One of the impressive things about biochemistry and cell biology is how it can produce physical correlates to things that we know and experience, but have no detailed explanation for. There’s a really interesting example out in Cell that has to do with the effects of sunlight on mood and learning. Those effects are real, but no one has understood quite how. Sunlight (generally speaking, its ultraviolet component) is well-known to be used by the body in vitamin D synthesis, and its other effects on the skin are very well known, both bad (sunburn, various forms of skin cancer) and good (relief from psoriasis and several other conditions). Those all make sense, and you can come up with reasonable hypotheses involving inflammation, damage/repair mechanisms, and so on. But how do you get CNS effects?
There was a report in 2014 from an MGH/Harvard team that UV exposure increases beta-endorphin levels in the skin, and that group showed that rodents can apparently become addicted to sunbathing through this effect. The authors of this new paper (a multicenter team from China) may have found another connection. Among other changes, exposure to UV light increases urocanic acid (UCA) in the blood, an effect that’s been known for many years. That’s a metabolite of histidine, and it’s known to be converted on to glutamic acid by the actions of urocanase enzyme. It’s probably coming from filaggrin, an important protein in the epidermis that’s notably high in histidine, but no one’s been sure what (if any) significance this has. The authors, though, have developed a new technique, a sort of patch-clamp mass spec assay, that can detect molecular species at the surface of an individual neuron, and that’s just the sort of thing you’d need to start making connections on a story like this.
What they find is that (1) urocanic acid itself is found in the brain (where it had never been reported). It’s in the CSF, and was detected at neurons in all the brain regions they studied (except the nucleus accumbens, which is known to be a bit different in its permeability to small molecules). Its association with UV exposure indicates that it crosses the blood-brain barrier, and that idea was confirmed by injecting UCA into the periphery and watching its concentration in neurons go up in the same manner. And once in the brain, it’s converted to glutamate (which is, of course, a well-known neurotransmitter). All the enzymes needed for the pathway are present in brain tissue, and the increase in glutamate seen on UCA exposure can be cancelled out by adding a urocanase inhibitor beforehand. (Interestingly, there are real, but smaller, effects on glutamate concentration seen in non-UV exposed experiments, suggesting that the UCA pathway is one of the sources of glutamate in the brain in general). The same effect on glutamate concentrations is seen with shRNA experiments, among others, and the team hit several enzymes in the pathway and saw the expected changes in metabolites each time.
The increased glutamate downstream of UV exposure does indeed set off more brain activity (as shown by electrophysiology experiments), and also shows significant effects on memory and motor-learning activity. Glutaminergic neurons have been implicated in such tasks, so this fits quite well. Overall, the paper seems to do a pretty thorough job of making the connections, and the authors (links added below) conclude that:
Because GLU plays multiple roles in the CNS, including protein biosynthesis at the amino acid level, disposal of excess or waste nitrogen, and signal transduction between neurons as the most abundant excitatory neurotransmitter, the UV-activated intracellular UCA-GLU metabolic pathway in neurons is likely to be involved in sunbathing-related neurological conditions in addition to learning and memory, such as mood improvement, addiction, cognition, and brain development.
We are all aware that the knee bone is connected to the thigh bone, but did you know that the brain was connected to the skin? You’d have to think that beta-endorphin and glutamate are not going to be the end of it (although those two are powerful enough for plenty of effects). One immediately wonders about the well-known effects of sunlight on seasonal depression, among other possibilities. Everything in the body is more or less hooked up to everything else at some level, which is why drug discovery is such a joy sometimes. But finding out these connections, one by one, is the only way we’re ever going to get a handle on disease and health. Another such connection has just been made.