In this study we propose to use immediate-early gene (IEG) expression imaging to assess the effects of brain irradiation on neuronal functioning, with the long term goal of identifying how the IEG Arc (activity regulated cytoskeleton-associated protein) is affected in the evolution of radiation- induced neuronal deficits. Therapeutic irradiation is commonly used to treat brain tumors but can cause significant damage to normal brain tissues. In general, overt tissue injury occurs after relatively high doses of irradiation, but after lower doses such tissue damage may not occur, however, hippocampus-dependent cognitive decline, including deficits in spatial learning and memory consolidation, can develop. The severity of such effects depends on the dose delivered to the medial temporal lobes, which contain the hippocampus, a region responsible for learning and memory. The pathogenesis of radiation-induced cognitive deficits is poorly understood, but is likely multifaceted, involving altered neurogenesis, chronic neuroinflammation, and chronic oxidative stress, all factors that can impact multiple neural processes and synaptic transmission. Our previous analyses of chronic neuroinflammation suggest that the depletion of synaptic activity-dependent proteins may play a critical role in cognitive decline. Particularly important in this context is the observation of alterations in the immediate-early gene product Arc, the expression of which has been used to dissect, cellular networks involved in encoding spatial and contextual information. Furthermore, the presence of chronically activated microglia is associated with the disruption of Arc expression and cognitive dysfunctions. Activated microglia may alter the coupling of neural activity with macromolecular synthesis implicated in learning and memory consolidation. Thus, Arc is closely associated with critical factors recently described as playing contributory if not causal roles in the development of radiation-induced cognitive impairments. We hypothesize that irradiation of the brain will adversely affect neuronal function, as assessed by the molecular distribution of Arc at the level of mRNA and protein expression. We further contend that this will be reflected in alterations in neurogenesis and behavioral performances, and that such effects will be dose dependent. Finally, we assert that these changes are influenced by the presence of activated microglia, and we will use mice deficient in chemokine receptor 2 to gain mechanistic insight into this relationship. Given the well-established temporal kinetics of Arc transcription, translocation and translation, we will be able to provide novel sight into the post-transcriptional infrastructure of gene expression underlying mechanisms associated with cognitive function. These studies will give new information about how ionizing irradiation impacts neuronal function in the brain. These types of data are currently unavailable and represent an essential first step for determining the risks of specific CNS-related effects and for the development of potential strategies to manage radiation brain injury.

Public Health Relevance

Although cranial irradiation is commonly used for the treatment of brain tumors, there is a significant probability that this treatment also produces adverse effects severely impacting quality of life (i.e. cognitive impairments). The proposed studies will provide new information about how ionizing irradiation impacts mechanisms of neuronal function in brain region associated with learning and memory processes. These types of data are currently unavailable and are essential for determining the risks of specific central nervous system related effects and for the development of potential strategies to manage radiation-mediated brain injury.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA133216-05
Application #
8461061
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Prasanna, Pat G
Project Start
2009-06-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$292,312
Indirect Cost
$103,113
Name
University of California San Francisco
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Morganti, Josh M; Jopson, Timothy D; Liu, Sharon et al. (2014) Cranial irradiation alters the brain's microenvironment and permits CCR2+ macrophage infiltration. PLoS One 9:e93650
Ramirez-Amaya, Victor; Angulo-Perkins, Arafat; Chawla, Monica K et al. (2013) Sustained transcription of the immediate early gene Arc in the dentate gyrus after spatial exploration. J Neurosci 33:1631-9
Belarbi, Karim; Jopson, Timothy; Arellano, Carla et al. (2013) CCR2 deficiency prevents neuronal dysfunction and cognitive impairments induced by cranial irradiation. Cancer Res 73:1201-10
Rosi, Susanna; Belarbi, Karim; Ferguson, Ryan A et al. (2012) Trauma-induced alterations in cognition and Arc expression are reduced by previous exposure to 56Fe irradiation. Hippocampus 22:544-54
Belarbi, Karim; Arellano, Carla; Ferguson, Ryan et al. (2012) Chronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal networks. Brain Behav Immun 26:18-23
Rosi, Susanna (2011) Neuroinflammation and the plasticity-related immediate-early gene Arc. Brain Behav Immun 25 Suppl 1:S39-49