Brain-derived Neurotrophic Factor (BDNF)
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How many times have you heard the phrase “my immunity is down because of…(fill in the blank: lack of sleep, a cold, psychological pressure, overwork, etc.)”. Frankly, after having spent a lifetime career in the Sciences (Biochemistry, Medicine), I was skeptical. I am a “just the facts, ma’am” kind of guy. I want to see data, not hear testimonials.

However, more and more evidence has started accumulating showing the effect of the brain on the immune response. In fact, a new field was born called neuroimmunology. From there, it was not a giant leap to demonstrate the effect of psychology on the brain-immunology axis. Not surprisingly, the field acquired a new name: psychoneuroimmunology.

The effects of “attitude” on the progression of breast cancer through the immune response have been demonstrated time and again in clinical studies. But the brain controls many functions other than the immune response. For instance, memory loss is caused by Alzheimer’s disease as well as by depression. The reaction to emotional tension can lead to overeating and obesity. There is a high degree of correlation between depression and type 2 diabetes. How can we put all these disparate observations together?


BDNF and its effect on metabolism

When scientists studied the development of the brain in embryos, they discovered the protein that facilitated the neuronal growth and plasticity also plays a role in memory and learning. This protein is called BDNF, or brain-derived neurotrophic factor. With time, BDNF was discovered to have a multitude of other functions.

It is well established that BDNF plays a role in the hypothalamic pathway that controls body weight and energy homeostasis. Recent evidence identifies BDNF as a player not only in central metabolism, but also in regulating energy metabolism in peripheral organs. For instance, low levels of BDNF result in higher levels of leptin. This is a hormone secreted by fat tissue that signals to the brain low storage of fat—resulting in the sensation of hunger.

Low levels of BDNF are found in patients with neurodegenerative diseases, including Alzheimer’s disease and major depression. In addition, BDNF levels are low in obesity and, independently so, in patients with type 2 diabetes. BDNF is expressed in non-neurogenic tissues, including skeletal muscle, and exercise increases BDNF levels not only in the brain and in plasma, but in skeletal muscle as well. Interestingly, in addition to its obvious effects on skeletal muscles, exercise has been shown to alleviate depression and dementia.


The environmental effects on cancer

It is well known that cancer is influenced by the microenvironment in which it grows. For instance, if the microenvironment is rich in blood vessels, the tumor cells will metastasize to distant organs more readily than if the tissue is poorly vascularized. But broader environmental effects on the tumors are poorly understood. In a recent paper in Cell (July 9, 2010), scientists from Ohio State University discovered that “simply placing mice in a more complex living environment” produced effects profound enough to significantly influence the growth of highly malignant cancers. According to the paper in Cell, the “enriched environment significantly reduced the cancer burden in two different mouse models: melanoma and colon cancer.” Specifically, “tumor mass shrank by 77% and tumor volume by 43%, and after three weeks in their new housing, 5% of mice showed no evidence of cancer.”

What caused this impressive effect on the cancers? Enriched environments allow the mice to run on treadmills and, in general, be more physically active. So, could exercise account for the effect? The investigators tested for the level of BDNF in the hypothalamus, an area responsible for memory and learning but also energy homeostasis (meaning maintenance of the body’s internal energy status in a steady state, regardless of external influences). They found that the effect of the complex environment was not caused by physical activity alone. Serum from animals held in an enriched environment inhibited cancer proliferation in vitro (cells in a test tube) and was found to be markedly lower in leptin. So, the picture is getting more complex, but also more interesting. It was not just exercise, but the salutary effects of the complex environment on the “psyche” of the mice that had this profound effect on the body’s resistance to cancer.


The pitfalls

Humans are not mice. The effect of the environment on the human brain is undoubtedly more complex than on a mouse brain. The physiology of the mouse differs significantly from human physiology. The mice used were from an inbred strain, meaning that their genetic background was almost identical; outside of identical twins, no such condition exists in man.

And yet… it is because of these highly controlled conditions that we can reduce the “noise” and demonstrate unequivocally the phenomena we are investigating—in this case, the effect of the environment on BDNF and on cancer resistance. It is such studies that will clarify the mechanism through which the environment affects our physical and mental health. Hopefully, it would also lead to the development of drugs that would counteract the effects of an injurious environment. Or perhaps, it will stimulate us to simply develop and maintain more health-promoting environments.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.