC may represent a major mechanism by which radiation could promote
persistent changes in gene expression. Changes in 5mC, induced by environmental exposures including
radiation and behavioral modification, also play arole in cancer and neurological diseases. Arc-related
changes might involve perturbation of 5mC and/or 5hmC in the hippocampus that affect Arc expression
and expression of other learning and memory genes in the same signaling pathways and networks. The
data generated for this project will be discussed.
74 | P a g e
