Chronic ultraviolet irradiation induces memory deficits via dysregulation of the dopamine pathway

Ultraviolet (UV) radiation exposure, whether transient or chronic, significantly impacts human health. Transient exposure causes sunburn and inflammation, while chronic exposure leads to skin inflammation, immunosuppression, cancer, and premature aging. Beyond skin effects, UV exposure influences hormone levels and small molecules like β-endorphins, nitric oxide, and urocanic acid in the skin and blood. Evidence suggests a skin-brain connection, as changes in UV-induced mediators in the blood can affect brain function. For example, UV-induced β-endorphin increases in the blood influence brain opioid systems, leading to UV light addiction in mice. Conversely, moderate UV exposure increases blood urocanic acid levels, which can enhance learning and memory. This suggests a complex interplay between skin, blood-borne mediators, and brain function. Neurotransmitters are crucial mediators in brain aging and neurodegenerative diseases. Skin and neuroendocrine systems produce neurotransmitters under specific conditions. Importantly, skin-produced neurotransmitters may affect specific brain areas, establishing a skin-brain axis. Dopamine, a key neurotransmitter linked to reward, motivation, and memory, increases in skin after UV exposure. Maintaining balanced dopamine signaling is critical; dysregulation can have detrimental effects on mental and physical health. While UV exposure causes neurobehavioral changes, the underlying neurotransmitter mechanisms remain largely unknown. This study hypothesized that neurotransmitters mediate skin-brain communication during UV-induced neurobehavioral shifts, aiming to uncover the specific mechanisms and identify key molecules.

Previous research has established the adverse effects of UV radiation on the skin, including inflammation, immunosuppression, and photoaging. Studies have also shown links between UV exposure and changes in various mediators in the skin and blood, such as β-endorphins, nitric oxide, and urocanic acid. These changes have been implicated in affecting brain function, suggesting a complex skin-brain axis. While some studies have explored the role of specific mediators like β-endorphin, the overall understanding of UV-induced neurobehavioral changes remains incomplete, prompting further investigation into the involved molecular mechanisms.

This study used a mouse model (six-week-old female SKH-1 hairless mice) to investigate the effects of chronic UV irradiation on brain function. Mice were randomly divided into two groups: a control (sham-irradiated) group and a UV-irradiated group. UV irradiation was performed three times a week for six weeks using TL20W/12RS UV lamps with wavelengths from 275–320 nm. UVC wavelengths were blocked with a Kodacel filter. Behavioral tests (OPR, NOR, and Y-maze) assessed hippocampal-dependent memory. Electrophysiological recordings of fEPSPs in hippocampal slices measured synaptic plasticity (LTP). Immunohistochemistry (IHC) using DCX and Ki-67 antibodies quantified hippocampal neurogenesis. Liquid chromatography-mass spectrometry (LC-MS) analyzed neuropeptides in serum, skin, adrenal glands, and specific brain regions. RNA sequencing (RNA-Seq) analyzed gene expression changes in UV-irradiated mice treated with or without the D1 receptor antagonist SCH23390. Statistical analyses included Mann-Whitney U test and one-way ANOVA with post-hoc tests. Additionally, mice received intraperitoneal injections of dopamine (1, 5, or 10 mg/kg) or dopamine receptor antagonists (SCH23390 and raclopride) for six weeks to further investigate the role of dopamine.

Chronic UV irradiation (3240 mJ/cm²) significantly impaired cognitive function in mice, as demonstrated by reduced discrimination indices in the object place recognition (OPR) and novel object recognition (NOR) tests and fewer alternations in the Y-maze test (P<0.0001). UV irradiation also resulted in significant deficits in hippocampal long-term potentiation (LTP) (P<0.05) and reduced hippocampal neurogenesis, evidenced by fewer DCX-positive (P<0.05) and Ki-67-positive (P<0.05) cells in the dentate gyrus (DG). LC-MS analysis revealed that UV irradiation significantly increased dopamine levels in serum (130-145% higher), skin, adrenal glands, and brain regions like the prefrontal cortex and hypothalamus. Treatment with the D1/D5 receptor antagonist SCH23390 (0.1 mg/kg) significantly improved memory performance in the OPR and Y-maze tests (P<0.05), restored LTP deficits (P<0.05), and increased the number of DCX-positive neurons in the DG (P<0.05) in UV-irradiated mice. RNA-Seq analysis showed that 70 genes were differentially expressed in UV-irradiated mice compared to controls, and SCH23390 treatment downregulated 38 genes. Gene ontology enrichment analysis showed significant enrichment of dopamine-related pathways, especially dopaminergic neuron differentiation pathways. Moreover, chronic peripheral dopamine administration (5 and 10 mg/kg) mimicked the effects of UV irradiation, leading to impaired memory in the OPR test (P<0.05) and reduced neurogenesis (P<0.01).

This study provides strong evidence for a causal link between chronic UV irradiation, dopamine dysregulation, and cognitive impairment. The findings demonstrate that UV irradiation leads to increased dopamine levels in the periphery and brain, activating the D1 receptor pathway and contributing to cognitive deficits and reduced neurogenesis. The beneficial effects of the D1 receptor antagonist highlight the role of this pathway in mediating UV-induced memory dysfunction. While the exact mechanism remains to be fully elucidated, the results suggest that UV irradiation may trigger dopamine release from the skin, leading to systemic effects on the brain. The transcriptomic changes observed further support the involvement of dopaminergic pathways. The study also demonstrates that elevated peripheral dopamine levels can directly induce cognitive impairment, reinforcing the critical role of dopamine homeostasis in maintaining brain health.

This research reveals a novel mechanism by which chronic UV irradiation impacts cognitive function through dopamine pathway dysregulation. The results underscore the need for UV protection to prevent neurological consequences. The efficacy of the D1 receptor antagonist suggests a potential therapeutic approach for UV-induced cognitive deficits. Future research should focus on clarifying the precise molecular mechanisms and exploring the clinical implications of these findings for human populations.

The study used a mouse model, and the findings may not directly translate to humans. The sample size in some experiments was relatively small. The mechanism of UV-induced dopamine increase requires further exploration. The specific contribution of other neurotransmitters beyond dopamine to UV-induced neurobehavioral changes remains to be investigated further. The long-term effects of UV exposure and the potential for recovery after cessation of UV exposure need further studies.