BDNF + Exercise = Good; Can I Take a Pill Instead?

Posted by Sam Maddox in Research News on August 05, 2016 # Research

Moses Chao

Here's a look at a new study about how active living benefits the brain, which is not news. The benefits of exercise are profound in maintaining a healthy body and sharp mind. What's new is that scientists are closing in on the molecular biology of exercise, and how activity seems to change the genetics of the brain. The study says things are coming along enough so as to be able to contemplate creating an “exercise pill.”

This latest work comes from the Moses Chao lab at NYU Langone Medical Center and its Skirball Institute of Biomolecular Medicine. Chao has long been a part of the Reeve Foundation research program. He was a member of the Science Advisory Council and its chair from 2005 - 2008. He currently serves on the Foundation's NeuroRecovery Network's Advisory Panel.

Chao's career has focused in large part on neurotrophic growth factors, key regulatory chemicals in the brain and spinal cord that promote neural health, including memory, learning, depression and cognition. In a press release from NYU, the growth factor BDNF (stands for brain-derived neurotrophic factor), which is the focus of the new work, is likened to “Miracle-Gro” for the nerve tissue.

Studies in people have already linked exercise with increased BDNF levels, and in turn lower rates of dementia. BDNF levels in the brains of people with Alzheimer's or Huntington's disease are half that of people who don't have either disease.

BDNF helps create new brain cells in the hippocampus, helps neurons remain vigorous, strengthens synapses (nerve-to-nerve connections) and boosts learning and memory. Lower levels of BDNF are associated with cognitive decline. Repeat: Exercise increases BDNF in the brain.

From the new paper:
Physical exercise produces many benefits in the brain that enhance cognitive function, blood flow and resistance to injury. One mechanism to account for the changes in brain plasticity is through the action of growth factors. A major contributor to the processes of learning and memory formation involves brain derived neurotrophic factor (BDNF) signaling pathways. It has been known for over two decades that physical activity or neuronal activity markedly enhances BDNF gene expression in the brain and that this increase in BDNF protein leads to activation of signaling pathways that result in exercise-dependent enhanced learning and memory formation.

BDNF has been well studied in spinal cord injury, too. For example, a 2002 study from the John Houle lab (then in Arkansas) found that increasing BDNF promotes axon regeneration from supraspinal neurons in the chronically injured spinal cord, with partial recovery of locomotor performance. Carl Cotman, a veteran neuroscientist at UC Irvine, and former chair of the Reeve Science Advisory Council, has a large portfolio of work related to growth factors, including BDNF. The Reggie Edgerton lab at UCLA, formerly a part of the Reeve International Consortium on Spinal Cord Research, has also published widely on the role of neurotrophic as they relate to spinal cord function.

So, to study how BDNF really works, Chao's team put two groups of mice in cages. One group had exercise wheels, and used them frequently. The work-out mice produced much more BDNF than the sedentary ones; the scientists found that strenuous exercise changes the way certain genes are switched on inside the brain.

From the NYU release:
...researchers report measuring the natural buildup of certain chemicals in the brain during the rodents' exercise, substances that kick-start production of a protein called brain-derived neurotrophic factor, or BDNF. Since the protein's discovery in the 1980s, BDNF has been labeled as "Miracle-Gro" for the brain ...

But why does this happen? Chao's paper noted that a chemical naturally produced in the liver, a ketone called beta-hydroxybutyrate (DBHB), activates the genetic code for the BDNF gene to produce more of it. DBHB is well known in the exercise literature – it builds up in the brain after strenuous activity. Ketones show up when the body burns off all its sugar reserves for energy and then starts to break down fat as an alternative energy source.

Chao's group found the key to the gene switch: proteins in the brain known as histone deacetylase complexes, or HDACs, normally suppress BDNF production by altering the environment of the BDNF gene. They figured out how to unblock ketone activity.

From NYU:
Using commercially available psychiatric drugs already known to stabilize mood and prevent seizures by inhibiting HDACs, the researchers found that they could "open up" the otherwise "closed" BDNF gene, making it easier to trigger its action and increase BDNF production by as much as 50 percent.

According to Chao and his colleagues, their study shows that DBHB naturally mimics the action of HDAC inhibitors in the brain.

What's it mean? Here's Chao, in the press release:
“We believe that our study shows a precise biological mechanism behind increased BDNF production in mammals due to exercise, Unraveling the mysteries of BDNF is important as we seek more ways to naturally keep mammalian brains healthy, including those of people. ... Our latest findings suggest how we might boost production of BDNF as studies have confirmed that doing so protects the brain.”

From the paper:
In this paper, we provide evidence that an endogenous molecule, DBHB, that crosses the blood brain barrier, is increased by physical exercise to enhance the expression of a fundamental trophic factor in the brain and in turn affect synaptic transmission. Further studies aiming at identifying molecules that can also serve the dual purpose of an energy fuel and epigenetic modulator will help us accumulate additional members of the ‘exercise pill.'

The identification of these molecules is of great interest as many people afflicted with depression or with neurodegenerative diseases are likely to benefit from the ability of exercise to stimulate BDNF through small metabolites, such as DBHB. The involvement of ketone bodies in many other syndromes, such as glucose utilization, diabetes and epilepsy, suggests they represent vital molecules with broad metabolic effects upon chromatin and gene expression.

For more on the Chao study and the effect of exercise on brain function, see coverage here from the New York Times.