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

Exposure to ultraviolet (UV) radiation can be transient or chronic in daily life. Transient UV exposure induces sunburn or skin inflammation, activates growth factor receptors, initiates subsequent signal transduction pathways, and releases cytokines. Chronic UV exposure can lead to chronic skin inflammation, immunosuppression, photocarcinogenesis, and photoaging1,2. Photoaging refers to premature skin aging caused by prolonged and excessive exposure to UV radiation, whether from the sun or artificial sources such as tanning beds3. UV exposure to the skin triggers skin-related biochemical responses and impacts signal transduction pathways in other organs. Furthermore, several studies have suggested that chronic UV exposure can alter the levels of hormones, proteins, and small molecules, such as melanocyte-stimulating hormone, β-endorphins, nitric oxide6,7, and urocanic acid4, in the skin or blood. Interestingly, studies have shown that changes in UV-induced mediators in the blood may also affect the brain5,8,9. UV exposure elevates the levels of β-endorphin, which is transmitted through the blood to the brain in the skin of mice, resulting in opioid-related antinociception and ultimately leading to addiction to UV light in mice5. Moderate UV exposure can increase blood urocanic acid levels and enhance learning and memory in the mouse brain via the glutamate biosynthetic pathway8. The serum level of corticosterone is notably increased after UV exposure in mice, potentially contributing to the UV irradiation-induced decrease in hippocampal neurogenesis9. These findings suggest a close interconnection between UV-induced changes in mediators in the skin and bloodstream and brain function. Sophisticated communication between the skin and brain maintains and regulates homeostasis and plays a pivotal role in aging and age-related diseases10. Neurotransmitters are crucial neuronal mediators involved in brain aging and disorders such as Parkinson’s Disease and Alzheimer’s disease11. Both the skin and neuroendocrine systems produce neurotransmitters under stimulating conditions10,12–14. Furthermore, neurotransmitters produced by the skin might influence specific brain areas that constitute the skin-brain axis15. For example, serotonin is a neurotransmitter generated in the skin that bridges the central and peripheral nervous systems, underscoring the close relationship between the nervous system and the skin16–18. Additionally, dopamine levels in the skin have been found to increase immediately after UV exposure19. Dopamine is instrumental in various brain functions and is commonly linked to feelings of pleasure, reward, motivation, and memory20. However, sustaining a balanced and regulated level of dopamine signaling in the brain is essential since excessive or dysregulated dopamine signaling can harm mental and physical health21,22. The biological implications of elevated dopamine levels in the blood, particularly regarding brain function, remain unexplored. Neurotransmitters play pivotal roles in determining the status of the brain during disease and aging11. While mounting evidence suggests that UV exposure to the skin may lead to neurobehavioral changes in the brain, only a few plausible neuronal mediators, such as β-endorphin, have been explored. Hence, the molecular and cellular mechanisms underlying UV-induced neurobehavioral changes remain largely undiscovered. Based on all the available evidence, we hypothesize that neurotransmitters serve as potential conduits for skin-brain communication in UV-induced neurobehavioral shifts. Thus, we aimed to uncover the specific neurotransmitter-mediated mechanisms underlying UV-induced neurobehavioral changes and to investigate potential neurotransmitters in the serum and brain post-UV irradiation to identify candidate molecules.

Prior work links skin exposure to UV with systemic mediators that affect the brain: UV-induced β-endorphin mediates antinociception and addictive-like UV-seeking in mice; moderate UV increases serum urocanic acid and enhances learning/memory via glutamate biosynthesis; UV elevates corticosterone and reduces hippocampal neurogenesis, implicating HPA-axis involvement. The skin expresses neuroendocrine capabilities, producing neurotransmitters (e.g., serotonin) that can influence the CNS within a skin-brain axis. Dopamine in skin increases immediately after UV exposure, and dopamine signaling exhibits an inverted-U relationship with cognition, where both deficiency and excess impair performance. However, direct mechanistic evidence linking UV-induced neurotransmitter changes, especially dopamine, to neurobehavioral outcomes has been limited, motivating the present mechanistic study.

Animals: Female SKH-1 hairless mice (6 weeks old; Orient Bio, South Korea) were acclimated 1 week with ad libitum food. All procedures were IACUC-approved (No. 20-0271, Seoul National University Hospital). UV irradiation: TL20W/12RS UV lamps (Philips; 275–320 nm) were used with a Kodacel filter to block UVC (<290 nm). UV intensity was monitored (Waldmann Model 585100). Under anesthesia, eyes were protected and only dorsal skin was irradiated; controls were anesthetized and sham-irradiated. UV exposure was performed 3 times per week for 6 weeks (e.g., total regimen depicted in Fig. 1b; UV dose referenced as 3240 mJ/cm2 in figure annotations). Behavioral tests: After 6 weeks, mice underwent hippocampus-dependent tasks. Object Place Recognition (OPR): handling (5 min/day × 4 days), habituation (15 min), training (two identical objects; 10 min), and test after 24 h with one object moved; exploration recorded and scored blinded; discrimination index (N−F)/(N+F). Novel Object Recognition (NOR): same phases as OPR; test after 24 h with one object replaced. Y-maze: 3-arm maze (30×6×15 cm; 120°); 7-min session under dim light; spontaneous alternations scored manually blinded. Electrophysiology: fEPSPs recorded from Schaffer collateral–CA1 pathway in 400 µm sagittal hippocampal slices at 31–32 °C in oxygenated ACSF. Stimulation at 40% max response. LTP induced by theta-burst (4 bursts, each 4 pulses at 100 Hz; 200 ms interburst). Data acquired/analysed with WinLTP. Tissue collection and immunohistochemistry: Brains fixed in 4% PFA, cryoprotected (30% sucrose), sectioned coronally at 35 µm, stored in cryoprotectant. Free-floating IHC with primary antibodies: DCX (Abcam ab18723, 1:200), Ki-67 (Abcam ab15580, 1:200); secondary Alexa Fluor 594-conjugated antibodies; DAPI counterstain; imaged by confocal microscopy. Neuropeptide/monoamine quantification: UHPLC–MS/MS (ExionLC + 6500+ QTRAP ESI) with Analyst v1.7. Waters Acquity HSS T3 column (2.1×100 mm, 1.8 µm), column 50 °C, tray 4 °C. Mobile phases: 0.1% formic acid in water (A), 5 mM ammonium formate in acetonitrile (B); 0.3 ml/min; 10 µl injection; MRM in positive/negative modes. Quantified dopamine in serum, skin, adrenal gland, and brain regions (VTA, SN, hippocampus, prefrontal cortex, hypothalamus). Pharmacology: Dopamine D1 receptor antagonist SCH23390 HCl (0.1 mg/kg i.p., 100 µl) and D2 receptor antagonist raclopride (1 mg/kg i.p., 100 µl) in 0.9% saline. Dopamine HCl administered i.p. (1, 5, or 10 mg/kg, 100 µl), daily over 6 weeks for chronic treatment experiments; serum dopamine quantified post-injection. RNA-Seq and analysis: mRNA isolated from total RNA (oligo-dT). TruSeq Stranded mRNA kit; 151 bp paired-end on NovaSeq. Libraries QC’d by Bioanalyzer; quantified by KAPA. DEGs defined with adjusted P<0.05 and log2FC >0.1 or <−0.1. GO biological pathway enrichment via clusterProfiler v4.6.2 with Fisher one-sided test and Benjamini–Hochberg correction (adjusted P<0.05 considered significant). Statistics: Mann–Whitney U tests, one-way or two-way ANOVA with appropriate post hoc tests (e.g., Dunn’s, Sidak) in GraphPad Prism v9.5.1; significance at P<0.05. Blinded scoring for behavioral assays.

Chronic dorsal-skin UV irradiation (3×/week for 6 weeks) produced hippocampus-dependent cognitive impairments and reduced neurogenesis: OPR discrimination index decreased (P=0.0002), NOR discrimination index decreased (P=0.0078), and Y-maze alternations reduced (P<0.0001) vs. sham. Hippocampal CA1 LTP was significantly impaired after UV (ANOVA, P<0.05; reduced fEPSP slope 51–60 min post-TBS), and DCX+ and Ki-67+ cell counts in dentate gyrus were reduced. LC–MS/MS screening of 28 neuropeptides revealed serum dopamine as the most increased analyte after UV (≈1.44-fold; P=0.0007); dopamine also increased in skin and adrenal glands, and in brain regions PFC and hypothalamus (no significant change in VTA, SN, or hippocampus). Systemic D1 receptor antagonism (SCH23390, 0.1 mg/kg i.p.) rescued UV-induced deficits: improved OPR discrimination, restored Y-maze alternations, and ameliorated CA1 LTP (two-way ANOVA interaction P<0.01; Saline-UV vs SCH-UV, P<0.05), and increased DCX+ cells in DG; D2 antagonism (raclopride, 1 mg/kg) did not significantly rescue OPR. RNA-Seq identified 70 DEGs (UV vs control); SCH23390 treatment in UV mice downregulated 38 genes, with GO enrichment highlighting dopaminergic neuron differentiation and dopamine-related pathways (notably Pax5, Foxa2, En1). Chronic peripheral dopamine injections (5 and 10 mg/kg, 6 weeks) elevated serum dopamine in a dose-dependent manner and reproduced cognitive and neurogenic deficits: reduced OPR discrimination index (P<0.05 vs saline) and decreased DG DCX+ cells (**P<0.01, ***P<0.001). Collectively, chronic UV elevates dopamine in periphery and select brain regions, engages D1 receptor signaling, and drives hippocampal memory deficits and impaired neurogenesis that can be mitigated by D1 receptor blockade.

The study demonstrates that chronic skin UV exposure induces cognitive impairment through dysregulated dopamine signaling, specifically via D1/D5 receptors. Elevated dopamine following UV—detected in serum, skin, adrenal glands, prefrontal cortex, and hypothalamus—aligns with known inverted U-shaped dopamine–cognition relationships, where excessive dopaminergic activity impairs synaptic plasticity and memory. Pharmacological blockade of D1 receptors reversed UV-induced deficits in hippocampal LTP, memory performance, and neurogenesis, underscoring a causal role of D1 receptor activation. Transcriptomic changes enriched for dopaminergic neuron differentiation pathways further support dopamine-related mechanisms in UV-induced neurobehavioral shifts. The lack of measured dopamine increase in the hippocampus suggests network-level modulation from other regions (e.g., hypothalamus, cortex) or sensitivity limitations of detection. Together, the findings position dopamine signaling as a key mediator in the skin–brain axis under chronic UV exposure, providing a mechanistic framework explaining how peripheral photic stress translates into central cognitive consequences.

Chronic UV irradiation of the skin elevates dopamine in peripheral organs and specific brain regions, activates dopamine D1 receptor signaling, and leads to hippocampal memory deficits, reduced synaptic plasticity, and impaired adult neurogenesis. Systemic D1 receptor antagonism rescues these deficits, and chronic peripheral dopamine administration reproduces key UV-induced phenotypes, implicating dopamine dysregulation as a mechanistic link in the skin–brain axis under UV stress. These results highlight the importance of UV protection for cognitive health and suggest that targeting dopamine D1/D5 receptor pathways may offer therapeutic avenues to mitigate UV-related neurobehavioral impairments. Future studies should delineate region-specific dopamine dynamics, define dose–response and timing effects within the inverted U framework, and evaluate the safety and efficacy of dopaminergic interventions in translational models and humans.

The study was conducted in mice, and individual responses in humans may vary, limiting direct translatability. UV exposure likely affects brain function via multiple mechanisms beyond dopamine signaling; the current work focuses on dopamine and may not capture other mediators. Detection sensitivity may have limited the identification of subtle dopamine changes in some brain regions (e.g., hippocampus). The safety, specificity, and efficacy of dopamine receptor–targeted pharmacological interventions require further validation in preclinical and clinical settings.