Astute scientists have been intrigued by the observation that anti-depressive drugs enter the brain quickly but take weeks to generate positive effects. Experimental evidence led them to the discovery that a decrease in the synthesis of new neurons in the hippocampus might be linked to depression. They also observed that the anti-depressive drugs increased the synthesis of new neurons. Further, they noted that the time to generate new neurons approximated the time it took the drugs to work. Since exercise also promotes synthesis of new neurons, they designed an experiment to test the idea that exercise could help ameliorate depression. For details on this research, click here. "Antidepressant effects of exercise: Evidence for an adult-neurogenesis hypothesis?" J Psychiatry Neurosci. 2006 March; 31(2): 84–92. This Research Update column highlights articles related to recent scientific inquiry into the process of human aging. It is not intended to promote any specific ingredient, regimen, or use and should not be construed as evidence of the safety, effectiveness, or intended uses of the Juvenon product. The Juvenon label should be consulted for intended uses and appropriate directions for use of the product.

By Benjamin V. Treadwell, Ph.D.

Sigmund Freud blamed mental problems on our parents and early upbringing. Pavlov said they were all a condition-response effect. These early investigators of the mind did not have today's investigative tools to examine what makes us tick at the biochemical level. More recent research into brain function has made it evident that the expression of a particular mental state — happiness, aggressiveness, depression, submissiveness — is the consequence of different physical-biochemical properties of specific regions of the brain.

Exercise Can Positively Affect Biochemical Properties of the Brain

These early investigators of the psyche were not all wrong, however. Their work set the stage for subsequent discovery of how physical properties of the brain can be altered by interaction with external or environmental factors. In other words, people can change the molecular and cellular structure of their brains! Physical exercise, as described below, can function as an anti-depressant and positively affect biochemical properties of the brain, whereas chronic static psychological stress can aggravate these conditions.

Much of the research described here has to do with the hippocampus — a specific area of the brain that is important for learning and cognitive abilities — as well as our state of happiness. It turns out that a malnourished hippocampus does not function optimally, and actually shrinks in size. The consequence of this condition can be expressed in a number of ways, including depression, poor cognitive ability, severe memory impairment, and lethargy.

How do anti-depressants really work?

Until recently, it was assumed that most drugs prescribed for depression were effective because they elevated the concentrations of neurotransmitters in the brain. It was reasoned, and to some extent supported by experimental investigation, that a low level of these chemicals is responsible for depression. It now appears that this assumption may not be entirely correct for the following reasons. First, the neurotransmitters are almost immediately elevated in patients after taking the anti-depressant drugs, yet their effect on alleviating the depressed state is not realized for several weeks. Secondly, it has now been demonstrated that the cells in the hippocampus of patients taking these drugs produce specific nerve-trophic (nourishing) protein molecules in much greater amounts than those not taking anti-depressants. So it appears the neurotransmitters are activating a pathway(s) in the brain that results in the production of additional factors to alleviate the depressed state.

Further research demonstrated that one of these brain nourishing factors, brain-derived neurotrophic factor (BDNF), protects the brain cells (neurons) and stimulates the synthesis of new neurons in the hippocampus. It also protects cells from death when under stress. In persons with major depression, it now has been shown that this region of the brain is much smaller than in their non-depressed counterparts. Furthermore, there is significant evidence that the BDNF-stimulated nerve growth actually results in a measurable increase in the size of the hippocampus.

In summary, anti-depressants appear to relieve the depressed state by reversing those events leading to a malnourished, shrunken hippocampus. The increased level of neurotransmitters may function indirectly by promoting the activation of genetic events leading to the production of brain cell nourishing growth factors, such as BDNF, and the growth of neurons as well as protection of pre-existing neurons. The result is a more active hippocampus capable of transmitting nerve impulses more efficiently. These new discoveries are stimulating research directed toward the development of new drugs that can directly activate the neurotrophic factors and more rapidly and effectively attenuate the depressed state.

Two aspects of this research are quite astounding

First, contrary to earlier beliefs, the brain can regenerate itself, at least in certain regions, by converting progenitor cells into active neurons. Second, the nervous tissue, with proper stimulation and nutrition, can strengthen the connections between neurons to produce more vigorous neural activity. In addition, other factors, such as stress, can have a significant effect on our level of happiness. Excessive stress, such as produced by a feeling of helplessness, can activate a biochemical pathway known as the pituitary-hypothalamus-adrenal axis with the subsequent production of stress hormones, corticosteroids. Excessive production of corticosteroids can negatively affect the health of the hippocampus by inhibiting the production of neurotrophic factors. This helps explain the well-known association between stress, depression and impaired cognition.

Exercise has a significant effect on hippocampal health

About 25 years ago, epidemiological studies first indicated the potential of physical exercise in alleviating symptoms present in patients with major depressive disorders. More recently, studies have clearly demonstrated that people, both young and old, who engage in exercise exhibit fewer symptoms of depression. People who exercise, even moderately, have a significantly lower incidence of major depressive disorders. But why?

Exercise, too, increases neurotransmitters, such as epinephrine, and nor-epinephrine. Part of the explanation for the benefits of exercise is that like the anti-depressants, moderate aerobic exercise increases neurotransmitter levels in the brain, and these in turn stimulate neurotrophic factors to nourish the hippocampus. However, the anti-depressive effect of exercise in animal studies is more immediate — within 2 weeks — rather than the more extensive time it takes (several weeks) with anti-depressant drug therapy. Exercise may be stimulating at least two pathways, one that overlaps the anti-depressant pathway, and another that is more direct. The latter appears to stimulate another type of neurotransmitter, which in turn produces specific molecules that function to promote survival of neurons in the hippocampus. Finally, exercise, at least in younger animals, has been demonstrated to increase the vascular network of the brain. This, too, will help promote neuro-development via increased delivery of nutrients to vital areas of the brain.