Running Grows the Brain

It is old news that exercise improves the brain–at any age, from children who walk to school, to the elderly who garden. Prolonged exercise, as in running, is what we evolved to do. Running–and the intellect involved to track down animals–led early humans into a unique form of hunting, one that required memory and calculation. But what is the physiological connection? How do the heart and skeletal muscles affect the brain?

Now, researchers are beginning to figure out the molecular basis: What specific genes and proteins do the job. It took a collection of scientists from Lebanon to NYU and Harvard to come up with this alphabet soup of a project, “Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate.”

The researchers set mice to running on their proverbial running wheels. After thirty days running, compared with slacker mice, the runners showed increased amounts of a brain protein called BDNF. BDNF is a protein that encourages nerves to grow; a member of the same family as nerve growth factor, the protein discovered by the famous Nobel laureate Rita Levi-Montalcini (who makes an appearance in The Highest Frontier). BDNF helps maintain synapses and grows new ones in the hippocampus, cortex and forebrain; basically everywhere needed for higher function.

So what is the molecular mechanism? The authors proposed and tested a form of “epigenetics,” a mechanism by which environmental experience alters chemical tags attached to the neurons’s DNA, or to histone proteins associated with the DNA. Epigenetic markers involve enzymes called histone deacetylases (HDAC). The HDAC removes an acetyl group from a histone, a binding protein that helps “pack” DNA and determines whether its gene gets transcribed to RNA. Here, DNA is wrapped two turns around a core of eight histones (colored).

The authors did experiments that showed that inhibitors of HDAC proteins (specifically HDAC2 and HDAC3) could prevent the histone deacetylation, leaving the DNA wrapped around histones marked with acetyl groups. Acetyl groups usually code for “go ahead” and transcribe a gene. So now the gene encoding BDNF goes ahead and gets transcribed to RNA, which then gets translated by ribosomes to make BDNF protein.

What all does this have to do with mice on their running wheels? The running mice make extra ketone bodies such as D-β-hydroxybutyrate (DBHB). Ketone bodies get made by your liver after intense exercise uses up carbohydrates. Excess ketone bodies can cause problems, but as a short-term response to exercise they supercharge the brain. In particular, DBHB blocks production of HDAC2 and HDAC3 (that is what the cross-blocked vertical lines mean, in the diagram above). Since DBHB blocks the HDACs, and the HDACs block expression of BDNF, the net result is that ketone bodies induce BDNF which enhances neurons and makes more synapses.

Start running.