Research data show that radiation has effects on brain function, such as thinking, memory and learning. Dr. Gwendolen E. Haley is leading a project to study the ability of antioxidant lipoic acid to reduce the effects of 56Fe radiation on hippocampus, the area of the brain that is integral in the learning process. The project also seeks to determine the short-term effects of 56Fe radiation on hippocampal function and if it is sex-dependent. Another aim is to determine if cognitive effects are associated with reduced levels of the enzyme choline acetyltransferase.
Overview
Effects of Alphalipoic Acid on Irradiation Induced Cognitive Deficits (Postdoctoral Fellowship)
Principal Investigator:
Gwendolen E. Haley, Ph.D.
Organization:
Oregon Health & Science University
Technical Summary
Radiation exposure of the brain occurs during space missions. The space radiation environment contains high-energy charged particles including protons and fully ionized atomic nuclei, such as iron-56 (56Fe), and may be a hazard to spaceflight crews during their mission. Major adverse effects of radiation exposure are impairments in hippocampus-dependent learning and memory and hippocampal plasticity. Since the hippocampus is involved in complex learning that requires the ability to learn about multiple relationships among stimuli, disturbances in hippocampal functioning reduce spatial learning and memory and the ability to explore the environment adequately.
Preliminary data support that radiation exposure impairs hippocampus-dependent cognitive function and that female mice might be more susceptible than male mice to Cesium-137 and 56Fe radiation-induced hippocampus-dependent cognitive impairments three months following irradiation. The potential effects of 56Fe radiation on cognition one-to-two weeks after irradiation are not known. Irradiation increases reactive oxygen species (ROS) levels that may contribute to these cognitive impairments. Preliminary data show that in male and female mice irradiated with 56Fe (3Gy) at six-to-nine months of age and fed a diet containing the antioxidant lipoic acid (LA), or a regular diet starting two-weeks prior to irradiation and throughout cognitive testing, LA prevented radiation-induced impairments in spatial memory retention in the water maze probe trials three months following irradiation. However, LA treatment caused cognitive impairments in sham-irradiated mice.
As there might be a fine balance in ROS that determines the direction of its effects on cognitive function, it is critical to determine the effects of LA on lower doses of irradiation. Besides its antioxidant properties, LA in its reduced form, dihydrolipoic acid (DHLA), increases acetylcholine production by activation of choline acetyltransferase and appears to increase glucose uptake in insulin-resistant neurons. The cholinergic system is involved in cognition. Therefore, following cognitive testing, immunohistochemistry with antibodies to choline acetyltransferase (ChAT) -- the synthesizing enzyme for acetylcholine -- will be used to visualize and quantify cholinergic cell bodies and fibers in pertinent brain regions. In addition, levels of ROS will be assessed by western blot in different behaviorally tested animals. This knowledge is important for evaluating the risk of developing cholinergic deficits and hippocampus-dependent impairments during space missions and the ability of LA to antagonize these effects.
Specific Aims
Preliminary data support that radiation exposure impairs hippocampus-dependent cognitive function and that female mice might be more susceptible than male mice to Cesium-137 and 56Fe radiation-induced hippocampus-dependent cognitive impairments three months following irradiation. The potential effects of 56Fe radiation on cognition one-to-two weeks after irradiation are not known. Irradiation increases reactive oxygen species (ROS) levels that may contribute to these cognitive impairments. Preliminary data show that in male and female mice irradiated with 56Fe (3Gy) at six-to-nine months of age and fed a diet containing the antioxidant lipoic acid (LA), or a regular diet starting two-weeks prior to irradiation and throughout cognitive testing, LA prevented radiation-induced impairments in spatial memory retention in the water maze probe trials three months following irradiation. However, LA treatment caused cognitive impairments in sham-irradiated mice.
As there might be a fine balance in ROS that determines the direction of its effects on cognitive function, it is critical to determine the effects of LA on lower doses of irradiation. Besides its antioxidant properties, LA in its reduced form, dihydrolipoic acid (DHLA), increases acetylcholine production by activation of choline acetyltransferase and appears to increase glucose uptake in insulin-resistant neurons. The cholinergic system is involved in cognition. Therefore, following cognitive testing, immunohistochemistry with antibodies to choline acetyltransferase (ChAT) -- the synthesizing enzyme for acetylcholine -- will be used to visualize and quantify cholinergic cell bodies and fibers in pertinent brain regions. In addition, levels of ROS will be assessed by western blot in different behaviorally tested animals. This knowledge is important for evaluating the risk of developing cholinergic deficits and hippocampus-dependent impairments during space missions and the ability of LA to antagonize these effects.
Specific Aims
- To determine the short-term effects of 56Fe radiation irradiation on hippocampal function and assess whether these effects are sex-dependent. Mice will be irradiated at 0, 0.1, 0.2, or 0.5 Gy and behaviorally tested 1-2 weeks following radiation.
- To determine whether the severity of the cognitive effects are associated with reduced ChAT immunoreactive cell bodies in the medial septum and nucleus basalis and ChAT immunoreactive fibers in the hippocampus and cortex. Following behavioral testing, ChAT cell number and fiber density will be determined using immunohistochemistry and measures of ROS by western blot.
- To determine the ability of the dietary supplement LA to antagonize the effects of 56Fe irradiation on hippocampus-dependent cognitive function, measures of ROS, and ChAT immunoreactive cell bodies in the medial septum and nucleus basalis and ChAT immunoreactive fibers in the hippocampus and cortex. Mice will be sham-irradiated or irradiated at a dose causing maximal cognitive injury in Aim 1 and receive regular diet or LA-containing diet starting one week prior to behavioral testing. Brains will be processed as in Aim 2.
This project's funding ended in 2011