Brain juice and stem cells: Revisiting an ancient view of cerebrospinal fluid

Illustration of the pain pathway in René Descartes’ Traite de l’homme (Treatise of Man), 1664. The long fiber running from the foot to the cavity in the head is pulled by the heat and releases a fluid that makes the muscles contract.

Christopher Walsh, MD, PhD, is chief of Genetics and a Howard Hughes Medical Institute Investigator at Children’s Hospital Boston, where his research focuses on genes that regulate the development and function of the human cerebral cortex. These genes are vital to normal development of the cortex, and many appear to have been altered evolutionarily to allow the unique aspects of the brain that underlie human cognitive abilities. Mutations in these genes are known to cause autism and epilepsy, as well as intellectual disabilities and other learning disorders.

In the second century, the Greek physician Galen proposed that the fluid in the brain provided energy for the entire body, theorizing that an external spirit (pneuma) from the lungs was transported to the heart, where, combined with blood, it would give rise to the vital spirit. Carried by the blood, the vital spirit was then thought to be transformed into an animal spirit before entering the cavities of the brain, then traveling through the nerves, “as sunshine passes through the air or water,” to energize the entire physical being.

In this view, the brain itself was a mere holder of the fluid. Our neuroanatomical term “thalamus,” referring to part of the brain stem, comes from the Greek word for “chamber,” implying that the brain was mainly important as a holder for CSF. The philosopher Descartes (1596-1650) thought that the brain was a pump that moved the fluid around to do the brain’s work, such as making a muscle contract. Seventeenth century Swedish scientist Emanuel Swedenborg referred to the CSF as a “spirituous lymph” and a “highly gifted juice.”

Alas, recent history has not been so kind to CSF. Its reputation as a dynamic, life-giving part of the nervous system receded. Instead, it came to be regarded as a supporting player, providing a fluid cushion for the brain and maintaining its ionic balance.

But recent proteomic studies have begun to characterize the contents of CSF, and suggest a model that harkens back to antiquity. The CSF circulating in embryos, it turns out, is enriched in hundreds of proteins that appear to be actively secreted into the CSF during development. The fluid may be doing more than just cushioning the brain – it may provide a rapid conduit for delivering proteins and growth signals throughout the developing nervous system.

Our own work, led by Maria Lehtinen, PhD, suggests that CSF regulates neural stem cell behavior in the brain. One of its components is Igf2 (insulin-like growth factor 2), which we’ve shown stimulates the stem cells in the brain to divide faster. Igf2 concentrations in CSF peak during the time that the cortex is most actively forming neurons, and then trails off after birth and into adulthood so that, alas, adult CSF has some but not much Igf2 and is less strong at supporting stem cell proliferation.

We also found that the brain itself is exquisitely tuned to these signals. The Igf1 receptor on brain stem cells, for example, interacts with apical proteins that basically queue it up, relocating it to the apical side of the cell that’s in direct contact with the CSF. In fact, the stem cells even put out finger-like processes to maximize the contact.

This scanning electron microscopy image of a developing mouse brain shows fine finger-like processes (cilia) that extend from the surface and interact with IgF2 and other factors in the cerebrospinal fluid.

We decided to directly test the idea that the CSF is telling the brain what to do. If you bathe a young, developing brain in CSF from a mature animal, and bathe mature brains in young CSF, the stem cells behave according to what CSF they’re in. This suggests that CSF proteins may actually play an instructive role in globally regulating neurogenesis in the brain. This opens up the even bigger question: how many other global brain states are specific CSF proteins modulating? Widespread distribution of CSF proteins is an intriguing mechanism to control other processes throughout the brain. Maybe it’s too early to say that the ancients got it right, but focusing on the properties of the CSF should be able to help us glimpse a few more clues to brain development.