Stress hormone-induced dysregulation of the brain selenoproteome and selenium homeostasis

Abstract

Chronic stress, a frequently reported issue among adults, is known to have detrimental effects on health, particularly in the brain. Chronic stress is linked to mood and memory disturbances thought to be caused, in part, by alterations in hippocampal functions. Chronic stress hormone exposure causes neuronal cell death, dendritic spine shrinkage, and loss of neuronal stem cells, among other impairments, which are thought to precede mood and memory disturbances. Long-term stress hormone exposure is also known to dysregulate antioxidant functions in the brain, making the brain susceptible to oxidative stress. Selenoproteins, on the other hand, help combat oxidative stress in the brain. These proteins are distinguishable by the inclusion of a selenocysteine amino acid containing the dietary element selenium (Se), making them well-suited for detoxifying reactive oxygen species (ROS). The brain is highly reliant on selenium supply to maintain selenoprotein synthesis, and the brain preferentially retains selenium compared to other tissues when dietary selenium levels are low. One reason is that the brain is highly metabolically active, which generates ROS that can damage cells. Regulation of brain selenium levels is mostly controlled by interactions between the selenium transport protein, selenoprotein P (SELENOP) and its receptor, low-density lipoprotein receptor 8 (LRP8), the latter being expressed on both neuronal and blood-brain-barrier-associated cells for entry. To date, studies have not adequately addressed the role of dietary selenium and selenoproteins in the context of long-term exposure to elevated stress hormones in the brain. We hypothesized that prolonged exposure to stress hormones causes a dysregulation in selenoprotein levels in the hippocampus leading to behavioral changes in mood and memory, and that this dysregulation is cell-type specific. To test this hypothesis, we employed both in vitro and in vivo experimentation. We treated both immortalized hippocampal, HT22, cells and primary neurons isolated from the hippocampus of postnatal mice with corticosterone (CORT), the principal stress hormone in rodents. We investigated the impacts of glucocorticoid and mineralocorticoid signaling, selenium levels, and cell-type specific selenoprotein changes in hippocampal cells. To assess behavior, we performed behavioral experiments to test alterations in positive and negative valence traits and spatial memory. We also utilized primary neurons to assess cell death vulnerability in cultures treated with and without CORT and erastin, a ferroptotic death inducer, and changes in electrophysiological properties of our cultures. We discovered that changes in selenoproteins, which require both glucocorticoid and mineralocorticoid receptor signaling, happen in a cell-type specific manner. Transcriptional alterations in genes encoding glutathione peroxidase 3 (Gpx3), selenoprotein T (Selenot), Selenop, and Lrp8 were the most frequently influenced by CORT in different cell populations. Finally, differences in selenium distribution were observed in tissues of CORT-treated mice. Brain selenium levels decreased, while selenium and serum selenoprotein levels increased in circulation. However, we were unable to demonstrate that behavioral alterations occurred in mice treated with CORT via injection or increased susceptibility to death in CORT-treated neuronal cultures, possibly due to treatment methodology. Together, these findings establish that long-term CORT treatment significantly alters selenoprotein expression in a cell-type dependent manner in the hippocampus and influences distribution of selenium throughout the body, reducing selenium supply to the brain and possibly making the brain more susceptible to oxidative damage.