Effects of UV irradiation on hippocampal neurogenesis and HPA axis activation in the mouse

Abstract

The hippocampus is important for memory and cognitive function. The hippocampal neurogenesis is suppressed by external stressful stimuli, which may result in memory and cognitive impairment. Recently, the relation of skin and the hippocampus has been reported. Depression is observed in patients with psoriasis and may be caused by psoriasis–induced hippocampal inflammation. We are exposed to ultraviolet (UV) light in our daily life since sunlight contains UV light. UV stimulation through skin and eyes regulates local inflammatory response and stress hormone synthesis. However, hippocampal changes in response to UV irradiation to the skin have not been studied. In this study, after UV irradiation of the mouse skin, I examined molecular changes related to the cognitive functions in the hippocampus and activation of the hypothalamic–pituitary–adrenal (HPA) axis. In chapter I, to find out whether UV irradiation could influence adult hippocampal neurogenesis and synaptic protein in the mouse, the hippocampus was analyzed after 6 times exposure at 200 mJ/cm2 of UV. From the results, UV exposure to the skin decreased doublecortin (DCX)–positive immature neurons and synaptic protein, including N–methyl–D–aspartate receptor 2A (NMDAR2A) and postsynaptic density protein–95 (PSD–95), in the hippocampus. Moreover, UV irradiation to the skin down–regulated hippocampal brain–derived neurotrophic factor expression and extracellular signal–regulated kinase signaling, which are known to modulate neurogenesis and synaptic plasticity. These changes are caused by increased corticosterone (CORT) levels in the blood. Therefore, UV–induced HPA axis activation was measured using RT–qPCR and ELISA in the skin, hypothalamus, adrenal gland, and blood. The cutaneous and central HPA axes were activated by UV irradiation, resulting in significant increases in serum CORT levels. Subsequently, UV irradiation to the skin activated the glucocorticoid signaling pathway in the hippocampal dentate gyrus. Thus, UV–induced hippocampal changes are thought to be the result in UV–induced increased CORT levels. Moreover, a total of 5400 mJ/cm2 of UV was irradiated to the mouse dorsal skin for 6 weeks. Interestingly, in this experimental condition, mice showed depression–like behavior in the tail suspension test. In chapter II, to examine the effect of the brain by UV irradiation in hairless mice, a single 200 mJ/cm2 of UV was exposed to the whole body. From the results, growth factors expression was regulated dynamically in the brain during 24 h. In addition, 10 days continuous UV stimulation through the skin or the eyes differently modulate growth factor expressions in the hippocampus. UV irradiation through the skin decreased vascular endothelial growth factor (VEGF), insulin–like growth factor 1, and neuropeptide Y expression. On the other hand, UV irradiation through the eyes decreased only VEGF expression. To compare the effect of the hippocampus depends on UV exposed tissue, hippocampal neurogenesis and synaptic protein expression were analyzed after the skin or the eyes were separately irradiated with UV rays for 8 weeks. The number of hippocampal DCX–positive cells and synapse protein, synaptophysin and PSD–95, was reduced in both UV–irradiation mice through the skin or the eyes. However, Ki67–positive cells were diminished by UV exposure through eyes only. The adrenocorticotropic hormone and CORT levels were increased by UV radiation through the eyes, and UV irradiation through the skin showed an increased tendency. In chapter III, to analyze whether the difference of the cutaneous HPA axis response was dependent on UV irradiation period, C57BL/6 mice were divided into four groups: 1) acute, 2) sub–chronic, 3) chronic UV–exposed group and 4) sham–exposed group. At 12 h after the last UV irradiation, HPA axis element expression was analyzed in whole skin tissues. Immunohistochemical staining was performed to examine the expression of urocortin (UCN), one of the corticotropin–releasing hormone family, and proopiomelanocortin (POMC) of the mouse skin. The results showed that UCN expression was increased in the epidermis and POMC expression was increased in both epidermis and dermis by UV exposure in a dose–dependent manner, compared with the sham–exposed group. Consistently, the UCN, POMC, melanocortin receptor 2, and cytochrome P450 11B1, mRNA expression also significantly increased in the whole skin tissues of the repeated UV–irradiated mice. On the other hand, the CORT concentration in whole skin remained unchanged by UV rays. This result might be due to the hair cycle because UV exposure blocked the anagen entry. UV–induced activation of the hair follicle and cutaneous HPA axis can have an effect on total CORT levels in the skin. In conclusion, these results indicate that repeated UV exposure to the skin increases circulating CORT via cutaneous and central HPA axis activation, and negatively affects hippocampal neurogenesis and synaptic protein. In addition, these effects are stronger when the eyes receive UV rays.