Oxidative stress and redox regulation on hippocampal-dependent cognitive functions

Abstract

Hippocampal-dependent cognitive functions rely on production of new neurons and maintenance of dendritic structures to provide the synaptic plasticity needed for learning and formation of new memories. Hippocampal formation is exquisitely sensitive to patho-physiological changes, and reduced antioxidant capacity and exposure to low dose irradiation can significantly impede hippocampal-dependent functions of learning and memory by reducing the production of new neurons and alter dendritic structures in the hippocampus. Although the mechanism leading to impaired cognitive functions is complex, persistent oxidative stress likely plays an important role in the SOD-deficient and radiation-exposed hippocampal environment. Aging is associated with increased production of pro-oxidants and accumulation of oxidative end products. Similar to the hippocampal defects observed in SOD-deficient mice and mice exposed to low dose irradiation, reduced capacity in learning and memory, diminishing hippocampal neurogenesis, and altered dendritic network are universal in the aging brains. Given the similarities in cellular and structural changes in the aged, SOD-deficient, and radiation-exposed hippocampal environment and the corresponding changes in cognitive decline, understanding the shared underlying mechanism will provide more flexible and efficient use of SOD deficiency or irradiation to model age-related changes in cognitive functions and identify potential therapeutic or intervention methods.

Keywords: Cognitive function; Hippocampal neurogenesis; Irradiation; SOD deficiency.

Figure 1. Redox potential and cell fate decision

Neural progenitor cells reside in a relatively hypoxic environment that favors self renewal (left panel). As the environment becomes more oxidized, signaling pathways that promote differentiation are activated, leading to the generation of new neurons (middle panel). The differentiation process also leads to increased production of intracellular oxygen free radicals. Higher number of astroglial cells are generated in an environment where the redox potential is more oxidized than the normal condition for neuronal differentiation (right panel), resulting in reduced production of new neurons.

Figure 2. In vivo lineage selection during neural progenitor cell differentiation was affected by SOD deficiency

The percentage of newborn neurons (A) and astroglia (B) in the SGZ of hippocampal dentate gyrus from each SOD deficient mouse strain was normalized to its wild type controls with the wild type value set as 100% (A) or 1 (B). Deviations from the wild type levels suggested changes in the lineage selection during progenitor cell differentiation in the SOD-deficient environment. Similarly, total number of newborn cells (C) or proliferating cells (D) in the SGZ of each SOD deficient mouse strain was normalized to its wild type controls. Mice were injected with 7 doses (C) (1× per day for 7 days) or 2 doses (D) (2× per day, 8 hours apart) of BrdU at 3 months of age and tissues collected for stereological cell counting 3 weeks after the 7^th BrdU injection (for total number of newborn cells and differentiation study) or 16 hours after the second BrdU injection (for proliferating cells), respectively. Discrepancy in Ki67 and BrdU detection of proliferating cells in Sod2−/+ may be due to the presence of Ki67 in all phases of the cell cycle, while BrdU can only be incorporated by cells in the S phase of cell cycle. Data derived from Fishman et al (Sod1−/+ and Sod2−/+ (70)) and Rola et al (Sod3−/− (71)). Progenitor cell proliferation was significantly reduced in Sod3−/− mice when measured by BrdU incorporation (p<0.05, Bonferroni post test). All the other comparisons in C and D did not reach significant level.